37 results on '"Jha, Aruni"'
Search Results
2. Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection in Mice
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Barker, Douglas, primary, Han, Xiaobing, additional, Wang, Eryu, additional, Dagley, Ashley, additional, Anderson, Deborah M., additional, Jha, Aruni, additional, Weaver, Scott C., additional, Julander, Justin, additional, Nykiforuk, Cory, additional, and Kodihalli, Shantha, additional
- Published
- 2023
- Full Text
- View/download PDF
3. Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection in Mice
- Author
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Barker, Douglas, Han, Xiaobing, Wang, Eryu, Dagley, Ashley, Anderson, Deborah M., Jha, Aruni, Weaver, Scott C., Julander, Justin, Nykiforuk, Cory, Kodihalli, Shantha, and MDPI AG
- Subjects
chikungunya ,Medical Pathology ,mouse model ,Viruses ,pharmacodynamics ,Medical Immunology ,Medical Pharmacology - Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen that causes chikungunya disease (CHIK); the disease is characterized by fever, muscle ache, rash, and arthralgia. This arthralgia can be debilitating and long-lasting, seriously impacting quality of life for years. Currently, there is no specific therapy available for CHIKV infection. We have developed a despeciated equine polyclonal antibody (CHIKV-EIG) treatment against CHIKV and evaluated its protective efficacy in mouse models of CHIKV infection. In immunocompromised (IFNAR−/−) mice infected with CHIKV, daily treatment for five consecutive days with CHIKV-EIG administered at 100 mg/kg starting on the day of infection prevented mortality, reduced viremia, and improved clinical condition as measured by body weight loss. These beneficial effects were seen even when treatment was delayed to 1 day after infection. In immunocompetent mice, CHIKV-EIG treatment reduced virus induced arthritis (including footpad swelling), arthralgia-associated cytokines, viremia, and tissue virus loads in a dose-dependent fashion. Collectively, these results suggest that CHIKV-EIG is effective at preventing CHIK and could be a viable candidate for further development as a treatment for human disease.
- Published
- 2023
4. Pharmacokinetic and Pharmacodynamic Effects of Polyclonal Antibodies against SARS-CoV2 in Mice
- Author
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Jha, Aruni, primary, Doyle-Eisele, Melanie, additional, Revelli, David, additional, Carnelley, Trevor, additional, Barker, Douglas, additional, and Kodihalli, Shantha, additional
- Published
- 2022
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5. Novel drug targets for asthma and COPD: Lessons learned from in vitro and in vivo models
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Baker, Katie E., Bonvini, Sara J., Donovan, Chantal, Foong, Rachel E., Han, Bing, Jha, Aruni, Shaifta, Yasin, Smit, Marieke, Johnson, Jill R., and Moir, Lyn M.
- Published
- 2014
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- View/download PDF
6. Simultaneous quantification of simvastatin and simvastatin hydroxy acid in blood serum at physiological pH by ultrahigh performance liquid chromatography–tandem mass spectrometry (UHPLC/MS/MS)
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Bews, Hilary J., Carlson, Jules C., Jha, Aruni, Basu, Sujata, Halayko, Andrew J., and Wong, Charles S.
- Published
- 2014
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- View/download PDF
7. Maternal diabetes promotes offspring lung dysfunction and inflammation in a sex-dependent manner
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Pascoe, Christopher D., primary, Basu, Sujata, additional, Schwartz, Jacquie, additional, Fonseca, Mario, additional, Kahnamoui, Shana, additional, Jha, Aruni, additional, Dolinsky, Vernon, additional, and Halayko, Andrew J., additional
- Published
- 2022
- Full Text
- View/download PDF
8. Models to study airway smooth muscle contraction in vivo, ex vivo and in vitro: Implications in understanding asthma
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Wright, David, Sharma, Pawan, Ryu, Min-Hyung, Rissé, Paul-Andre, Ngo, Melanie, Maarsingh, Harm, Koziol-White, Cynthia, Jha, Aruni, Halayko, Andrew J., and West, Adrian R.
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- 2013
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9. A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?
- Author
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Jha, Aruni, Sharma, Pawan, Anaparti, Vidyanand, Ryu, Min H., and Halayko, Andrew J.
- Subjects
Ion channels -- Health aspects ,Smooth muscle -- Health aspects ,Hypertension -- Physiological aspects ,Airway (Medicine) -- Health aspects ,Biological sciences - Abstract
Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of [Ca.sup.2+]. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and [Ca.sup.2+] mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM. Key words: asthma, COPD, AHR. La contraction du muscle lisse respiratoire (MLR) controle le calibre des voies respiratoires. Le retrecissement des voies respiratoires est excessif dans les cas de maladies pulmonaires obstructives comme l'asthme et les MPOC. Le mecanisme par lequel le tonus du MLR est deregule dans la maladie n'est pas clairement compris. Les travaux de recherche recents realises sur les canaux ioniques, particulierement TRPA1, presentent de nouvelles donnees qui expliquent la deterioration de la fonction respiratoire. TRPA1, un membre de la superfamille des canaux TRP, est un canal cationique chimio-sensible qui peut etre active par une variete de stimuli externes et internes, menant a un influx de [Ca.sup.2+]. Des canaux TRPA1 fonctionnels ont ete identifies dans des tissus neuronaux et non-neuronaux du poumon, incluant le MLR. Dans les voies respiratoires, ces canaux peuvent reguler la liberation de mediateurs qui sont des marqueurs de l'inflammation respiratoire dans l'asthme et les MPOC. Par exemple, TRPA1 controle la liberation de mediateurs inflammatoires et la mobilisation du [Ca.sup.2+] in vitro et in vivo induites par la fumee de cigarette, des reponses liees a la pathologie des MPOC. Des travaux recents ont revele que l'inhibition pharmacologique ou genetique de TRPA1 inhibe l'inflammation respiratoire provoquee par un allergene in vitro et l'hyperreactivite bronchique (HRB) in vivo. Dans l'ensemble, il semble que les canaux TRPA1 peuvent etre des determinants de la contractilite du MLR et du controle de l'inflammation locale, ce qui les place parmi les constituants de nouveaux mecanismes qui controlent la fonction (patho)physiologique des voies respiratoires et du MLR. [Traduit par la Redaction] Mots-cles: asthme, MPOC, HRB., Introduction Airway smooth muscle (ASM) controls the caliber of airways by facilitating the contraction and relaxation of the airways. In disease states such as asthma and chronic obstructive pulmonary disease [...]
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- 2015
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- View/download PDF
10. Characterization of the dystrophin-glycoprotein complex in airway smooth muscle: role of δ-sarcoglycan in airway responsiveness
- Author
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Sharma, Pawan, Jha, Aruni, Stelmack, Gerald L., Detillieux, Karen, Basu, Sujata, Klonisch, Thomas, Unruh, Helmut, and Halayko, Andrew J.
- Subjects
Dystrophin -- Health aspects ,Glycoproteins -- Health aspects ,Smooth muscle -- Health aspects ,Airway (Medicine) -- Health aspects ,Biological sciences - Abstract
The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether δ-sarcoglycan (δ-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in δ-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in δ-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and β-dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in δ-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo. Key words: airway smooth muscle, caveolae, contraction, airway responsiveness, dystrophin glycoprotein complex. Le complexe DGC (<>) est une partie integrante des micro-domaines des caveoles, et son interaction avec la caveoline-1 est essentielle au phenotype et aux proprietes fonctionnelles du muscle lisse respiratoire (MLR). Le complexe sarcoglycane confere la stabilite au complexe dystroglycane mais son role dans la contraction du MLR et la physiologie pulmonaire n'est pas compris. Les auteurs ont teste si le δ-sarcoglycane (δ-SG), par son interaction avec le DGC, est un determinant de la contraction du MLR ex vivo et de la mecanique respiratoire in vivo. Ils ont mesure la contraction isometrique provoquee par la metacholine (MCh) ainsi que la mecanique respiratoire chez des souris deficientes en δ-SG et des souris sauvages. Finalement, ils ont realise des analyses par immuno-buvardage et par microscopie electronique a transmission afin d'evaluer l'expression de DGC et les caracteristiques ultrastructurales du muscle lisse tracheal. Les resultats revelent une reduction de la force isometrique induite par la MCh en fonction de l'age, ainsi qu'un reduction significative de la resistance respiratoire a de fortes concentrations de MCh (50,0 mg/mL) chez les souris deficientes en δ-SG. Les changements sur le plan de la contraction et de la fonction pulmonaire etaient en correlation avec la diminution de l'abondance de caveoline-1 et de β-dystroglycane, de meme qu'avec la perte des caveoles de la membrane cellulaire du muscle lisse tracheal des souris deficientes en δ-SG, en fonction de l'age. Dans l'ensemble, ces resultats confirment et approfondissent la comprehension du role fonctionnel du DGC dans les proprietes contractiles du MLR, et demontrent comment en resulte une deterioration de la fonction pulmonaire in vivo. [Traduit par la Redaction] Mots-cles: muscle lisse respiratoire, caveole, contraction, reactivite bronchique, complexe dystrophine glycoproteine., Introduction The dystrophin-glycoprotein complex (DGC) confers a structural link between laminin-2 in the extracellular matrix (ECM) and the F-actin cytoskeleton (Ervasti and Campbell 1993; Lapidos et al. 2004) and also [...]
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- 2015
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11. Pharmacokinetic and Pharmacodynamic Effects of Polyclonal Antibodies against SARS-CoV2 in Mice.
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Jha, Aruni, Doyle-Eisele, Melanie, Revelli, David, Carnelley, Trevor, Barker, Douglas, and Kodihalli, Shantha
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MICE , *SARS-CoV-2 , *PHARMACOKINETICS , *COVID-19 treatment , *TRANSGENIC mice , *INTRAVENOUS therapy - Abstract
Despite ongoing vaccination efforts to prevent SARS-CoV-2 infections, treatment tools are still necessary to address the ongoing COVID-19 pandemic. We report here that COVID-HIGIV, a human immunoglobulin product for treatment of COVID-19, provided a significant survival benefit in SARS-CoV-2 infected transgenic mice compared to controls. COVID-HIGIV also has similar pharmacokinetic profiles in healthy and SARS-CoV-2 infected mice over time after intravenous administration, with identical or comparable Tmax, Cmax, AUC0–∞ and Cl. AUC0–last increased and mean residence time, T1/2, and Vd reduced in infected animals compared to healthy animals. These data suggest that COVID-HIGIV may be an effective treatment for SARS-CoV-2 infection when given early after exposure. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Integrating Proteomes for Lung Tissues and Lavage Reveals Pathways That Link Responses in Allergen-Challenged Mice
- Author
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Mahood, Thomas H., primary, Pascoe, Christopher D., additional, Karakach, Tobias K., additional, Jha, Aruni, additional, Basu, Sujata, additional, Ezzati, Peyman, additional, Spicer, Victor, additional, Mookherjee, Neeloffer, additional, and Halayko, Andrew J., additional
- Published
- 2021
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13. Integrating Lung Tissue and Lavage Proteomes Reveals Unique Pathways in Allergen-Challenged Mice
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Mahood, Thomas H, Pascoe, Christopher D, Jha, Aruni, Basu, Sujata, Ezzati, Peyman, Spicer, Victor, Mookherjee, Neeloffer, and Halayko, Andrew J
- Subjects
respiratory system ,respiratory tract diseases - Abstract
Independent proteomic analysis do not capture the biological interactions between the tissue and extracellular biological compartments when examined in isolation. To address this, we analyzed and compared the proteome from lung tissue and from bronchoalveolar lavage fluid (BALF) of individual allergen-naïve and allergen-challenged BALB/c mice, a common pre-clinical model of allergic asthma. Collectively, we quantified 2,695 proteins from both tissue and BALF of allergen-naïve and -exposed mice. We created an integrated dataset to examine tissue-BALF proteome interactions. Multivariate analysis identified this Integrated-Tissue-BALF (ITB) dataset as being distinct from either the lung tissue or the BALF dataset. Pathway and network analysis of the ITB dataset uncovered protein hubs that span both the tissue and BALF, but are not significantly enriched in either sample dataset alone. This work reveals that by combining individual datasets provides insight about protein networks that integrate biology in lung tissue and the airway space in response to allergen challenge.
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- 2020
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14. Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction
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Pascoe, Christopher D., primary, Jha, Aruni, additional, Ryu, Min Hyung, additional, Ragheb, Mirna, additional, Vaghasiya, Jignesh, additional, Basu, Sujata, additional, Stelmack, Gerald L., additional, Srinathan, Sadeesh, additional, Kidane, Biniam, additional, Kindrachuk, Jason, additional, O'Byrne, Paul M., additional, Gauvreau, Gail M., additional, Ravandi, Amir, additional, Carlsten, Christopher, additional, and Halayko, Andrew J., additional
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- 2020
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15. Integrating Proteomes for Lung Tissue and Lavage Reveals Pathways that Link Responses in Allergen-Challenged Mice
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Mahood, Thomas H, primary, Pascoe, Christopher D, additional, Karakach, Tobias K, additional, Jha, Aruni, additional, Basu, Sujata, additional, Ezzati, Peyman, additional, Spicer, Victor, additional, Mookherjee, Neeloffer, additional, and Halayko, Andrew J, additional
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- 2020
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16. Can circular RNAs be used as prenatal biomarkers for congenital diaphragmatic hernia?
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Wagner, Richard, primary, Jha, Aruni, additional, Ayoub, Lojine, additional, Kahnamoui, Shana, additional, Patel, Daywin, additional, Mahood, Thomas H., additional, Halayko, Andrew J., additional, Lacher, Martin, additional, Pascoe, Christopher D., additional, and Keijzer, Richard, additional
- Published
- 2019
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17. Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma
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Jha, Aruni, Ryu, Min H, OO, Ojo, Bews, Hilary J, Carlson, Jules C, Schwartz, Jacquie, Basu, Sujata, Wong, Charles S, and Halayko, Andrew J
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Mice, Inbred BALB C ,Simvastatin ,Neutrophils ,Pyroglyphidae ,Anti-Inflammatory Agents ,nutritional and metabolic diseases ,respiratory system ,Allergens ,Research Papers ,Asthma ,respiratory tract diseases ,Eosinophils ,Disease Models, Animal ,polycyclic compounds ,Animals ,Cytokines ,lipids (amino acids, peptides, and proteins) ,Female ,Lung - Abstract
BACKGROUND AND PURPOSE: Systemically delivered statins can blunt airway inflammation in ovalbumin‐challenged mice. However, in asthma clinical trials the beneficial effects of introducing oral statins are not compelling. We have invetigated this discrepancy using a clinically relevant murine model of allergic asthma, and by including a prophylactic study arm. EXPERIMENTAL APPROACH: Adult mice were: 1) challenged with house dust mite (HDM) alone or with subcutaneous (s.c.) simvastatin for two weeks; or 2) also treated with simvastatin for one week prior to HDM challenge. We assayed lung function, inflammatory cell influx and cytokine profile, goblet cell abundance, and simvastatin concentration in serum, lung lavage and tissue. KEY RESULTS: Ultrahigh performance liquid chromatography–tandem mass spectrometry revealed that pharmacologically active simvastatin reached peak serum concentration after 8 h, but declined rapidly. Prophylactic treatment doubled peak serum simvastatin and repeated s.c. delivery established stable serum levels, but simvastatin was undetectable in the lungs. Both simvastatin treatment arms suppressed indices of HDM‐induced airway inflammation and goblet cell hyperplasia, but this was significantly greater with prophylactic therapy, in particular, inhibition of neutrophil and eosinophil influx, and cytokine accumulation. Conversely, neither acute nor prophylactic delivery of simvastatin prevented HDM challenge‐induced airway hyperreactivity. CONCLUSION AND IMPLICATIONS: Systemically administered simvastatin accumulates in the blood, but not in lung tissues, and reduces leukocyte influx and associated lung inflammation. Prophylactic therapy has the greatest anti‐inflammatory effects, but as observed in human clinical trials, systemic simvastatin therapy does not prevent allergic airway hyperreactivity.
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- 2018
18. Gestational Diabetes Adversely Affects Pancreatic Islet Architecture and Function in the Male Rat Offspring
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Agarwal, Prasoon, primary, Brar, Navdeep, additional, Morriseau, Taylor S, additional, Kereliuk, Stephanie M, additional, Fonseca, Mario A, additional, Cole, Laura K, additional, Jha, Aruni, additional, Xiang, Bo, additional, Hunt, Kristin L, additional, Seshadri, Nivedita, additional, Hatch, Grant M, additional, Doucette, Christine A, additional, and Dolinsky, Vernon W, additional
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- 2019
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19. The importance of reporting house dust mite endotoxin abundance: impact on the lung transcriptome.
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Pascoe, Christopher D., Jha, Aruni, Basu, Sujata, Mahood, Thomas, Lee, Amy, Hinshaw, Sam, Falsafi, Reza, Hancock, Robert E. W., Mookherjee, Neeloffer, and Halayko, Andrew J.
- Abstract
The abundance of lipopolysaccharide (LPS) in house dust mite (HDM) preparations is broad and mirrors the variability seen in the homes of people with asthma. LPS in commercially available stocks ranges from 31 to 5,2000 endotoxin units. The influence of vastly different LPS loads on the mechanisms that define the immune and inflammatory phenotype of HDM-challenged mice has not been defined. This aim of the study was to understand the lung phenotype of mice challenged with HDM extract containing high or low levels of LPS. Female BALB/c mice were sensitized for 2 wk with commercial HDM extract containing either high (36,000 endotoxin units; HHDM) or low (615 endotoxin units; LHDM) levels of LPS. Lung phenotype was characterized by measuring lung function, total and differential cell counts, cytokine abundance, and the lung transcriptome by RNA-sequencing. LPS levels in HDM stocks used for preclinical asthma research in mice remain poorly reported. In 2019, only 14% of papers specified LPS concentration in HDM lots. Specific differences existed in airway responsiveness between mice challenged with HHDM or LHDM. HHDM- and LHDM-induced cytokine profiles of bronchial lavage were significantly different and the lung transcriptome was differentially enriched for genes involved in DNA damage repair or cilium movement, following HHDM or LHDM challenge, respectively. The abundance of LPS in commercially available HDM influences the phenotype of allergic airways inflammation in mice. Failure to report the level of LPS in HDM extracts used in animal models of airway disease will lead to inconsistency in reproducibility and reliability of published data. [ABSTRACT FROM AUTHOR]
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- 2020
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20. Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma
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Jha, Aruni, primary, Ryu, Min H, additional, OO, Ojo, additional, Bews, Hilary J, additional, Carlson, Jules C, additional, Schwartz, Jacquie, additional, Basu, Sujata, additional, Wong, Charles S, additional, and Halayko, Andrew J, additional
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- 2018
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21. Tumor necrosis factor regulates NMDA receptor-mediated airway smooth muscle contractile function and airway responsiveness
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Anaparti, Vidyanand, primary, Pascoe, Christopher D., additional, Jha, Aruni, additional, Mahood, Thomas H., additional, Ilarraza, Ramses, additional, Unruh, Helmut, additional, Moqbel, Redwan, additional, and Halayko, Andrew J., additional
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- 2016
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22. High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells
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Ojo, Oluwaseun O., primary, Ryu, Min Hyung, additional, Jha, Aruni, additional, Unruh, Helmut, additional, and Halayko, Andrew J., additional
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- 2015
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23. LSC Abstract – High mobility group box 1 modulates lung innate immunity by promoting wound healing and cytokine release in human bronchial epithelial cells
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Ojo, Oluwaseun, primary, Ryu, Min Hyung, additional, Stelmack, Gerald, additional, Jha, Aruni, additional, Schwartz, Jacquie, additional, and Halayko, Andrew, additional
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- 2015
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24. Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation
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Ryu, Min H., primary, Jha, Aruni, additional, Ojo, Oluwaseun O., additional, Mahood, Thomas H., additional, Basu, Sujata, additional, Detillieux, Karen A., additional, Nikoobakht, Neda, additional, Wong, Charles S., additional, Loewen, Mark, additional, Becker, Allan B., additional, and Halayko, Andrew J., additional
- Published
- 2014
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- View/download PDF
25. Airway mesenchymal cell death by mevalonate cascade inhibition: Integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins
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Ghavami, Saeid, primary, Sharma, Pawan, additional, Yeganeh, Behzad, additional, Ojo, Oluwaseun O., additional, Jha, Aruni, additional, Mutawe, Mark M., additional, Kashani, Hessam H., additional, Los, Marek J., additional, Klonisch, Thomas, additional, Unruh, Helmut, additional, and Halayko, Andrew J., additional
- Published
- 2014
- Full Text
- View/download PDF
26. Prophylactic Benefit Of Simvastatin On Allergic Airway Inflammation And Hyper-Responsiveness In Mice
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Jha, Aruni, primary, Basu, Sujata, additional, Bews, Hilary, additional, Carlson, Jules C., additional, Wong, Charles, additional, and Halayko, Andrew J., additional
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- 2012
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27. Characterization of the dystrophin-glycoprotein complex in airway smooth muscle: role of δ-sarcoglycan in airway responsiveness1.
- Author
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Sharma, Pawan, Jha, Aruni, Stelmack, Gerald L., Detillieux, Karen, Basu, Sujata, Klonisch, Thomas, Unruh, Helmut, and Halayko, Andrew J.
- Subjects
- *
DYSTROPHIN , *GLYCOPROTEINS , *SMOOTH muscle , *SARCOGLYCANS , *AIRWAY (Anatomy) , *CAVEOLINS - Abstract
The dystrophin-glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether δ-sarcoglycan (δ-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in δ-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in δ-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and β-dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in δ-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
28. A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?1.
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Jha, Aruni, Sharma, Pawan, Anaparti, Vidyanand, Ryu, Min H., and Halayko, Andrew J.
- Subjects
- *
TRP channels , *ANKYRINS , *AIRWAY (Anatomy) , *SMOOTH muscle contraction , *OBSTRUCTIVE lung diseases , *INFLAMMATION - Abstract
Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of Ca2+. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and Ca2+ mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
29. Characterization of the dystrophin-glycoprotein complex in airway smooth muscle: role of δ-sarcoglycan in airway responsiveness1.
- Author
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Sharma, Pawan, Jha, Aruni, Stelmack, Gerald L., Detillieux, Karen, Basu, Sujata, Klonisch, Thomas, Unruh, Helmut, and Halayko, Andrew J.
- Subjects
DYSTROPHIN ,GLYCOPROTEINS ,SMOOTH muscle ,SARCOGLYCANS ,AIRWAY (Anatomy) ,CAVEOLINS - Abstract
Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2015
- Full Text
- View/download PDF
30. A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?1.
- Author
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Jha, Aruni, Sharma, Pawan, Anaparti, Vidyanand, Ryu, Min H., and Halayko, Andrew J.
- Subjects
TRP channels ,ANKYRINS ,AIRWAY (Anatomy) ,SMOOTH muscle contraction ,OBSTRUCTIVE lung diseases ,INFLAMMATION - Abstract
Copyright of Canadian Journal of Physiology & Pharmacology is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2015
- Full Text
- View/download PDF
31. Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation.
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Min H. Ryu, Jha, Aruni, Ojo, Oluwaseun O., Mahood, Thomas H., Basu, Sujata, Detillieux, Karen A., Nikoobakht, Neda, Wong, Charles S., Loewen, Mark, Becker, Allan B., and Halayko, Andrew J.
- Subjects
- *
ASTHMA , *EPIDEMIOLOGICAL research , *DISEASE susceptibility , *PERFLUOROOCTANOIC acid , *OVALBUMINS - Abstract
Emerging epidemiological evidence reveals a link between lung disease and exposure to indoor pollutants such as perfluorinated compounds (PFCs). PFC exposure during critical developmental stages may increase asthma susceptibility. Thus, in a murine model, we tested the hypothesis that early life and continued exposure to two ubiquitous household PFCs, perfluorooctanoic acid (PFOA) and perflurooctanesulfonic acid (PFOS), can induce lung dysfunction that exacerbates allergen-induced airway hyperresponsiveness (AHR) and inflammation. Balb/c mice were exposed to PFOA or PFOS (4 mg/kg chow) from gestation day 2 to 12 wk of age by feeding pregnant and nursing dams, and weaned pups. Some pups were also sensitized and challenged with ovalbumin (OVA). We assessed lung function and inflammatory cell and cytokine expression in the lung and examined bronchial goblet cell number. PFOA, but not PFOS, without the OVA sensitization/challenge induced AHR concomitant with a 25-fold increase of lung macrophages. PFOA exposure did not affect OVA-induced lung inflammatory cell number. In contrast, PFOS exposure inhibited OVA-induced lung inflammation, decreasing total cell number in lung lavage by 68.7%. Interferon-γ mRNA in the lung was elevated in all PFC-exposed groups. Despite these effects, neither PFOA nor PFOS affected OVA-induced AHR. Our data do not reveal PFOA or PFOS exposure as a risk factor for more severe allergic asthma-like symptoms, but PFOA alone can induce airway inflammation and alter airway function. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
32. Maternal diabetes promotes offspring lung dysfunction and inflammation in a sex-dependent manner.
- Author
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Pascoe CD, Basu S, Schwartz J, Fonseca M, Kahnamoui S, Jha A, Dolinsky V, and Halayko AJ
- Subjects
- Animals, Diet, High-Fat adverse effects, Female, Humans, Inflammation, Lung, Male, Mice, Pregnancy, Diabetes, Gestational chemically induced, Prenatal Exposure Delayed Effects
- Abstract
Exposure to maternal diabetes is increasingly recognized as a risk factor for chronic respiratory disease in children. It is currently unclear; however, whether maternal diabetes affects the lung health of male and female offspring equally. This study characterizes the sex-specific impact of a murine model of diet-induced gestational diabetes (GDM) on offspring lung function and airway inflammation. Female adult mice are fed a high-fat (45% kcal) diet for 6 wk prior to mating. Control offspring are from mothers fed a low-fat (10% kcal) diet. Offspring were weaned and fed a chow diet until 10 wk of age, at which point lung function was measured and lung lavage was collected. Male, but not female, offspring exposed to GDM had increased lung compliance and reduced lung resistance at baseline. Female offspring exposed to GDM displayed increased methacholine reactivity and elevated levels of proinflammatory cytokines [e.g., interleukin (IL)-1β, IL-5, and CXCL1] in lung lavage. Female GDM offspring also displayed elevated abundance of matrix metalloproteinases (MMP) within their airways, namely, MMP-3 and MMP-8. These results indicate disparate effects of maternal diabetes on lung health and airway inflammation of male and female offspring exposed to GDM. Female mice may be at greater risk of inflammatory lung conditions, such as asthma, whereas male offspring display changes that more closely align with models of chronic obstructive pulmonary disease. In conclusion, there are important sex-based differences in the impact of maternal diabetes on offspring lung health that could signal differences in future disease risk.
- Published
- 2022
- Full Text
- View/download PDF
33. Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction.
- Author
-
Pascoe CD, Jha A, Ryu MH, Ragheb M, Vaghasiya J, Basu S, Stelmack GL, Srinathan S, Kidane B, Kindrachuk J, O'Byrne PM, Gauvreau GM, Ravandi A, Carlsten C, and Halayko AJ
- Subjects
- Administration, Inhalation, Animals, Humans, Methacholine Chloride, Mice, Phosphatidylcholines, Allergens, Asthma
- Abstract
Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor and the production of oxylipins via protein kinase C-dependent pathways.Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma., Competing Interests: Conflict of interest: C.D. Pascoe has nothing to disclose. Conflict of interest: A. Jha has nothing to disclose. Conflict of interest: M.H. Ryu has nothing to disclose. Conflict of interest: M. Ragheb has nothing to disclose. Conflict of interest: J. Vaghasiya has nothing to disclose. Conflict of interest: S. Basu has nothing to disclose. Conflict of interest: G.L. Stelmack has nothing to disclose. Conflict of interest: S. Srinathan has nothing to disclose. Conflict of interest: B. Kidane has nothing to disclose. Conflict of interest: J. Kindrachuk has nothing to disclose. Conflict of interest: P.M. O'Byrne has received consulting and/or speakers fees from AstraZeneca, GSK, Chiesi and Meranari, and grants in aid from AstraZeneca, Medimmune, GSK, Novartis and Merck, outside the submitted work. Conflict of interest: G.M. Gauvreau has nothing to disclose. Conflict of interest: A. Ravandi has nothing to disclose. Conflict of interest: C. Carlsten has nothing to disclose. Conflict of interest: A.J. Halayko has nothing to disclose., (Copyright ©ERS 2021.)
- Published
- 2021
- Full Text
- View/download PDF
34. Can circular RNAs be used as prenatal biomarkers for congenital diaphragmatic hernia?
- Author
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Wagner R, Jha A, Ayoub L, Kahnamoui S, Patel D, Mahood TH, Halayko AJ, Lacher M, Pascoe CD, and Keijzer R
- Subjects
- Biomarkers, Female, Humans, Pregnancy, RNA, Circular, Hernias, Diaphragmatic, Congenital diagnostic imaging, Hernias, Diaphragmatic, Congenital genetics
- Abstract
Competing Interests: Conflict of interest: R. Wagner has nothing to disclose. Conflict of interest: A. Jha has nothing to disclose. Conflict of interest: L. Ayoub has nothing to disclose. Conflict of interest: S. Kahnamoui has nothing to disclose. Conflict of interest: D. Patel has nothing to disclose. Conflict of interest: T.H. Mahood has nothing to disclose Conflict of interest: A.J. Halayko has nothing to disclose. Conflict of interest: M. Lacher has nothing to disclose. Conflict of interest: C.D. Pascoe has nothing to disclose. Conflict of interest: R. Keijzer has nothing to disclose.
- Published
- 2020
- Full Text
- View/download PDF
35. Tumor necrosis factor regulates NMDA receptor-mediated airway smooth muscle contractile function and airway responsiveness.
- Author
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Anaparti V, Pascoe CD, Jha A, Mahood TH, Ilarraza R, Unruh H, Moqbel R, and Halayko AJ
- Subjects
- Animals, Bronchi physiology, Bronchoconstriction, Calcium Signaling, Cells, Cultured, Gene Expression, Humans, Mice, Inbred BALB C, Muscle Contraction, Protein Subunits genetics, Protein Subunits metabolism, Receptors, N-Methyl-D-Aspartate genetics, Transcriptional Activation, Muscle, Smooth physiology, Receptors, N-Methyl-D-Aspartate metabolism, Tumor Necrosis Factor-alpha physiology
- Abstract
We have shown that N-methyl-d-aspartate receptors (NMDA-Rs) are receptor-operated calcium entry channels in human airway smooth muscle (HASM) during contraction. Tumor necrosis factor (TNF) augments smooth muscle contractility by influencing pathways that regulate intracellular calcium flux and can alter NMDA-R expression and activity in cortical neurons and glial cells. We hypothesized that NMDA-R-mediated Ca(2+) and contractile responses of ASM can be altered by inflammatory mediators, including TNF. In cultured HASM cells, we assessed TNF (10 ng/ml, 48 h) effect on NMDA-R subunit abundance by quantitative PCR, confocal imaging, and immunoblotting. We observed dose- and time-dependent changes in NMDA-R composition: increased obligatory NR1 subunit expression and altered regulatory NR2 and inhibitory NR3 subunits. Measuring intracellular Ca(2+) flux in Fura-2-loaded HASM cultures, we observed that TNF exposure enhanced cytosolic Ca(2+) mobilization and changed the temporal pattern of Ca(2+) flux in individual myocytes induced by NMDA, an NMDA-R selective analog of glutamate. We measured airway responses to NMDA in murine thin-cut lung slices (TCLS) from allergen-naive animals and observed significant airway contraction. However, NMDA acted as a bronchodilator in TCLS from house dust mice-challenged mice and in allergen-naive TCLS subjected to TNF exposure. All contractile or bronchodilator responses were blocked by a selective NMDA-R antagonist, (2R)-amino-5-phosphonopentanoate, and bronchodilator responses were prevented by N(G)-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) or indomethacin (cyclooxygenase inhibitor). Collectively, we show that TNF augments NMDA-R-mediated Ca(2+) mobilization in HASM cells, whereas in multicellular TCLSs allergic inflammation and TNF exposure leads to NMDA-R-mediated bronchodilation. These findings reveal the unique contribution of ionotrophic NMDA-R to airway hyperreactivity., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
- Full Text
- View/download PDF
36. High-mobility group box 1 promotes extracellular matrix synthesis and wound repair in human bronchial epithelial cells.
- Author
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Ojo OO, Ryu MH, Jha A, Unruh H, and Halayko AJ
- Subjects
- Aged, Animals, Cell Line, Extracellular Matrix Proteins metabolism, Humans, Mice, Inbred BALB C, Mitogen-Activated Protein Kinases metabolism, Models, Biological, Protein Biosynthesis, Pulmonary Disease, Chronic Obstructive pathology, Receptor for Advanced Glycation End Products metabolism, Smad2 Protein metabolism, Tissue Donors, Toll-Like Receptor 4 metabolism, Bronchi pathology, Epithelial Cells metabolism, Extracellular Matrix metabolism, HMGB1 Protein metabolism, Wound Healing
- Abstract
High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) protein that binds Toll-like receptors (e.g., TLR4) and the receptor for advanced glycated end products (RAGE). The direct effects of HMGB1 on airway structural cells are not fully known. As epithelial cell responses are fundamental drivers of asthma, including abnormal repair-restitution linked to changes in extracellular matrix (ECM) synthesis, we tested the hypothesis that HMGB1 promotes bronchial epithelial cell wound repair via TLR4 and/or RAGE signaling that regulates ECM (fibronectin and the γ2-chain of laminin-5) and integrin protein abundance. To assess impact of HMGB1 we used molecular and pharmacological inhibitors of RAGE or TLR4 signaling in scratch wound, immunofluorescence, and immunoblotting assays to assess wound repair, ECM synthesis, and phosphorylation of intracellular signaling. HMGB1 increased wound closure, and this effect was attenuated by blocking RAGE and TLR4 signaling. HMGB1-induced fibronectin and laminin-5 (γ2 chain) was diminished by blocking RAGE and/or blunting TLR4 signaling. Similarly, induction of α3-integrin receptor for fibronectin and laminin-5 was also diminished by blocking TLR4 signaling and RAGE. Lastly, rapid and/or sustained phosphorylation of SMAD2, ERK1/2, and JNK signaling modulated HMGB1-induced wound closure. Our findings suggest a role for HMGB1 in human airway epithelial cell repair and restitution via multiple pathways mediated by TLR4 and RAGE that underpin increased ECM synthesis and modulation of cell-matrix adhesion., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
37. Chronic exposure to perfluorinated compounds: Impact on airway hyperresponsiveness and inflammation.
- Author
-
Ryu MH, Jha A, Ojo OO, Mahood TH, Basu S, Detillieux KA, Nikoobakht N, Wong CS, Loewen M, Becker AB, and Halayko AJ
- Subjects
- Animals, Asthma chemically induced, Asthma pathology, Female, Goblet Cells pathology, Interferon-gamma immunology, Lung pathology, Mice, Mice, Inbred BALB C, Pregnancy, Air Pollutants toxicity, Alkanesulfonic Acids toxicity, Asthma immunology, Caprylates toxicity, Fluorocarbons toxicity, Goblet Cells immunology, Lung immunology, Maternal Exposure adverse effects
- Abstract
Emerging epidemiological evidence reveals a link between lung disease and exposure to indoor pollutants such as perfluorinated compounds (PFCs). PFC exposure during critical developmental stages may increase asthma susceptibility. Thus, in a murine model, we tested the hypothesis that early life and continued exposure to two ubiquitous household PFCs, perfluorooctanoic acid (PFOA) and perflurooctanesulfonic acid (PFOS), can induce lung dysfunction that exacerbates allergen-induced airway hyperresponsiveness (AHR) and inflammation. Balb/c mice were exposed to PFOA or PFOS (4 mg/kg chow) from gestation day 2 to 12 wk of age by feeding pregnant and nursing dams, and weaned pups. Some pups were also sensitized and challenged with ovalbumin (OVA). We assessed lung function and inflammatory cell and cytokine expression in the lung and examined bronchial goblet cell number. PFOA, but not PFOS, without the OVA sensitization/challenge induced AHR concomitant with a 25-fold increase of lung macrophages. PFOA exposure did not affect OVA-induced lung inflammatory cell number. In contrast, PFOS exposure inhibited OVA-induced lung inflammation, decreasing total cell number in lung lavage by 68.7%. Interferon-γ mRNA in the lung was elevated in all PFC-exposed groups. Despite these effects, neither PFOA nor PFOS affected OVA-induced AHR. Our data do not reveal PFOA or PFOS exposure as a risk factor for more severe allergic asthma-like symptoms, but PFOA alone can induce airway inflammation and alter airway function., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
- Full Text
- View/download PDF
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