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1. Substantial modification of the gene expression profile following exposure of macrophages to welding-related nanoparticles

Author

Étienne Audureau, Angélique Simon-Deckers, Marie-Laure Franco-Montoya, Balasubramanyam Annangi, Ali Kermanizadeh, Jorge Boczkowski, and Sophie Lanone

Subjects
Medicine, Science
Abstract

Abstract Anthropic nanoparticles (NP) are increasingly produced and emitted, with accompanying concerns for human health. Currently there is no global understanding as to the exact mechanistics of NP toxicity, as the traditional nanotoxicological approaches only provide a restricted overview. To address this issue, we performed an in-depth transcriptomic analysis of human macrophages exposed to a panel of welding-related metal oxide NP that we previously identified in welders lungs (Fe2O3, Fe3O4, MnFe2O4 and CrOOH NP). Utilizing the specified analysis criteria (|fold change| ≥1.5, p ≤ 0.001), a total of 2164 genes were identified to be differentially expressed after THP-1 macrophage exposure to the different NP. Performing Gene Ontology enrichment analysis, for cellular content, biological processes and Swiss-Prot/Protein Information Resource keywords the data show for the first time a profound modification of gene differential expression in response to the different NP, among which MnFe2O4 NP were the most potent to induce THP-1 macrophage activation. The transcriptomic analysis utilized in the study, provides novel insights into mechanisms that could contribute to NP-induced adverse effects and support the need for widened approaches to supplement existing knowledge of the processes underlying NP toxicity which would have not been possible using traditional nanotoxicological studies.

Published
2018
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2. Salivary Telomere Length and Lung Function in Adolescents Born Very Preterm: A Prospective Multicenter Study.

Author

Alice Hadchouel, Laetitia Marchand-Martin, Marie-Laure Franco-Montoya, Laetitia Peaudecerf, Pierre-Yves Ancel, Christophe Delacourt, and EPIPAGEADO study group

Subjects
Medicine, Science
Abstract

Preterm birth is associated with abnormal respiratory functions throughout life. The mechanisms underlying these long-term consequences are still unclear. Shortening of telomeres was associated with many conditions, such as chronic obstructive pulmonary disease. We aimed to search for an association between telomere length and lung function in adolescents born preterm. Lung function and telomere length were measured in 236 adolescents born preterm and 38 born full-term from the longitudinal EPIPAGE cohort. Associations between telomere length and spirometric indices were tested in univariate and multivariate models accounting for confounding factors in the study population. Airflows were significantly lower in adolescents born preterm than controls; forced expiratory volume in one second was 12% lower in the extremely preterm born group than controls (p

Published
2015
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3. Effect of two models of intrauterine growth restriction on alveolarization in rat lungs: morphometric and gene expression analysis.

Author

Elodie Zana-Taieb, Laura Butruille, Marie-Laure Franco-Montoya, Emmanuel Lopez, Flore Vernier, Isabelle Grandvuillemin, Danièle Evain-Brion, Philippe Deruelle, Olivier Baud, Christophe Delacourt, and Pierre-Henri Jarreau

Subjects
Medicine, Science
Abstract

Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and -R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization.

Published
2013
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4. Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development.

Author

Alice Hadchouel, Fabrice Decobert, Marie-Laure Franco-Montoya, Isabelle Halphen, Pierre-Henri Jarreau, Olivier Boucherat, Emmanuel Martin, Alexandra Benachi, Serge Amselem, Jacques Bourbon, Claude Danan, and Christophe Delacourt

Subjects
Medicine, Science
Abstract

BACKGROUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of

Published
2008
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5. Effects of phosphodiesterase 4 inhibition on alveolarization and hyperoxia toxicity in newborn rats.

Author

Céline Méhats, Marie-Laure Franco-Montoya, Olivier Boucherat, Emmanuel Lopez, Thomas Schmitz, Elodie Zana, Danièle Evain-Brion, Jacques Bourbon, Christophe Delacourt, and Pierre-Henri Jarreau

Subjects
Medicine, Science
Abstract

BACKGROUND: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury. METHODOLOGY/FINDINGS: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count. CONCLUSIONS: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

Published
2008
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6. Surfactant maturation is not delayed in human fetuses with diaphragmatic hernia.

Author

Olivier Boucherat, Alexandra Benachi, Bernadette Chailley-Heu, Marie-Laure Franco-Montoya, Caroline Elie, Jelena Martinovic, and Jacques R Bourbon

Subjects
Medicine
Abstract

BACKGROUND: Pulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question. METHODS AND FINDINGS: We investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-beta1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-beta1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression. CONCLUSIONS: Our results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.

Published
2007
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7. Targeting p16

Author

Maéva, Zysman, Bruno Ribeiro, Baptista, Laure-Aléa, Essari, Sara, Taghizadeh, Charlotte, Thibault de Ménonville, Clément, Giffard, Amelle, Issa, Marie-Laure, Franco-Montoya, Marielle, Breau, Rachid, Souktani, Abdel, Aissat, Laurence, Caeymaex, Muriel, Lizé, Jeanne Tran, Van Nhieu, Camille, Jung, Robert, Rottier, Marcio Do, Cruzeiro, Serge, Adnot, Ralph, Epaud, François, Chabot, Sophie, Lanone, Jorge, Boczkowski, and Laurent, Boyer

Subjects
Adult, Adolescent, Infant, Newborn, Editorials, Apoptosis, Mice, Transgenic, Fibroblasts, Hyperoxia, Sampling Studies, Mice, Inbred C57BL, Pulmonary Alveoli, Disease Models, Animal, Mice, Random Allocation, Young Adult, Animals, Newborn, Alveolar Epithelial Cells, Animals, Humans, Regeneration, Child, Lung, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, Bronchopulmonary Dysplasia
Published
2020

8. Overexpression of

Author

Alice, Hadchouel, Marie-Laure, Franco-Montoya, Sophie, Guerin, Marcio, Do Cruzeiro, Mickaël, Lhuillier, Bruno, Ribeiro Baptista, Laurent, Boyer, Sophie, Lanone, and Christophe, Delacourt

Subjects
Enzyme Activation, Mice, Inbred C57BL, Pulmonary Alveoli, Time Factors, Animals, Matrix Metalloproteinase 2, Mice, Transgenic, Proteoglycans, RNA, Messenger, Hyperoxia, Antibodies
Abstract

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (

Published
2020

9. Targeting p16(INK4a) Promotes Lipofibroblasts and Alveolar Regeneration after Early-Life Injury

Author

Charlotte Thibault de Ménonville, Muriel Lizé, François Chabot, Ralph Epaud, Sophie Lanone, Marie-Laure Franco-Montoya, Jeanne Tran Van Nhieu, Marcio Do Cruzeiro, Rachid Souktani, Bruno Ribeiro Baptista, Abdel Aissat, Sara Taghizadeh, Robert Rottier, Maeva Zysman, Clement Giffard, Laurence Caeymaex, Amelle Issa, Laurent Boyer, Laure-Aléa Essari, Camille Jung, Marielle Breau, Jorge Boczkowski, Serge Adnot, Cell biology, Pediatric Surgery, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lorraine (UL), Wenzhou Medical University [Wenzhou, China] (WMU), Centre de Ressource Biologique [CHI Créteil] (Centre de Recherche Clinique), Centre Hospitalier Intercommunal de Créteil (CHIC), University Medical Center Göttingen (UMG), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lanone, Sophie, IMRB - GEIC2O/'Genetic and Environmental Interactions in COPD, Cystic fibrosis and Other (rare) respiratory diseases' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
Pulmonary and Respiratory Medicine, 0303 health sciences, Lung, business.industry, Regeneration (biology), adult consequences of bronchopulmonary dysplasia, Endogeny, respiratory system, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Early life, respiratory tract diseases, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, Cancer research, medicine, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, p16INK4a lipofibroblasts, alveolar regeneration, business, neoplasms, 030304 developmental biology
Abstract

International audience; Rationale: Promoting endogenous pulmonary regeneration is crucial after damage to restore normal lungs and prevent the onset of chronic adult lung diseases.Objectives: To investigate whether the cell-cycle inhibitor p16INK4a limits lung regeneration after newborn bronchopulmonary dysplasia (BPD), a condition characterized by the arrest of alveolar development, leading to adult sequelae.Methods: We exposed p16INK4a-/- and p16INK4a ATTAC (apoptosis through targeted activation of caspase 8) transgenic mice to postnatal hyperoxia, followed by pneumonectomy of the p16INK4a-/- mice. We measured p16INK4a in blood mononuclear cells of preterm newborns, 7- to 15-year-old survivors of BPD, and the lungs of patients with BPD.Measurements and Main Results: p16INK4a concentrations increased in lung fibroblasts after hyperoxia-induced BPD in mice and persisted into adulthood. p16INK4a deficiency did not protect against hyperoxic lesions in newborn pups but promoted restoration of the lung architecture by adulthood. Curative clearance of p16INK4a-positive cells once hyperoxic lung lesions were established restored normal lungs by adulthood. p16INK4a deficiency increased neutral lipid synthesis and promoted lipofibroblast and alveolar type 2 (AT2) cell development within the stem-cell niche. Besides, lipofibroblasts support self-renewal of AT2 cells into alveolospheres. Induction with a PPARγ (peroxisome proliferator-activated receptor γ) agonist after hyperoxia also increased lipofibroblast and AT2 cell numbers and restored alveolar architecture in hyperoxia-exposed mice. After pneumonectomy, p16INK4a deficiency again led to an increase in lipofibroblast and AT2 cell numbers in the contralateral lung. Finally, we observed p16INK4a mRNA overexpression in the blood and lungs of preterm newborns, which persisted in the blood of older survivors of BPD.Conclusions: These data demonstrate the potential of targeting p16INK4a and promoting lipofibroblast development to stimulate alveolar regeneration from childhood to adulthood.

Published
2020

10. Combined Effects of in Utero and Adolescent Tobacco Smoke Exposure on Lung Function in C57Bl/6J Mice

Author

Mélissa Baravalle-Einaudi, Marie-Laure Franco-Montoya, Guillaume Lezmi, Alice Hadchouel, Jorge Boczkowski, Christophe Delacourt, Shamila Vibhushan, David Drummond, Université Paris Cité (UPCité), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Pediatric Gastroenterology Service, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, urologic and male genital diseases, C57bl 6j, Mice, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Tobacco, medicine, Animals, Lung, Lung function, Fetus, business.industry, Research, Tobacco smoke exposure, Public Health, Environmental and Occupational Health, respiratory system, medicine.disease, respiratory tract diseases, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, 030228 respiratory system, Maternal Exposure, In utero, Immunology, Female, Tobacco Smoke Pollution, Airway, business
Abstract

Background: Fetal determinants of airway function, such as in utero exposure to maternal cigarette smoke (CS), may create a predisposition to adult airflow obstruction and chronic obstructive pulmonary disease (COPD) in adulthood. It has been suggested that active smoking in adolescence and preexisting airflow obstruction have synergistic deleterious effects. Objective: We used a mouse model to investigate whether there is a synergistic effect of exposure to CS in utero and during adolescence on lung function. Methods: Female C57Bl/6J mice were exposed to CS or to filtered room air during pregnancy. Exposure to CS began 2 weeks before mating and continued until delivery. After birth, the pups were not exposed to CS until day 21 (D21). Between D21 and D49, corresponding to “adolescence,” litters were randomized for an additional 4 weeks of exposure to CS. Lung morphometry, lung mechanics, and the expression of genes involved in senescence were evaluated in different subsets of mice on D21 and D49. Results: In utero exposure to CS induced significant lung function impairment by D21. CS exposure between D21 and D49 induced significant functional impairment only in mice exposed to CS prenatally. On D49, no difference was observed between subgroups in terms of lung p53, p16, p21, and Bax mRNA levels. Conclusions: Our findings suggest that prenatal and adolescent CS exposure have a synergistic effect on lung function in mice. The combined effect did not appear to be a consequence of early pulmonary senescence. Citation: Drummond D, Baravalle-Einaudi M, Lezmi G, Vibhushan S, Franco-Montoya ML, Hadchouel A, Boczkowski J, Delacourt C. 2017. Combined effects of in utero and adolescent tobacco smoke exposure on lung function in C57Bl/6J mice. Environ Health Perspect 125:392–399; http://dx.doi.org/10.1289/EHP54

Published
2017

11. Substantial modification of the gene expression profile following exposure of macrophages to welding-related nanoparticles

Author

Balasubramanyam Annangi, Angélique Simon-Deckers, Sophie Lanone, Jorge Boczkowski, Etienne Audureau, Ali Kermanizadeh, Marie-Laure Franco-Montoya, Lanone, Sophie, Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - GEIC2O/'Genetic and Environmental Interactions in COPD, Cystic fibrosis and Other (rare) respiratory diseases' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Copenhagen = Københavns Universitet (UCPH), CHU Henri Mondor, and University of Copenhagen = Københavns Universitet (KU)

Subjects
0301 basic medicine, THP-1 Cells, Science, Computational biology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, Transcriptome, 03 medical and health sciences, Occupational Exposure, Gene expression, Macrophage, Humans, THP1 cell line, Welding, Gene, Multidisciplinary, Chemistry, 030111 toxicology, Gene Expression Profiling, Oxides, Fold change, Gene expression profiling, Gene Expression Regulation, Metals, Toxicity, Nanoparticles, Medicine, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract

Anthropic nanoparticles (NP) are increasingly produced and emitted, with accompanying concerns for human health. Currently there is no global understanding as to the exact mechanistics of NP toxicity, as the traditional nanotoxicological approaches only provide a restricted overview. To address this issue, we performed an in-depth transcriptomic analysis of human macrophages exposed to a panel of welding-related metal oxide NP that we previously identified in welders lungs (Fe2O3, Fe3O4, MnFe2O4 and CrOOH NP). Utilizing the specified analysis criteria (|fold change| ≥1.5, p ≤ 0.001), a total of 2164 genes were identified to be differentially expressed after THP-1 macrophage exposure to the different NP. Performing Gene Ontology enrichment analysis, for cellular content, biological processes and Swiss-Prot/Protein Information Resource keywords the data show for the first time a profound modification of gene differential expression in response to the different NP, among which MnFe2O4 NP were the most potent to induce THP-1 macrophage activation. The transcriptomic analysis utilized in the study, provides novel insights into mechanisms that could contribute to NP-induced adverse effects and support the need for widened approaches to supplement existing knowledge of the processes underlying NP toxicity which would have not been possible using traditional nanotoxicological studies.

Published
2018

12. Pulmonary exposure to metallic nanomaterials during pregnancy irreversibly impairs lung development of the offspring

Author

Murielle Salomé, Jérôme Rose, Audrey Ridoux, Bernhard Hesse, Delphine Vantelon, Jean-Claude Pairon, Shamila Vibhushan, Florence Canoui-Poitrine, Erwan Paineau, Emmanuel Paul, Bernard Angeletti, Sophie Lanone, Marie-Laure Franco-Montoya, Christophe Delacourt, Arnaud Tiendrebeogo, Jorge Boczkowski, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Physique des Solides (LPS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), European Synchrotron Radiation Facility (ESRF), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Santé-Travail Paris-Est [Créteil], Université Paris-Est Créteil, Faculté de Médecine [Créteil] (UPEC-Médecine), ANR-11-LABX-0064,SERENADE,Vers une conception de nanomatériaux innovants, durables et sûrs(2011), ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Beaussier, Catherine, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Collège de France (CdF)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Lanone, Sophie, Vers une conception de nanomatériaux innovants, durables et sûrs - - SERENADE2011 - ANR-11-LABX-0064 - LABX - VALID, and INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE - - Amidex2011 - ANR-11-IDEX-0001 - IDEX - VALID

Subjects
Male, Vascular Endothelial Growth Factor A, 0301 basic medicine, Silver, Materials science, Amniotic fluid, Offspring, Organogenesis, Placenta, Biomedical Engineering, Metal Nanoparticles, [SDU.STU]Sciences of the Universe [physics]/Earth Sciences, 02 engineering and technology, Toxicology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Andrology, Mice, 03 medical and health sciences, Fetal Stage, medicine, Animals, Respiratory system, Lung, lung development, Titanium, Air Pollutants, Inhalation Exposure, Pregnancy, 030111 toxicology, Cerium, respiratory system, 021001 nanoscience & nanotechnology, medicine.disease, Fibroblast Growth Factors, Mice, Inbred C57BL, medicine.anatomical_structure, Maternal Exposure, Prenatal Exposure Delayed Effects, Immunology, [SDU.STU] Sciences of the Universe [physics]/Earth Sciences, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Nanoparticles, Gestation, Female, pregnancy, 0210 nano-technology
Abstract

International audience; Due to the growing commercial applications of manufactured nanoparticles (NPs), toxicological studies on NPs, especially during the critical window of development, are of major importance. The aim of the study was to assess the impact of respiratory exposure to metallic and metal oxide NPs during pregnancy on lung development of the offspring and to determine the key parameters involved in lung alterations. Pregnant mice were exposed to weekly doses of 100 mu g (total dose 300 mu g) of titanium dioxide (TiO2), cerium oxide (CeO2), silver (Ag) NPs or saline solution by nonsurgical intratracheal instillation. The offspring lungs were analyzed at different stages of lung development: fetal stage (gestational day 17.5), pulmonary alveolarization (post-delivery day 14.5) and lung maturity (post-delivery day 49.5). Regardless of the type of NP, maternal exposure during gestation induced long-lasting impairment of lung development of the offspring. This effect was accompanied by: i) decreased placental efficiency together with the presence of NPs in placenta, ii) no increase of inflammatory mediators present in amniotic fluid, placenta or offspring lungs and iii) decreased pulmonary expression of vascular endothelial growth factor-alpha (VEGF-alpha) and matrix metalloproteinase 9 (MMP-9) at the fetal stage, and fibroblast growth factor-18 (FGF-18) at the alveolarization stage. Respiratory exposure to metallic NPs during pregnancy induces stereotyped impairment of lung development with a lasting effect in adult mice, independently of the chemical nature of the NP.

Published
2017

13. Gene expression profiling in lung fibroblasts reveals new players in alveolarization

Author

Roberto Incitti, Marie-Laure Franco-Montoya, Olivier Boucherat, Christophe Delacourt, Christelle Thibault, Jacques R. Bourbon, and Bernadette Chailley-Heu

Subjects
Physiology, Biology, Bioinformatics, Dexamethasone, Novel gene, Pregnancy, Genetics, medicine, Animals, Hox gene, Lung, Oligonucleotide Array Sequence Analysis, Homeodomain Proteins, Hyperoxia, Regulation of gene expression, Gene Expression Profiling, Wnt signaling pathway, Rats, Cell biology, Pulmonary Alveoli, Gene expression profiling, medicine.anatomical_structure, Animals, Newborn, Gene Expression Regulation, Female, medicine.symptom, Microarray profiling
Abstract

Little is known about the molecular basis of lung alveolarization. We used a microarray profiling strategy to identify novel genes that may regulate the secondary septation process. Rat lung fibroblasts were extemporaneously isolated on postnatal days 2, 7, and 21, i.e., before, during, and after septation, respectively. Total RNA was extracted, and cRNAs were hybridized to Affymetrix rat genome 230 2.0 microarrays. Expression levels of a selection of genes were confirmed by real-time PCR. In addition to genes already known to be upregulated during alveolarization including drebrin, midkine, Fgfr3, and Fgfr4, the study allowed us to identify two remarkable groups of genes with opposite profiles, i.e., gathering genes either transiently up- or downregulated on day 7. The former group includes the transcription factors retinoic acid receptor ( RXR)-γ and homeobox ( Hox) a2, a4, and a5 and genes involved in Wnt signaling ( Wnt5a, Fzd1, and Ndp); the latter group includes the extracellular matrix components Comp and Opn and the signal molecule Slfn4. Profiling in whole lung from fetal life to adulthood confirmed that changes were specific for alveolarization. Two treatments that arrest septation, hyperoxia and dexamethasone, inhibited the expression of genes that are upregulated during alveolarization and conversely enhanced that of genes weakly expressed during alveolarization and upregulated thereafter. The possible roles of these genes in secondary septation are discussed. Gene expression profiling analysis on freshly isolated cells represents a powerful approach to provide new information about differential regulation of genes during alveolarization and pathways potentially involved in the pathogenesis of bronchopulmonary dysplasia.

Published
2007

14. Nitric Oxide Donor Restores Lung Growth Factor and Receptor Expression in Hyperoxia-Exposed Rat Pups

Author

Marie-Laure Franco-Montoya, Pierre-Henri Jarreau, Christophe Delacourt, Olivier Boucherat, Jacques R. Bourbon, and Emmanuel Lopez

Subjects
Vascular Endothelial Growth Factor A, Pulmonary and Respiratory Medicine, Angiogenesis, Receptor expression, medicine.medical_treatment, Clinical Biochemistry, Hyperoxia, Nitric oxide, Rats, Sprague-Dawley, Andrology, chemistry.chemical_compound, medicine, Animals, Nitric Oxide Donors, RNA, Messenger, Receptor, Lung, Molecular Biology, Platelet-Derived Growth Factor, biology, Growth factor, Gene Expression Regulation, Developmental, Cell Biology, respiratory system, Receptors, Fibroblast Growth Factor, Vascular Endothelial Growth Factor Receptor-2, Elastin, Rats, Fibroblast Growth Factors, medicine.anatomical_structure, Animals, Newborn, chemistry, Immunology, biology.protein, medicine.symptom, Nitroso Compounds
Abstract

Exposure of newborn rats to hyperoxia impairs alveolarization. Nitric oxide (NO) may prevent this evolution. Angiogenesis and factors involved in this process, but also other growth factors (GFs) involved in alveolar development, are likely potential therapeutic targets for NO. We studied the effects of the NO donor, [Z]-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1, 2-diolate, also termed DETANONOate (D-NO), on hyperoxia-induced changes in key regulatory factors of alveolar development in neonatal rats, and its possible preventive effect on the physiologic consequences of hyperoxia. Newborn rat pups were randomized at birth to hyperoxia (95% O2) or room air exposure for 6 or 10 d, while receiving D-NO or its diluent. On Day 6, several GFs and their receptors were studied at pre- and/or post-translational levels. Elastin transcript determination on Day 6, and elastin deposition in tissue and morphometric analysis of the lungs on Day 10, were also performed. Hyperoxia decreased the expression of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2, fibroblast growth factor (FGF)-18, and FGF receptors (FGFRs) FGFR3 and FGFR4, increased mortality, and impaired alveolarization and capillary growth. D-NO treatment of hyperoxia-exposed pups restored the expression level of FGF18 and FGFR4, induced an increase of both VEGF mRNA and protein, enhanced elastin expression, and partially restored elastin deposition in alveolar walls. Although, under the present conditions, D-NO failed to prevent the physiologic consequences of hyperoxia in terms of survival and lung alveolarization, our findings demonstrate molecular effects of NO on GFs involved in alveolar development that may have contributed to the protective effects previously reported for NO.

Published
2006

15. Overexpression of Alveolar Macrophage Gelatinase B (MMP-9) in Patients with Idiopathic Pulmonary Fibrosis

Author

Benoit Wallaert, Marie-Laure Franco-Montoya, Philippe Gosset, Alain Harf, Emmanuelle Lechapt-Zalcman, Hassan Lemjabbar, and Chantal Lafuma

Subjects
Male, Pulmonary and Respiratory Medicine, Pathology, medicine.medical_specialty, Pulmonary Fibrosis, Blotting, Western, Clinical Biochemistry, Matrix metalloproteinase, Extracellular matrix, Idiopathic pulmonary fibrosis, Internal medicine, Macrophages, Alveolar, medicine, Humans, Zymography, Collagenases, RNA, Messenger, Molecular Biology, DNA Primers, Microscopy, Confocal, Lung, Base Sequence, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Cell Biology, Middle Aged, respiratory system, medicine.disease, Immunohistochemistry, respiratory tract diseases, Bronchoalveolar lavage, medicine.anatomical_structure, Endocrinology, Matrix Metalloproteinase 9, Alveolar macrophage, Female, Steroids, business, Immunosuppressive Agents
Abstract

Alveolar macrophages (AM) express gelatinase B, a member of the matrix metalloproteinase family involved in the degradation and remodeling of extracellular matrix components. We evaluated the expression of gelatinase B in the course of idiopathic pulmonary fibrosis (IPF) by studying alveolar macrophages in culture AM and bronchoalveolar lavage fluid from 12 untreated patients with IPF, 11 patients with IPF under treatment with steroid and immunosuppressive agents, and 10 control subjects. By using zymography and quantitative image analysis, latent gelatinase B, as well an 88-kD active form, were investigated in culture medium (24 h) of AMs and were found to be significantly increased (P < 0.01) in untreated patients exhibiting severe IPF when compared with control subjects (4.1 +/- 1.7 versus 0.3 +/- 0.2 10(5) arbitrary units [AU]/10(4) AM for the 92-kD form). Concomitant studies of gelatinase B levels associated with cultured AM extracts or freshly harvested AM showed similar results, both at the mRNA and protein levels, respectively. Immunocytochemical studies on freshly harvested AM demonstrated that the enzyme was located mainly at the cell, suggesting some involvement of gelatinase B in AM migration. In contrast, gelatinase B activity secreted by AM tended to be normal in patients with IPF under steroid and immunosuppressive treatment. Simultaneously, level of the gelatinase B activity in epithelial lining fluid was increased in untreated IPF patients, whereas it was normal in treated patients. These results suggest that AM of patients with IPF are primed for gelatinase B expression and that steroid and immunosuppressive treatment induces negative modulation of the gelatinase B overexpression. We conclude that gelatinase B may play a role in lung remodeling in IPF.

Published
1999

16. Effect of two models of intrauterine growth restriction on alveolarization in rat lungs: morphometric and gene expression analysis

Author

Danièle Evain-Brion, Christophe Delacourt, Olivier Baud, Philippe Deruelle, Marie-Laure Franco-Montoya, Laura Butruille, Elodie Zana-Taïeb, Emmanuel Lopez, Pierre-Henri Jarreau, Isabelle Grandvuillemin, Flore Vernier, Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus (UMR_S 767), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Environnement périnatal et croissance - EA 4489 (EPS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), INSERM U955, équipe 4, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Réanimation et Pédiatrie Néonatales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale (IMRB), This work has been supported by a Legs Poix grant of la Chancellerie des Universitésde Paris, 2006 and by the Air Liquide Foundation, 2011., Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut Mondor de Recherche Biomédicale (IMRB), Guellaen, Georges, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], La grossesse normale et pathologique: développement et fonctions du placenta et de l'utérus ( UMR_S 767 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut de Recherche pour le Développement ( IRD ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Environnement périnatal et croissance, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Vascular research center of Marseille ( VRCM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-PremUp Foundation, and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Mondor de Recherche Biomédicale ( IMRB )

Subjects
Male, medicine.medical_specialty, Low protein, intrauterine growth restriction, Normal diet, lcsh:Medicine, Intrauterine growth restriction, Biology, Arginine, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, 030225 pediatrics, Internal medicine, bronchopulmonary dysplasia, Diet, Protein-Restricted, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Science, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Lung, 030304 developmental biology, lung development, 2. Zero hunger, 0303 health sciences, Fetal Growth Retardation, Multidisciplinary, lcsh:R, FGF18, respiratory system, medicine.disease, Rats, Pulmonary Alveoli, Nitric oxide synthase, alveolarization, Endocrinology, medicine.anatomical_structure, chronic neonatal lung disease, Animals, Newborn, Bronchopulmonary dysplasia, biology.protein, Gestation, Female, lcsh:Q, Research Article
Abstract

International audience; Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and -R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization.

Published
2013

17. Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia

Author

Pierre-Henri Jarreau, Emmanuelle Bouzigon, Johanna M. Huusko, Roberto Incitti, Ines Layouni, Jacques R. Bourbon, Richard Lenclen, Claude Danan, Florence Demenais, Mikko Hallman, Alice Hadchouel, Juliana Patkai, Christophe Delacourt, Xavier Durrmeyer, Marie-Laure Franco-Montoya, INSERM U955, équipe 4, Service de Pneumologie Allergologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de réanimation néonatale de Créteil, CHI Créteil, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of pediatrics, Oulu University Hospital-Institute of Clinical Medicine, PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation néonatale Port-Royal, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Néonatale, CHI Poissy-Saint-Germain, Unité Fonctionnelle de Recherche Clinique, Programme Hospitalier de Recherche Clinique AOR 07 018, Assistance Publique - Hôpitaux de Paris. Hadchouel was funded by INSERM., CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP]-PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), and CHU Cochin [AP-HP]

Subjects
Male, Pathology, Gene Expression, MESH : Genotype, Disease, Critical Care and Intensive Care Medicine, MESH: Animals, Newborn, MESH: Genotype, 0302 clinical medicine, Polymorphism (computer science), MESH : Female, MESH: Animals, MESH: Bronchopulmonary Dysplasia, Finland, Bronchopulmonary Dysplasia, 0303 health sciences, education.field_of_study, MESH : Rats, MESH : Animals, Newborn, MESH: Polymorphism, Single Nucleotide, MESH: Finland, MESH : Polymorphism, Single Nucleotide, Respiratory disease, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, Gestational age, MESH: European Continental Ancestry Group, MESH : Proteoglycans, 3. Good health, MESH : Infant, Premature, medicine.anatomical_structure, MESH: Proteoglycans, Female, Proteoglycans, MESH : Genome-Wide Association Study, Infant, Premature, MESH : Finland, MESH : Bronchopulmonary Dysplasia, Pulmonary and Respiratory Medicine, MESH: Infant, Premature, medicine.medical_specialty, MESH: Gene Expression, Genotype, MESH: Rats, MESH : Lung, MESH : Male, Population, Black People, MESH : Infant, Newborn, Polymorphism, Single Nucleotide, White People, Article, MESH : African Continental Ancestry Group, premature, lung, MESH : European Continental Ancestry Group, 03 medical and health sciences, 030225 pediatrics, Intensive care, medicine, Animals, Humans, Genetic Predisposition to Disease, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, development, 030304 developmental biology, Lung, MESH: Humans, business.industry, MESH : Humans, Infant, Newborn, medicine.disease, infant, MESH: Male, Rats, MESH : Gene Expression, Animals, Newborn, Bronchopulmonary dysplasia, Immunology, MESH: Genome-Wide Association Study, MESH : Genetic Predisposition to Disease, MESH : Animals, MESH: African Continental Ancestry Group, DNA microarrays, business, MESH: Female, Genome-Wide Association Study
Abstract

International audience; RATIONALE: Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility. OBJECTIVES: To identify genetic variants involved in bronchopulmonary dysplasia through a genome-wide association study. METHODS: We prospectively evaluated 418 premature neonates (gestational age

Published
2011

18. Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development

Author

Bernadette Chailley-Heu, Christelle Thibault, Marie-Laure Franco-Montoya, Jacques R. Bourbon, Christophe Delacourt, Roberto Incitti, and Olivier Boucherat

Subjects
Genetically modified mouse, Physiology, Angiogenesis, Down-Regulation, Biology, Fibroblast growth factor, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, Genetics, Animals, Transgenes, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Regulation of gene expression, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Gene Expression Regulation, Developmental, FGF18, respiratory system, Molecular biology, Cell biology, Up-Regulation, Gene expression profiling, Fibroblast Growth Factors, Pulmonary Alveoli, Animals, Newborn, 030220 oncology & carcinogenesis, Doxycycline, SNAI1, Myofibroblast
Abstract

Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage.

Published
2011

19. Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

Author

Thomas Schmitz, Danièle Evain-Brion, Jacques R. Bourbon, Pierre-Henri Jarreau, Céline Méhats, Emmanuel Lopez, Elodie Zana, Christophe Delacourt, and Marie-Laure Franco-Montoya

Subjects
medicine.medical_specialty, Ontogeny, Biology, Isozyme, Rats, Sprague-Dawley, 03 medical and health sciences, Cyclic nucleotide, chemistry.chemical_compound, 0302 clinical medicine, PDE4B, Pregnancy, Internal medicine, medicine, Cyclic AMP, Animals, Humans, RNA, Messenger, Gene, Lung, 030304 developmental biology, 0303 health sciences, Mesenchymal stem cell, Gene Expression Regulation, Developmental, Infant, Cyclic Nucleotide Phosphodiesterases, Type 4, Rats, Isoenzymes, medicine.anatomical_structure, Endocrinology, chemistry, Female, Signal transduction, 030217 neurology & neurosurgery, Developmental Biology
Abstract

During the perinatal period, lungs undergo changes to adapt to air breathing. The genes involved in these changes are developmentally regulated by various signaling pathways, including the cyclic nucleotide cAMP. As PDE4s are critical enzymes for regulation of cAMP levels, the objective of this study was to investigate PDE4's ontogeny in developing rat lung during the perinatal period. Pulmonary PDE4 activity, PDE4A-D, PDE4B, and PDE4D variant expression levels, PDE4B and PDE4D protein levels, and PDE4D localization in distal lung were determined. PDE4 activity increased towards term, dropped at birth, and increased thereafter to reach a plateau at the end of the second week of life. PDE4B2 and PDE4D long forms demonstrated a pattern of expression that increased markedly at birth. After birth, PDE4D was expressed in alveolar epithelial and mesenchymal cells. The study, therefore, evidenced striking variations in expression patterns among the PDE4 family that differed from changes in global PDE4 activity.

Published
2010

20. Defective angiogenesis in hypoplastic human fetal lungs correlates with nitric oxide synthase deficiency that occurs despite enhanced angiopoietin-2 and VEGF

Author

Jacques R. Bourbon, Virginie Masse, Jelena Martinovic, Bernard Thébaud, Caroline Elie, Olivier Boucherat, Alexandra Benachi, Christophe Delacourt, Marie-Laure Franco-Montoya, Centre de Recherche en Cancérologie, Université Laval, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Department of Pediatrics-Division of Neonatology, University of Alberta [Edmonton], Service d'Obstétrique et Gynécologie, Université Laval [Québec] (ULaval), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], University of Alberta, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Guellaen, Georges

Subjects
Vascular Endothelial Growth Factor A, MESH : Hypertension, Pulmonary, Physiology, Angiogenesis, Neovascularization, 0302 clinical medicine, MESH: Pregnancy, Pregnancy, MESH : Angiopoietin-2, MESH : Angiopoietin-1, MESH : Female, Lung, 0303 health sciences, biology, Neovascularization, Pathologic, Nitric Oxide Synthase Type III, Receptor, TIE-2, MESH: Receptor, TIE-2, 3. Good health, Nitric oxide synthase, Vascular endothelial growth factor A, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH : Vascular Endothelial Growth Factor A, Female, medicine.symptom, MESH: Nitric Oxide Synthase Type III, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Hypertension, Pulmonary, MESH : Lung, MESH : Nitric Oxide Synthase Type III, Article, Angiopoietin-2, 03 medical and health sciences, MESH: Angiopoietin-1, MESH: Angiopoietin-2, Physiology (medical), Internal medicine, medicine, Angiopoietin-1, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Receptor, TIE-2, Humans, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Hypertension, Pulmonary, business.industry, MESH: Vascular Endothelial Growth Factor A, MESH : Humans, Congenital diaphragmatic hernia, MESH : Neovascularization, Pathologic, Cell Biology, medicine.disease, Pulmonary hypertension, MESH : Pregnancy, Endocrinology, biology.protein, business, MESH: Neovascularization, Pathologic, MESH: Female
Abstract

International audience; Lung hypoplasia (LH) is a life-threatening congenital abnormality with various causes. It involves vascular bed underdevelopment with abnormal arterial muscularization leading to pulmonary hypertension. Because underlying molecular changes are imperfectly known and sometimes controversial, we determined key factors of angiogenesis along intrauterine development, focusing at the angiopoietin (ANG)/Tie-2 system. Lung specimens from medical terminations of pregnancy (9-37 wk) were used, including LH due to congenital diaphragmatic hernia (CDH) or other causes, and nonpulmonary disease samples were used as controls. ELISA determination indicated little ANG-1 change during pregnancy and no effect of LH, whereas Tie-2 declined similarly between 9 and 37 wk in LH and controls. By contrast, ANG-2 markedly increased in LH from 24 wk, whereas it remained stable in controls. Because VEGF increased also, this was interpreted as an attempt to overcome vascular underdevelopment. Hypothesizing that its inefficiency might be due to impaired downstream mechanism, endothelial nitric oxide synthase (eNOS) was determined by semiquantitative Western blot and found to be reduced by approximately 75%, mostly in the instance of CDH. In conclusion, angiogenesis remains defective in hypoplastic lungs despite reactive enhancement of VEGF and ANG-2 production, which could be due, at least in part, to insufficient eNOS expression.

Published
2010

21. Pulmonary effects of keratinocyte growth factor in newborn rats exposed to hyperoxia

Author

Christophe Delacourt, Jacques R. Bourbon, Stéphanie Lorotte, Xavier Durrmeyer, Marie-Laure Franco-Montoya, and Pierre-Henri Jarreau

Subjects
Pathology, Physiology, Apoptosis, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Enhancer binding, Medicine, Lung, Phospholipids, Hyperoxia, 0303 health sciences, Pulmonary Surfactant-Associated Protein B, medicine.diagnostic_test, Respiratory disease, respiratory system, 3. Good health, ErbB Receptors, medicine.anatomical_structure, Female, Keratinocyte growth factor, medicine.symptom, Bronchoalveolar Lavage Fluid, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Fibroblast Growth Factor 7, Lung injury, Andrology, 03 medical and health sciences, Physiology (medical), CCAAT-Enhancer-Binding Protein-alpha, Animals, Humans, 030304 developmental biology, Cell Proliferation, business.industry, Cell Biology, DNA, Transforming Growth Factor alpha, medicine.disease, Survival Analysis, respiratory tract diseases, Rats, Pulmonary Alveoli, Bronchoalveolar lavage, 030228 respiratory system, Bronchopulmonary dysplasia, chemistry, Animals, Newborn, Gene Expression Regulation, business, Cell Adhesion Molecules
Abstract

Acute lung injury and compromised alveolar development characterize bronchopulmonary dysplasia (BPD) of the premature neonate. High levels of keratinocyte growth factor (KGF), a cell-cell mediator with pleiotrophic lung effects, are associated with low BPD risk. KGF decreases mortality in hyperoxia-exposed newborn rodents, a classic model of injury-induced impaired alveolarization, although the pulmonary mechanisms of this protection are poorly defined. These were explored through in vitro and in vivo approaches in the rat. Hyperoxia decreased by 30% the rate of wound closure of a monolayer of fetal alveolar epithelial cells, due to cell death, which was overcome by recombinant human KGF (100 ng/ml). In rat pups exposed to >95% O2 from birth, increased viability induced by intraperitoneal injection of KGF (2 μg/g body wt) every other day was associated with prevention of neutrophil influx in bronchoalveolar lavage (BAL), prevention of decreases in whole lung DNA content and cell proliferation rate, partial prevention of apoptosis increase, and a markedly increased proportion of surfactant protein B-immunoreactive cells in lung parenchyma. Increased lung antioxidant capacity is likely to be due in part to enhanced CAAT/enhancer binding protein α expression. By contrast, KGF neither corrected changes induced by hyperoxia in parameters of lung morphometry that clearly indicated impaired alveolarization nor had any significant effect on tissue or BAL surfactant phospholipids. These findings evidence KGF alveolar epithelial cell protection, enhancing effects on alveolar repair capacity, and anti-inflammatory effects in the injured neonatal lung that may account, at least in part, for its ability to reduce mortality. They argue in favor of a therapeutic potential of KGF in the injured neonatal lung.

Published
2009

22. Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development

Author

Isabelle Halphen, Marie-Laure Franco-Montoya, Pierre-Henri Jarreau, Claude Danan, Fabrice Decobert, Jacques R. Bourbon, Emmanuel Martin, Alice Hadchouel, Olivier Boucherat, Serge Amselem, Alexandra Benachi, Christophe Delacourt, Institut Mondor de recherche biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Service de réanimation néonatale Port-Royal, CHU Cochin [AP-HP], Service de médecine néonatale de Port-Royal, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), IntegraGen, Service d'Obstétrique et Gynécologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -CHU Necker - Enfants Malades [AP-HP], Bases moléculaires et cellulaires des maladies génétiques, Unité Fonctionnelle de Recherche Clinique, CHI Créteil, Faculté de Médecine, IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges

Subjects
Male, MMP2, MESH : Polymorphism, Genetic, MESH : Prospective Studies, lcsh:Medicine, MESH: Rats, Sprague-Dawley, Matrix metalloproteinase, Rats, Sprague-Dawley, 0302 clinical medicine, MESH: Matrix Metalloproteinase 16, MESH: Animals, MESH : Female, Prospective Studies, lcsh:Science, Lung, MESH: Bronchopulmonary Dysplasia, Bronchopulmonary Dysplasia, 0303 health sciences, Multidisciplinary, MESH : Gene Expression Regulation, MESH : Rats, MESH: Infant, Newborn, MESH: Surface-Active Agents, Gestational age, respiratory system, Respiratory Medicine/Respiratory Pediatrics, MESH: Gene Expression Regulation, Trachea, medicine.anatomical_structure, MESH : Infant, Premature, MMP14, Female, MMP16, Infant, Premature, Research Article, MESH: Infant, Premature, MESH : Bronchopulmonary Dysplasia, MESH: Rats, MESH : Trachea, MESH : Lung, MESH : Male, Single-nucleotide polymorphism, Biology, MESH : Infant, Newborn, Andrology, Surface-Active Agents, 03 medical and health sciences, 030225 pediatrics, MESH: Polymorphism, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, MESH: Lung, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Polymorphism, Genetic, MESH: Humans, lcsh:R, MESH : Humans, Infant, Newborn, MESH : Matrix Metalloproteinase 16, Matrix Metalloproteinase 16, medicine.disease, MESH: Prospective Studies, MESH: Male, MESH : Rats, Sprague-Dawley, Rats, Gene Expression Regulation, Bronchopulmonary dysplasia, Immunology, lcsh:Q, MESH : Surface-Active Agents, Pediatrics and Child Health/Neonatology, MESH : Animals, MESH: Female, MESH: Trachea, Developmental Biology
Abstract

International audience; BACKGOUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of

Published
2008

23. Decreased lung fibroblast growth factor 18 and elastin in human congenital diaphragmatic hernia and animal models

Author

Olivier Boucherat, Bernadette Chailley-Heu, Marie-Laure Franco-Montoya, Jelena Martinovic, Bernard Thébaud, Anne-Marie Barlier-Mur, Jacques R. Bourbon, Alexandra Benachi, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de maternité [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Department of Pediatrics-Division of Neonatology, University of Alberta, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - CHU Necker - Enfants Malades [AP-HP], University of Alberta [Edmonton], and Guellaen, Georges

Subjects
Male, Pathology, MESH: Pulmonary Alveoli, MESH: Amino Acid Sequence, MESH: Base Sequence, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Diaphragmatic hernia, MESH: Animals, Vitamin A, Lung, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Vitamin A, 0303 health sciences, biology, MESH: Infant, Newborn, respiratory system, MESH: Infant, 3. Good health, Trachea, MESH: Hernia, Diaphragmatic, medicine.anatomical_structure, Female, MESH: Fibroblast Growth Factors, Pulmonary and Respiratory Medicine, medicine.medical_specialty, MESH: Rats, Molecular Sequence Data, MESH: Elastin, MESH: Sheep, 03 medical and health sciences, 030225 pediatrics, Intensive care, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Animals, Humans, Hernia, MESH: Lung, Amino Acid Sequence, RNA, Messenger, Rats, Wistar, 030304 developmental biology, MESH: RNA, Messenger, Hernia, Diaphragmatic, Fetus, Sheep, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, business.industry, Infant, Newborn, Infant, Congenital diaphragmatic hernia, MESH: Rats, Wistar, medicine.disease, Nitrofen, MESH: Male, Elastin, Rats, Fibroblast Growth Factors, Pulmonary Alveoli, Disease Models, Animal, Endocrinology, chemistry, biology.protein, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Disease Models, Animal, business, MESH: Female, MESH: Trachea
Abstract

International audience; RATIONALE: Lung hypoplasia in congenital diaphragmatic hernia (CDH) seems to involve impaired alveolar septation. We hypothesized that disturbed deposition of elastin and expression of fibroblast growth factor 18 (FGF18), an elastogenesis stimulus, occurs in CDH. OBJECTIVES: To document FGF18 and elastin in human CDH and ovine surgical and rat nitrofen models and to use models to evaluate the benefit of treatments. METHODS: Human CDH and control lungs were collected post mortem. Diaphragmatic hernia was created in sheep at 85 days; fetal lungs were collected at 139 days (term = 145 days). Pregnant rats received nitrofen at 12 days; fetal lungs were collected at 21 days (term = 22 days). Some of the sheep fetuses with hernia underwent tracheal occlusion (TO); some of the nitrofen-treated pregnant rats received vitamin A. Both treatments are known to promote lung growth. MEASUREMENTS AND MAIN RESULTS: Coincidental with the onset of secondary septation, FGF18 protein increased threefold in control human lungs, which failed to occur in CDH. FGF18 labeling was found in interstitial cells of septa. Elastin staining demonstrated poor septation and markedly decreased elastin density in CDH lungs. Consistently, lung FGF18 transcripts were diminished 60 and 83% by CDH in sheep and rats, respectively, and elastin density and expression were diminished. TO and vitamin A restored FGF18 and elastin expression in sheep and rats, respectively. TO restored elastin density. CONCLUSIONS: Impaired septation in CDH is associated with decreased FGF18 expression and elastic fiber deposition. Simultaneous correction of FGF18 and elastin defects by TO and vitamin A suggests that defective elastogenesis may result, at least partly, from FGF18 deficiency.

Published
2007

24. Surfactant maturation is not delayed in human fetuses with diaphragmatic hernia

Author

Alexandra Benachi, Bernadette Chailley-Heu, Jacques R. Bourbon, Olivier Boucherat, Marie-Laure Franco-Montoya, Jelena Martinovic, Caroline Elie, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'obstétrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'informatique médicale et biostatistiques [CHU Necker], Service de foetopathologie, This work was supported by a Legs Poix grant from the Chancellerie des Universités de Paris, Autard, Delphine, Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Necker - Enfants Malades [AP-HP]

Subjects
Leptin, Male, Pediatrics and Child Health, lcsh:Medicine, Pediatrics, 0302 clinical medicine, MESH: Pregnancy, Pulmonary surfactant, Pregnancy, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Gene Expression Regulation, Developmental, Pathology, Diaphragmatic hernia, MESH: Animals, MESH: Nerve Tissue Proteins, Lung, Respiratory Medicine, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH: Infant, Newborn, MESH: Pulmonary Surfactants, Gene Expression Regulation, Developmental, General Medicine, humanities, 3. Good health, MESH: Hernia, Diaphragmatic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, MESH: Neuregulin-1, Perspectives, medicine.medical_specialty, Fibroblast Growth Factor 7, Neuregulin-1, Blotting, Western, Molecular Sequence Data, MESH: Sheep, Nerve Tissue Proteins, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Surfactant therapy, 03 medical and health sciences, Pulmonary hypoplasia, Fetus, 030225 pediatrics, Internal medicine, medicine, MESH: Blotting, Western, Animals, Humans, MESH: Lung, Neuregulin 1, Hernia, Diaphragmatic, MESH: Molecular Sequence Data, MESH: Humans, Sheep, business.industry, lcsh:R, MESH: Fibroblast Growth Factor 7, Infant, Newborn, Congenital diaphragmatic hernia, Neonates, MESH: Fetus, Pulmonary Surfactants, MESH: Leptin, medicine.disease, MESH: Male, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Endocrinology, biology.protein, business, Hernias, Diaphragmatic, Congenital, MESH: Female, Developmental Biology
Abstract

International audience; BACKGROUND: Pulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question. METHODS AND FINDINGS: We investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-beta1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-beta1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression. CONCLUSIONS: Our results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.

Published
2006

25. Effect of intratracheal adenoviral vector administration on lung development in newborn rats

Author

Micheline Levame, Chantal Lafuma, Alain Harf, Isabelle Deprez, Marie-Paule Jacob, Marie-Laure Franco-Montoya, Paul Waszak, and Christophe Delacourt

Subjects
Gene Expression Regulation, Viral, Pathology, medicine.medical_specialty, Recombinant Fusion Proteins, Genetic Vectors, Bronchi, Transfection, Andrology, Genes, Reporter, Tropoelastin, Parenchyma, Genetics, medicine, Animals, Lung volumes, RNA, Messenger, Molecular Biology, Lung, Inflammation, biology, Dose-Response Relationship, Drug, Cell growth, Adenoviruses, Human, Genetic transfer, Defective Viruses, Epithelial Cells, respiratory system, Elastic Tissue, beta-Galactosidase, Proliferating cell nuclear antigen, Elastin, Rats, Trachea, Dose–response relationship, medicine.anatomical_structure, Instillation, Drug, Animals, Newborn, biology.protein, Molecular Medicine, Adenovirus E1A Proteins, Lung Volume Measurements, Bronchoalveolar Lavage Fluid, Immunostaining, Cell Division
Abstract

Local overexpression of genes that promote lung defense or repair may be helpful in protecting the immature neonatal lung from injuries, but whether the vectors used to administer these genes affect physiological postnatal lung growth has not been investigated. We explored the effect on alveolarization of E1-deleted Adnull vector (Ad5-LMP-null) given intratracheally to 3-day-old rats. Three Adnull doses were evaluated 10(8), 5 x 10(8), and 10(9) TCID(50). Lung morphometry on day 21 showed significant growth disorders with the two higher doses. With 5 x 10(8) TCID(50), absolute lung volume increased significantly (+16%), as did absolute (+20%) and specific (+32%) alveolar airspace volumes, whereas alveolar surface density decreased by 13% (p < 0.009 for all parameters). Lung inflammation was mild, nonsignificant, and occurred mainly with the highest Adnull dose, indicating that it was unlikely to contribute to our results. Adnull instillation induced a significant#10; decrease in terminal bronchiolar cell proliferation as evaluated by proliferating cell nuclear antigen immunostaining (p = 0.02), as well as a 23% decrease in absolute parenchyma elastic fiber length (p = 0.02). Furthermore, lung tropoelastin mRNA content decreased by 25% (p < 0.02). In conclusion, E1-deleted adenoviral vectors can induce lung growth disorders when instilled into the airways of neonatal rats. Interactions with lung matrix turnover may be the main explanation to these deleterious effects.

Published
2002

26. Effects of Phosphodiesterase 4 Inhibition on Alveolarization and Hyperoxia Toxicity in Newborn Rats

Author

Elodie Zana, Thomas Schmitz, Jacques R. Bourbon, Olivier Boucherat, Pierre-Henri Jarreau, Céline Méhats, Emmanuel Lopez, Danièle Evain-Brion, Christophe Delacourt, and Marie-Laure Franco-Montoya

Subjects
medicine.medical_specialty, Phosphodiesterase Inhibitors, lcsh:Medicine, Hyperoxia, Lung injury, Weight Gain, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, lcsh:Science, Rolipram, 030304 developmental biology, Inflammation, 0303 health sciences, Multidisciplinary, Lung, medicine.diagnostic_test, business.industry, lcsh:R, Phosphodiesterase, Lung Injury, respiratory system, Respiratory Medicine/Respiratory Pediatrics, medicine.disease, Rats, respiratory tract diseases, 3. Good health, Pulmonary Alveoli, Endocrinology, medicine.anatomical_structure, Bronchoalveolar lavage, Animals, Newborn, Bronchopulmonary dysplasia, Toxicity, Immunology, Physiology/Respiratory Physiology, lcsh:Q, Pediatrics and Child Health/Neonatology, Phosphodiesterase 4 Inhibitors, medicine.symptom, business, 030217 neurology & neurosurgery, Research Article, medicine.drug
Abstract

BACKGROUND: Prolonged neonatal exposure to hyperoxia is associated with high mortality, leukocyte influx in airspaces, and impaired alveolarization. Inhibitors of type 4 phosphodiesterases are potent anti-inflammatory drugs now proposed for lung disorders. The current study was undertaken to determine the effects of the prototypal phosphodiesterase-4 inhibitor rolipram on alveolar development and on hyperoxia-induced lung injury. METHODOLOGY/FINDINGS: Rat pups were placed under hyperoxia (FiO2>95%) or room air from birth, and received rolipram or its diluent daily until sacrifice. Mortality rate, weight gain and parameters of lung morphometry were recorded on day 10. Differential cell count and cytokine levels in bronchoalveolar lavage and cytokine mRNA levels in whole lung were recorded on day 6. Rolipram diminished weight gain either under air or hyperoxia. Hyperoxia induced huge mortality rate reaching 70% at day 10, which was prevented by rolipram. Leukocyte influx in bronchoalveolar lavage under hyperoxia was significantly diminished by rolipram. Hyperoxia increased transcript and protein levels of IL-6, MCP1, and osteopontin; rolipram inhibited the increase of these proteins. Alveolarization was impaired by hyperoxia and was not restored by rolipram. Under room air, rolipram-treated pups had significant decrease of Radial Alveolar Count. CONCLUSIONS: Although inhibition of phosphodiesterases 4 prevented mortality and lung inflammation induced by hyperoxia, it had no effect on alveolarization impairment, which might be accounted for by the aggressiveness of the model. The less complex structure of immature lungs of rolipram-treated pups as compared with diluent-treated pups under room air may be explained by the profound effect of PDE4 inhibition on weight gain that interfered with normal alveolarization.

Published
2008

27. Profiling target genes of FGF18 in the postnatal mouse lung: possible relevance for alveolar development.

Author

Marie-Laure Franco-Montoya

Subjects
*TRANSGENE expression, *ALVEOLAR process, *FIBROBLAST growth factors, *POLYMERASE chain reaction, *DEVELOPMENTAL biology, *LABORATORY mice
Abstract

Better understanding alveolarization mechanisms could help improve prevention and treatment of diseases characterized by reduced alveolar number. Although signaling through fibroblast growth factor (FGF) receptors is essential for alveolarization, involved ligands are unidentified. FGF18, the expression of which peaks coincidentally with alveolar septation, is likely to be involved. Herein, a mouse model with inducible, lung-targeted FGF18 transgene was used to advance the onset of FGF18 expression peak, and genome-wide expression changes were determined by comparison with littermate controls. Quantitative RT-PCR was used to confirm expression changes of selected up- and downregulated genes and to determine their expression profiles in the course of lung postnatal development. This allowed identifying so-far unknown target genes of the factor, among which a number are known to be involved in alveolarization. The major target was adrenomedullin, a promoter of lung angiogenesis and alveolar development, whose transcript was increased 6.9-fold. Other genes involved in angiogenesis presented marked expression increases, including Wnt2 and cullin2. Although it appeared to favor cell migration notably through enhanced expression of Snai1/2, FGF18 also induced various changes consistent with prevention of epithelial-mesenchymal transition. Together with antifibrotic effects driven by induction of E prostanoid receptor 2 and repression of numerous myofibroblast markers, this could prevent alveolar septation-driving mechanisms from becoming excessive and deleterious. Last, FGF18 up- or downregulated genes of extracellular matrix components and epithelial cell markers previously shown to be up- or downregulated during alveolarization. These findings therefore argue for an involvement of FGF18 in the control of various developmental events during the alveolar stage. [ABSTRACT FROM AUTHOR]

Published
2011
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