38 results on '"Radicioni, Giorgia"'
Search Results
2. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort
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Radicioni, Giorgia, Ceppe, Agathe, Ford, Amina A, Alexis, Neil E, Barr, R Graham, Bleecker, Eugene R, Christenson, Stephanie A, Cooper, Christopher B, Han, MeiLan K, Hansel, Nadia N, Hastie, Annette T, Hoffman, Eric A, Kanner, Richard E, Martinez, Fernando J, Ozkan, Esin, Paine, Robert, III, Woodruff, Prescott G, O'Neal, Wanda K, Boucher, Richard C, and Kesimer, Mehmet
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- 2021
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3. Airway Mucin Concentration as a Marker of Chronic Bronchitis
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Kesimer, Mehmet, Ford, Amina A, Ceppe, Agathe, Radicioni, Giorgia, Cao, Rui, Davis, C William, Doerschuk, Claire M, Alexis, Neil E, Anderson, Wayne H, Henderson, Ashley G, Barr, R Graham, Bleecker, Eugene R, Christenson, Stephanie A, Cooper, Christopher B, Han, MeiLan K, Hansel, Nadia N, Hastie, Annette T, Hoffman, Eric A, Kanner, Richard E, Martinez, Fernando, Paine, Robert, Woodruff, Prescott G, O'Neal, Wanda K, and Boucher, Richard C
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Clinical Research ,Lung ,Cystic Fibrosis ,Chronic Obstructive Pulmonary Disease ,Rare Diseases ,Respiratory ,Good Health and Well Being ,Aged ,Analysis of Variance ,Asthma ,Biomarkers ,Bronchitis ,Chronic ,Disease Progression ,Female ,Humans ,Male ,Mass Spectrometry ,Middle Aged ,Mucin 5AC ,Mucin-5B ,Mucins ,Pulmonary Disease ,Chronic Obstructive ,ROC Curve ,Respiratory System ,Smoking ,Sputum ,Surveys and Questionnaires ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis.MethodsWe characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort.ResultsMean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort.ConclusionsAirway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.).
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- 2017
4. Proximal and Distal Bronchioles Contribute to the Pathogenesis of Non-Cystic Fibrosis Bronchiectasis (NCFB)
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Asakura, Takanori, primary, Okuda, Kenichi, additional, Chen, Gang, additional, Dang, Hong, additional, Kato, Takafumi, additional, Mikami, Yu, additional, Schworer, Stephen A, additional, Gilmore, Rodney C, additional, Radicioni, Giorgia, additional, Hawkins, Padraig, additional, Barbosa Cardenas, Selene Margarita, additional, Saito, Minako, additional, Cawley, Anne Marie, additional, De la Cruz, Gabriela, additional, Chua, Michael, additional, Alexis, Neil E., additional, Masugi, Yohei, additional, Noone, Peadar G, additional, Ribeiro, Carla M P, additional, Kesimer, Mehmet, additional, Olivier, Kenneth N., additional, Hasegawa, Naoki, additional, Randell, Scott H, additional, O'Neal, Wanda K, additional, and Boucher, Richard C, additional
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- 2023
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5. Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease
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Singanayagam, Aran, Footitt, Joseph, Marczynski, Matthias, Radicioni, Giorgia, Cross, Michael T., Finney, Lydia J., Trujillo-Torralbo, Maria-Belen, Calderazzo, Maria, Zhu, Jie, Aniscenko, Julia, Clarke, Thomas B., Molyneaux, Philip L., Bartlett, Nathan W., Moffatt, Miriam F., Cookson, William O., Wedzicha, Jadwiga, Evans, Christopher M., Boucher, Richard C., Kesimer, Mehmet, Lieleg, Oliver, Mallia, Patrick, and Johnston, Sebastian L.
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Lung diseases, Obstructive -- Development and progression -- Complications and side effects ,Mucins -- Health aspects -- Physiological aspects ,Airway (Medicine) -- Health aspects -- Physiological aspects ,Virus diseases -- Complications and side effects ,Health care industry - Abstract
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac-/) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations., Introduction Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disorder punctuated by acute exacerbations that are frequently precipitated by rhinoviruses (RVs) (1, 2). Exacerbations are the major cause of [...]
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- 2022
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6. Proximal and Distal Bronchioles Contribute to the Pathogenesis of Non–Cystic Fibrosis Bronchiectasis.
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Asakura, Takanori, Okuda, Kenichi, Chen, Gang, Dang, Hong, Kato, Takafumi, Mikami, Yu, Schworer, Stephen A., Gilmore, Rodney C., Radicioni, Giorgia, Hawkins, Padraig, Barbosa Cardenas, Selene Margarita, Saito, Minako, Cawley, Anne Marie, De la Cruz, Gabriela, Chua, Michael, Alexis, Neil E., Masugi, Yohei, Noone, Peadar G., Ribeiro, Carla M. P., and Kesimer, Mehmet
- Abstract
Rationale: Non–cystic fibrosis bronchiectasis (NCFB) may originate in bronchiolar regions of the lung. Accordingly, there is a need to characterize the morphology and molecular characteristics of NCFB bronchioles. Objectives: Test the hypothesis that NCFB exhibits a major component of bronchiolar disease manifest by mucus plugging and ectasia. Methods: Morphologic criteria and region-specific epithelial gene expression, measured histologically and by RNA in situ hybridization and immunohistochemistry, identified proximal and distal bronchioles in excised NCFB lungs. RNA in situ hybridization and immunohistochemistry assessed bronchiolar mucus accumulation and mucin gene expression. CRISPR-Cas9–mediated IL-1R1 knockout in human bronchial epithelial cultures tested IL-1α and IL-1β contributions to mucin production. Spatial transcriptional profiling characterized NCFB distal bronchiolar gene expression. Measurements and Main Results: Bronchiolar perimeters and lumen areas per section area were increased in proximal, but not distal, bronchioles in NCFB versus control lungs, suggesting proximal bronchiolectasis. In NCFB, mucus plugging was observed in ectatic proximal bronchioles and associated nonectatic distal bronchioles in sections with disease. MUC5AC and MUC5B mucins were upregulated in NCFB proximal bronchioles, whereas MUC5B was selectively upregulated in distal bronchioles. Bronchiolar mucus plugs were populated by IL-1β–expressing macrophages. NCFB sterile sputum supernatants induced human bronchial epithelial MUC5B and MUC5AC expression that was >80% blocked by IL-1R1 ablation. Spatial transcriptional profiling identified upregulation of genes associated with secretory cells, hypoxia, interleukin pathways, and IL-1β–producing macrophages in mucus plugs and downregulation of epithelial ciliogenesis genes. Conclusions: NCFB exhibits distinctive proximal and distal bronchiolar disease. Both bronchiolar regions exhibit bronchiolar secretory cell features and mucus plugging but differ in mucin gene regulation and ectasia. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes
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Van Buren, Eric, primary, Radicioni, Giorgia, additional, Lester, Sarah, additional, O’Neal, Wanda K., additional, Dang, Hong, additional, Kasela, Silva, additional, Garudadri, Suresh, additional, Curtis, Jeffrey L., additional, Han, MeiLan K., additional, Krishnan, Jerry A., additional, Wan, Emily S., additional, Silverman, Edwin K., additional, Hastie, Annette, additional, Ortega, Victor E., additional, Lappalainen, Tuuli, additional, Nawijn, Martijn C., additional, Berge, Maarten van den, additional, Christenson, Stephanie A., additional, Li, Yun, additional, Cho, Michael H., additional, Kesimer, Mehmet, additional, and Kelada, Samir N. P., additional
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- 2023
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8. Characterization of the cell penetrating properties of a human salivary proline-rich peptide
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Radicioni, Giorgia, Stringaro, Annarita, Molinari, Agnese, Nocca, Giuseppina, Longhi, Renato, Pirolli, Davide, Scarano, Emanuele, Iavarone, Federica, Manconi, Barbara, Cabras, Tiziana, Messana, Irene, Castagnola, Massimo, and Vitali, Alberto
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- 2015
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9. Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes
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Dang, Hong, Christenson, Stephanie A., Garudadri, Suresh, Nawijn, Martijn C., Berge, Maarten van den, Li, Yun, Curtis, Jeffrey L., Silverman, Edwin K., Hastie, Annette, Kasela, Silva, Cho, Michael H., Ortega, Victor E., Lappalainen, Tuuli, Krishnan, Jerry A., Wan, Emily S., Kesimer, Mehmet, Kelada, Samir N. P., Van Buren, Eric, Radicioni, Giorgia, Lester, Sarah, O’Neal, Wanda K., and Han, MeiLan K.
- Abstract
Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822–1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10–1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02–1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.
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- 2023
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10. Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia
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Abdullah, Lubna H., Coakley, Raymond, Webster, Megan J., Zhu, Yunxiang, Tarran, Robert, Radicioni, Giorgia, Kesimer, Mehmet, Boucher, Richard C., Davis, William C., and Ribeiro, Carla M. P.
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- 2018
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11. E-Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin Secretion
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Reidel, Boris, Radicioni, Giorgia, Clapp, Phillip W., Ford, Amina A., Abdelwahab, Sabri, Rebuli, Meghan E., Haridass, Prashamsha, Alexis, Neil E., Jaspers, Ilona, and Kesimer, Mehmet
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- 2018
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12. Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes
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Van Buren, Eric, primary, Radicioni, Giorgia, additional, Lester, Sarah, additional, O’Neal, Wanda K., additional, Dang, Hong, additional, Kasela, Silva, additional, Garudadri, Suresh, additional, Curtis, Jeffrey L., additional, Han, Meilan, additional, Krishnan, Jerry A., additional, Wan, Emily S., additional, Silverman, Edwin K., additional, Hastie, Annette, additional, Ortega, Victor E., additional, Lappalainen, Tuuli, additional, Christenson, Stephanie A., additional, Li, Yun, additional, Cho, Michael H., additional, Kesimer, Mehmet, additional, and Kelada, Samir N. P., additional
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- 2022
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13. Cystic Fibrosis Airway Mucus Hyperconcentration Produces a Vicious Cycle of Mucin, Pathogen, and Inflammatory Interactions that Promotes Disease Persistence
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Batson, Bethany D., primary, Zorn, Bryan T., additional, Radicioni, Giorgia, additional, Livengood, Stephanie S., additional, Kumagai, Tadahiro, additional, Dang, Hong, additional, Ceppe, Agathe, additional, Clapp, Phillip W., additional, Tunney, Michael, additional, Elborn, J. Stuart, additional, McElvaney, Noel G., additional, Muhlebach, Marianne S., additional, Boucher, Richard C., additional, Tiemeyer, Michael, additional, Wolfgang, Matthew C., additional, and Kesimer, Mehmet, additional
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- 2022
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14. Structural and functional studies on a proline-rich peptide isolated from swine saliva endowed with antifungal activity towards Cryptococcus neoformans
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Conti, Stefania, Radicioni, Giorgia, Ciociola, Tecla, Longhi, Renato, Polonelli, Luciano, Gatti, Rita, Cabras, Tiziana, Messana, Irene, Castagnola, Massimo, and Vitali, Alberto
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- 2013
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15. Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B
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Costain, Gregory, Liu, Zhen, Mennella, Vito, Radicioni, Giorgia, Goczi, Adrienn N, Albulescu, Alexandra, Walker, Susan, Ngan, Bo, Manson, David, Vali, Reza, Khan, Meraj, Palaniyar, Nades, Hill, David B., Hall, David A., Marshall, Christian R., Knowles, Michael, Zariwala, Maimoona A., Kesimer, Mehmet, Dell, Sharon D., Costain, Gregory, Liu, Zhen, Mennella, Vito, Radicioni, Giorgia, Goczi, Adrienn N, Albulescu, Alexandra, Walker, Susan, Ngan, Bo, Manson, David, Vali, Reza, Khan, Meraj, Palaniyar, Nades, Hill, David B., Hall, David A., Marshall, Christian R., Knowles, Michael, Zariwala, Maimoona A., Kesimer, Mehmet, and Dell, Sharon D.
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Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.
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- 2022
16. Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes.
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Buren, Eric Van, Radicioni, Giorgia, Lester, Sarah, O'Neal, Wanda K., Dang, Hong, Kasela, Silva, Garudadri, Suresh, Curtis, Jeffrey L., Han, MeiLan K., Krishnan, Jerry A., Wan, Emily S., Silverman, Edwin K., Hastie, Annette, Ortega, Victor E., Lappalainen, Tuuli, Nawijn, Martijn C., Berge, Maarten van den, Christenson, Stephanie A., Li, Yun, and Cho, Michael H.
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MUCUS , *OBSTRUCTIVE lung diseases , *CHRONIC obstructive pulmonary disease , *LOCUS (Genetics) , *SPUTUM , *MUCINS , *PHENOTYPES , *SINGLE nucleotide polymorphisms - Abstract
Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822–1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10–1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02–1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB. Author summary: Chronic obstructive pulmonary disease (COPD) is characterized by presence of emphysema and/or chronic bronchitis. Excessive mucus production is a defining phenotype of chronic bronchitis, and is associated with several important features of COPD, including exacerbations and loss of lung function. Recent studies have demonstrated that the amount of mucus produced in COPD patients is an important marker of disease state. We investigated whether common genetic variants are associated with the concentration of two key proteins in mucus, MUC5AC and MUC5B, and whether the variants we identified are also associated with COPD outcomes. We identified multiple genetic variants that were associated with MUC5AC or MUC5B concentration. The strongest association we detected, for MUC5B on chromosome 11, was also associated with features of COPD, including chronic bronchitis and acute exacerbations, in one COPD study population but not another. Results from a much larger study, the UK Biobank, indicate that this variant is associated with chronic mucus production and chronic cough, which are key features of chronic bronchitis. Thus, we conclude that the concentration of key proteins in mucus are influenced by genetic variation, and that a variant on chromosome 11 that affects MUC5B may in turn alter COPD outcomes. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B
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Costain, Gregory, primary, Liu, Zhen, additional, Mennella, Vito, additional, Radicioni, Giorgia, additional, Goczi, Adrienn N., additional, Albulescu, Alexandra, additional, Walker, Susan, additional, Ngan, Bo, additional, Manson, David, additional, Vali, Reza, additional, Khan, Meraj, additional, Palaniyar, Nades, additional, Hill, David B., additional, Hall, David A., additional, Marshall, Christian R., additional, Knowles, Michael, additional, Zariwala, Maimoona A., additional, Kesimer, Mehmet, additional, and Dell, Sharon D., additional
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- 2022
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18. Mucus concentration–dependent biophysical abnormalities unify submucosal gland and superficial airway dysfunction in cystic fibrosis
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Kato, Takafumi, primary, Radicioni, Giorgia, additional, Papanikolas, Micah J., additional, Stoychev, Georgi V., additional, Markovetz, Matthew R., additional, Aoki, Kazuhiro, additional, Porterfield, Melody, additional, Okuda, Kenichi, additional, Barbosa Cardenas, Selene M., additional, Gilmore, Rodney C., additional, Morrison, Cameron B., additional, Ehre, Camille, additional, Burns, Kimberlie A., additional, White, Kristen K., additional, Brennan, Tara A., additional, Goodell, Henry P., additional, Thacker, Holly, additional, Loznev, Henry T., additional, Forsberg, Lawrence J., additional, Nagase, Takahide, additional, Rubinstein, Michael, additional, Randell, Scott H., additional, Tiemeyer, Michael, additional, Hill, David B., additional, Kesimer, Mehmet, additional, O’Neal, Wanda K., additional, Ballard, Stephen T., additional, Freeman, Ronit, additional, Button, Brian, additional, and Boucher, Richard C., additional
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- 2022
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19. Hyperconcentrated Mucus Unifies Submucosal Gland and Superficial Airway Dysfunction in Cystic Fibrosis
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Kato, Takafumi, primary, Radicioni, Giorgia, additional, Papanikolas, Micah J, additional, Stoychev, Georgi V, additional, Markovetz, Matthew R, additional, Aoki, Kazuhiro, additional, Porterfield, Mindy, additional, Okuda, Kenichi, additional, Cardenas, Selene M Barbosa, additional, Gilmore, Rodney C, additional, Morrison, Cameron B, additional, Ehre, Camille, additional, Burns, Kimberlie A, additional, White, Kristen K, additional, Goodell, Henry P, additional, Thacker, Holly, additional, Loznev, Henry T, additional, Forsberg, Lawrence J, additional, Nagase, Takahide, additional, Rubinstein, Michael, additional, Randell, Scott H, additional, Tiemeyer, Michael, additional, Hill, David B, additional, Kesimer, Mehmet, additional, O'Neal, Wanda K, additional, Ballard, Stephen T, additional, Freeman, Ronit, additional, Button, Brian, additional, and Boucher, Richard C, additional
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- 2021
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20. Airway Mucus Hyperconcentration in Non–Cystic Fibrosis Bronchiectasis
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Ramsey, Kathryn A., primary, Chen, Alice C. H., additional, Radicioni, Giorgia, additional, Lourie, Rohan, additional, Martin, Megan, additional, Broomfield, Amy, additional, Sheng, Yong H., additional, Hasnain, Sumaira Z., additional, Radford-Smith, Graham, additional, Simms, Lisa A., additional, Burr, Lucy, additional, Thornton, David J., additional, Bowler, Simon D., additional, Livengood, Stephanie, additional, Ceppe, Agathe, additional, Knowles, Michael R., additional, Noone, Peadar G., additional, Donaldson, Scott H., additional, Hill, David B., additional, Ehre, Camille, additional, Button, Brian, additional, Alexis, Neil E., additional, Kesimer, Mehmet, additional, Boucher, Richard C., additional, and McGuckin, Michael A., additional
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- 2020
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21. Endotracheal tube mucus as a source of airway mucus for rheological study
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Markovetz, Matthew R., primary, Subramani, Durai B., additional, Kissner, William J., additional, Morrison, Cameron B., additional, Garbarine, Ian C., additional, Ghio, Andrew, additional, Ramsey, Kathryn A., additional, Arora, Harendra, additional, Kumar, Priya, additional, Nix, David B., additional, Kumagai, Tadahiro, additional, Krunkosky, Thomas M., additional, Krause, Duncan C., additional, Radicioni, Giorgia, additional, Alexis, Neil E., additional, Kesimer, Mehmet, additional, Tiemeyer, Michael, additional, Boucher, Richard C., additional, Ehre, Camille, additional, and Hill, David B., additional
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- 2019
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22. Localization of Secretory Mucins MUC5AC and MUC5B in Normal/Healthy Human Airways
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Okuda, Kenichi, primary, Chen, Gang, additional, Subramani, Durai B., additional, Wolf, Monroe, additional, Gilmore, Rodney C., additional, Kato, Takafumi, additional, Radicioni, Giorgia, additional, Kesimer, Mehmet, additional, Chua, Michael, additional, Dang, Hong, additional, Livraghi-Butrico, Alessandra, additional, Ehre, Camille, additional, Doerschuk, Claire M., additional, Randell, Scott H., additional, Matsui, Hirotoshi, additional, Nagase, Takahide, additional, O’Neal, Wanda K., additional, and Boucher, Richard C., additional
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- 2019
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23. Intercellular Communication between Airway Epithelial Cells Is Mediated by Exosome-Like Vesicles
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Gupta, Richa, primary, Radicioni, Giorgia, additional, Abdelwahab, Sabri, additional, Dang, Hong, additional, Carpenter, Jerome, additional, Chua, Michael, additional, Mieczkowski, Piotr A., additional, Sheridan, John T., additional, Randell, Scott H., additional, and Kesimer, Mehmet, additional
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- 2019
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24. Airways mucus pathogenesis in patients with non-cystic fibrosis bronchiectasis
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Ramsey, Kathryn, primary, Radicioni, Giorgia, additional, Hill, David, additional, Ehre, Camille, additional, Button, Brian, additional, Alexis, Neil E, additional, Knowles, Michael, additional, Donaldson, Scott, additional, Kesimer, Mehmet, additional, Mcguckin, Michael, additional, and Boucher, Richard, additional
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- 2018
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25. Antagonistic Effect of a Salivary Proline-Rich Peptide on the Cytosolic Ca2+ Mobilization Induced by Progesterone in Oral Squamous Cancer Cells.
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Palmerini, Carlo Alberto, Mazzoni, Manuela, Radicioni, Giorgia, Marzano, Valeria, Granieri, Letizia, Iavarone, Federica, Longhi, R, Messana, Irene, Cabras, Tiziana, Sanna, Maria Teresa, Castagnola, Massimo, Vitali, Alberto, Iavarone, Federica (ORCID:0000-0002-2074-5531), Messana, Irene (ORCID:0000-0002-1436-6105), Cabras , Tiziana, Sanna , Maria Teresa, Castagnola, Massimo (ORCID:0000-0002-0959-7259), Palmerini, Carlo Alberto, Mazzoni, Manuela, Radicioni, Giorgia, Marzano, Valeria, Granieri, Letizia, Iavarone, Federica, Longhi, R, Messana, Irene, Cabras, Tiziana, Sanna, Maria Teresa, Castagnola, Massimo, Vitali, Alberto, Iavarone, Federica (ORCID:0000-0002-2074-5531), Messana, Irene (ORCID:0000-0002-1436-6105), Cabras , Tiziana, Sanna , Maria Teresa, and Castagnola, Massimo (ORCID:0000-0002-0959-7259)
- Abstract
A salivary proline-rich peptide of 1932 Da showed a dose-dependent antagonistic effect on the cytosolic Ca2+ mobilization induced by progesterone in a tongue squamous carcinoma cell line. Structure-activity studies showed that the activity of the peptide resides in the C-terminal region characterized by a proline stretch flanked by basic residues. Furthermore, lack of activity of the retro-inverso peptide analogue suggested the involvement of stereospecific recognition. Mass spectrometry-based shotgun analysis, combined with Western blotting tests and biochemical data obtained with the Progesterone Receptor Membrane Component 1 (PGRMC1) inhibitor AG205, showed strong evidence that p1932 performs its modulatory action through an interaction with the progesterone receptor PGRMC1, which is predominantly expressed in this cell line and, clearly, plays a role in progesterone induced Ca2+ response. Thus, our results point to p1932 as a modulator of the transduction signal pathway mediated by this protein and, given a well-established involvement of PGRMC1 in tumorigenesis, highlight a possible therapeutic potential of p1932 for the treatment of oral cancer.
- Published
- 2016
26. Structural studies and SH3 domain binding properties of a human antiviral salivary proline-rich peptide
- Author
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Righino, Benedetta, Pirolli, Davide, Radicioni, Giorgia, Marzano, Valeria, Longhi, Renato, Arcovito, Alessandro, Sanna, Maria Teresa, De Rosa, Maria Cristina, Paoluzi, Serena, Cesareni, Gianni, Messana, Irene, Castagnola, Massimo, Vitali, Alberto, Pirolli, Davide (ORCID:0000-0003-2303-2577), Arcovito, Alessandro (ORCID:0000-0002-8384-4844), Sanna , Maria Teresa, Messana, Irene (ORCID:0000-0002-1436-6105), Castagnola, Massimo (ORCID:0000-0002-0959-7259), Righino, Benedetta, Pirolli, Davide, Radicioni, Giorgia, Marzano, Valeria, Longhi, Renato, Arcovito, Alessandro, Sanna, Maria Teresa, De Rosa, Maria Cristina, Paoluzi, Serena, Cesareni, Gianni, Messana, Irene, Castagnola, Massimo, Vitali, Alberto, Pirolli, Davide (ORCID:0000-0003-2303-2577), Arcovito, Alessandro (ORCID:0000-0002-8384-4844), Sanna , Maria Teresa, Messana, Irene (ORCID:0000-0002-1436-6105), and Castagnola, Massimo (ORCID:0000-0002-0959-7259)
- Abstract
Human saliva contains hundreds of small proline-rich peptides originated by the proteolytic cleavage of the salivary basic Proline-Rich Proteins. Nevertheless only for few of them a specific biological activity has been assigned to date. Among them, the 1932 Da peptide (p1932) has been patented as an anti-HIV agent. In order to shed light on the possible mechanism of action of this peptide, we assessed in this study, by means of molecular dynamics calculations, circular dichroism and FTIR spectroscopic techniques, that p1932 has an intrinsic propensity to adopt a polyproline-II helix arrangement. This structural feature combined with the presence of PxxP motifs in its primary structure, represents an essential property for the exploitation of several biological activities. Next to these findings, we recently demonstrated the ability of this peptide to be internalized within cells of the oral mucosa, thus we focused onto a possible intracellular target, represented by the SH3 domains family. Its ability to interact with selected SH3 domains was finally assayed by Surface Plasmon Resonance spectroscopy. As a result, only Fyn, Hck and c-Src SH3 domains gave positive results in terms of interaction, showing dissociation constants ranging from nanomolar to micromolar values having the best performer a KD of 148 nM. It is noteworthy that all the interacting domains belong to the Src kinases family, suggesting a role for p1932 as a modulator of the signal transduction pathways mediated by these kinases.
- Published
- 2016
27. Allergic asthma is distinguished by sensitivity of allergen-specific CD4+T cells and airway structural cells to type 2 inflammation
- Author
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Cho, Josalyn L., primary, Ling, Morris F., additional, Adams, David C., additional, Faustino, Lucas, additional, Islam, Sabina A., additional, Afshar, Roshi, additional, Griffith, Jason W., additional, Harris, Robert S., additional, Ng, Aylwin, additional, Radicioni, Giorgia, additional, Ford, Amina A., additional, Han, Andre K., additional, Xavier, Ramnik, additional, Kwok, William W., additional, Boucher, Richard, additional, Moon, James J., additional, Hamilos, Daniel L., additional, Kesimer, Mehmet, additional, Suter, Melissa J., additional, Medoff, Benjamin D., additional, and Luster, Andrew D., additional
- Published
- 2016
- Full Text
- View/download PDF
28. Structural studies and SH3 domain binding properties of a human antiviral salivary proline-rich peptide
- Author
-
Righino, Benedetta, primary, Pirolli, Davide, additional, Radicioni, Giorgia, additional, Marzano, Valeria, additional, Longhi, Renato, additional, Arcovito, Alessandro, additional, Sanna, Maria Teresa, additional, De Rosa, Maria Cristina, additional, Paoluzi, Serena, additional, Cesareni, Gianni, additional, Messana, Irene, additional, Castagnola, Massimo, additional, and Vitali, Alberto, additional
- Published
- 2016
- Full Text
- View/download PDF
29. Antagonistic Effect of a Salivary Proline-Rich Peptide on the Cytosolic Ca2+ Mobilization Induced by Progesterone in Oral Squamous Cancer Cells
- Author
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Palmerini, Carlo Alberto, primary, Mazzoni, Michela, additional, Radicioni, Giorgia, additional, Marzano, Valeria, additional, Granieri, Letizia, additional, Iavarone, Federica, additional, Longhi, Renato, additional, Messana, Irene, additional, Cabras, Tiziana, additional, Sanna, Maria Teresa, additional, Castagnola, Massimo, additional, and Vitali, Alberto, additional
- Published
- 2016
- Full Text
- View/download PDF
30. Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs
- Author
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Kesimer, Mehmet, primary, Cullen, John, additional, Cao, Rui, additional, Radicioni, Giorgia, additional, Mathews, Kyle G., additional, Seiler, Gabriela, additional, and Gookin, Jody L., additional
- Published
- 2015
- Full Text
- View/download PDF
31. Airway Epithelial Derived Exosomes on Protecting and Remodeling of the Lung
- Author
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Abdelwahab, Sabri, primary, Gupta, Richa, additional, Radicioni, Giorgia, additional, Jones, Lisa, additional, Dang, Hong, additional, O'Neal, Wanda, additional, and Mehmet, Kesimer, additional
- Published
- 2015
- Full Text
- View/download PDF
32. Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.
- Author
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Cho, Josalyn L., Ling, Morris F., Adams, David C., Faustino, Lucas, Islam, Sabina A., Afshar, Roshi, Griffith, Jason W., Harris, Robert S., Aylwin Ng, Radicioni, Giorgia, Ford, Amina A., Han, Andre K., Xavier, Ramnik, Kwok, William W., Boucher, Richard, Moon, James J., Hamilos, Daniel L., Kesimer, Mehmet, Suter, Melissa J., and Medoff, Benjamin D.
- Subjects
AIRWAY (Anatomy) ,ASTHMA risk factors ,IMMUNE response ,ALLERGENS ,EPITHELIAL cells ,PHYSIOLOGY - Abstract
The article presents a study which examined the differences in airway immune response or airway structural cells during airborne allergen exposure to determine how asthma is developed in allergic individuals. Also cited are the use of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) in the study, and the factors affecting allergic asthma development including the increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.
- Published
- 2016
- Full Text
- View/download PDF
33. Antagonistic Effect of a Salivary Proline-Rich Peptide on the Cytosolic Ca2+ Mobilization Induced by Progesterone in Oral Squamous Cancer Cells.
- Author
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Palmerini, Carlo Alberto, Mazzoni, Michela, Radicioni, Giorgia, Marzano, Valeria, Granieri, Letizia, Iavarone, Federica, Longhi, Renato, Messana, Irene, Cabras, Tiziana, Sanna, Maria Teresa, Castagnola, Massimo, and Vitali, Alberto
- Subjects
SALIVARY glands ,PROLINE ,DRUG efficacy ,CYTOSOL ,PEPTIDES ,PROGESTERONE ,SQUAMOUS cell carcinoma ,PHYSIOLOGY - Abstract
A salivary proline-rich peptide of 1932 Da showed a dose-dependent antagonistic effect on the cytosolic Ca
2+ mobilization induced by progesterone in a tongue squamous carcinoma cell line. Structure-activity studies showed that the activity of the peptide resides in the C-terminal region characterized by a proline stretch flanked by basic residues. Furthermore, lack of activity of the retro-inverso peptide analogue suggested the involvement of stereospecific recognition. Mass spectrometry-based shotgun analysis, combined with Western blotting tests and biochemical data obtained with the Progesterone Receptor Membrane Component 1 (PGRMC1) inhibitor AG205, showed strong evidence that p1932 performs its modulatory action through an interaction with the progesterone receptor PGRMC1, which is predominantly expressed in this cell line and, clearly, plays a role in progesterone induced Ca2+ response. Thus, our results point to p1932 as a modulator of the transduction signal pathway mediated by this protein and, given a well-established involvement of PGRMC1 in tumorigenesis, highlight a possible therapeutic potential of p1932 for the treatment of oral cancer. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
34. Airway Mucin Concentration as a Marker of Chronic Bronchitis.
- Author
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O'Neal, Wanda K., Boucher, Richard C., Kesimer, Mehmet, Ford, Amina A., Ceppe, Agathe, Radicioni, Giorgia, Cao, Rui, Davis, C. William, Doerschuk, Claire M., Alexis, Neil E., Anderson, Wayne H., Henderson, Ashley G., Barr, R. Graham, Kanner, Richard E., Paine III, Robert, Martinez, Fernando, Bleecker, Eugene R., Hastie, Annette T., Christenson, Stephanie A., and Woodruff, Prescott G.
- Subjects
- *
AIRWAY (Anatomy) , *MUCINS , *CHRONIC bronchitis , *OBSTRUCTIVE lung diseases , *TUMOR markers - Abstract
Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentration of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in persons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis.Methods: We characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using questionnaires administered to participants, chest tomography, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and refractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitated by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an independent 94-participant cohort.Results: Mean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in participants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concentration and a diagnosis of chronic bronchitis yielded areas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort.Conclusions: Airway mucin concentrations may quantitate a key component of the chronic bronchitis pathophysiologic cascade that produces sputum and mediates disease severity. Studies designed to explore total mucin concentrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.). [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
35. Dysregulated Airway Host Defense in Hyper IgE Syndrome due to STAT3 Mutations.
- Author
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Sun L, Walls SA, Dang H, Quinney NL, Sears PR, Sadritabrizi T, Hasegawa K, Okuda K, Asakura T, Chang X, Zheng M, Mikami Y, Dizmond FU, Danilova D, Zhou L, Deshmukh A, Cholon DM, Radicioni G, Rogers TD, Kissner WJ, Markovetz MR, Guhr Lee TN, Gutay MI, Esther CR, Chua M, Grubb BR, Ehre C, Kesimer M, Hill DB, Ostrowski LE, Button B, Gentzsch M, Robinson C, Olivier KN, Freeman AF, Randell SH, O'Neal WK, Boucher RC, and Chen G
- Abstract
Rationale: Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense., Objectives: To identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection., Methods: STAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1β) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed., Measurements and Main Results: Mucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1β exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a γ-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells., Conclusions: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.
- Published
- 2024
- Full Text
- View/download PDF
36. Endotracheal tube mucus as a source of airway mucus for rheological study.
- Author
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Markovetz MR, Subramani DB, Kissner WJ, Morrison CB, Garbarine IC, Ghio A, Ramsey KA, Arora H, Kumar P, Nix DB, Kumagai T, Krunkosky TM, Krause DC, Radicioni G, Alexis NE, Kesimer M, Tiemeyer M, Boucher RC, Ehre C, and Hill DB
- Subjects
- Adult, Aged, Aged, 80 and over, Cations, Monovalent, Female, Healthy Volunteers, Humans, Intubation, Intratracheal, Male, Middle Aged, Polysaccharides classification, Polysaccharides isolation & purification, Potassium metabolism, Proteins classification, Proteins isolation & purification, Sodium metabolism, Sputum chemistry, Trachea physiology, Mucus chemistry, Potassium analysis, Rheology methods, Sodium analysis, Trachea chemistry
- Abstract
Muco-obstructive lung diseases (MOLDs), like cystic fibrosis and chronic obstructive pulmonary disease, affect a spectrum of subjects globally. In MOLDs, the airway mucus becomes hyperconcentrated, increasing osmotic and viscoelastic moduli and impairing mucus clearance. MOLD research requires relevant sources of healthy airway mucus for experimental manipulation and analysis. Mucus collected from endotracheal tubes (ETT) may represent such a source with benefits, e.g., in vivo production, over canonical sample types such as sputum or human bronchial epithelial (HBE) mucus. Ionic and biochemical compositions of ETT mucus from healthy human subjects were characterized and a stock of pooled ETT samples generated. Pooled ETT mucus exhibited concentration-dependent rheologic properties that agreed across spatial scales with reported individual ETT samples and HBE mucus. We suggest that the practical benefits compared with other sample types make ETT mucus potentially useful for MOLD research.
- Published
- 2019
- Full Text
- View/download PDF
37. The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome.
- Author
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Radicioni G, Cao R, Carpenter J, Ford AA, Wang T, Li L, and Kesimer M
- Subjects
- Humans, Multiprotein Complexes chemistry, Multiprotein Complexes metabolism, Protein Binding, Protein Interaction Mapping, Protein Interaction Maps, Proteome, Proteomics methods, Carrier Proteins metabolism, Immunity, Innate, Immunity, Mucosal, Mucins metabolism, Respiratory Mucosa immunology, Respiratory Mucosa metabolism
- Abstract
Chronic lung diseases such as cystic fibrosis, chronic bronchitis, and asthma are characterized by hypersecretion and poor clearance of mucus, which are associated with poor prognosis and mortality. Little is known about the relationship between the biophysical properties of mucus and its molecular composition. The mucins MUC5B and MUC5AC are traditionally believed to generate the characteristic biophysical properties of airway mucus. However, the contribution of hundreds of globular proteins to the biophysical properties of mucus is not clear. Approximately one-third of the total mucus proteome comprises distinct, multi-protein complexes centered around airway mucins. These complexes constitute a discrete entity we call the "mucin interactome". The data suggest that while the majority of these proteins interact with mucins via electrostatic and weak interactions, some interact through very strong hydrophobic and/or covalent interactions. Using reagents that interfere with protein-protein interactions, the complexes can be disassembled, and mucus rheology can be dramatically altered. Using MUC5B-glutathione S-transferase (GST) and MUC5B-galectin-3 as a representative of these interactions, we provide evidence that individual mucin protein interactions can alter the biophysical properties of mucus and modulate the biological function of the protein. We propose that the key mechano- and bio-active functions of mucus depend on the dynamic interactions between mucins and globular proteins. These observations challenge the paradigm that mucins are the only molecules that confer biophysical properties of mucus. These observations may ultimately lead to a greater understanding of the system and guide the development of strategies for more effective interventions using better therapeutic agents.
- Published
- 2016
- Full Text
- View/download PDF
38. Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.
- Author
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Cho JL, Ling MF, Adams DC, Faustino L, Islam SA, Afshar R, Griffith JW, Harris RS, Ng A, Radicioni G, Ford AA, Han AK, Xavier R, Kwok WW, Boucher R, Moon JJ, Hamilos DL, Kesimer M, Suter MJ, Medoff BD, and Luster AD
- Subjects
- Adult, Asthma complications, Asthma pathology, Cytokines, Humans, Hypersensitivity complications, Hypersensitivity pathology, Inflammation complications, Lung pathology, Mucus metabolism, Muscle, Smooth immunology, Muscle, Smooth pathology, Phenotype, Allergens immunology, Asthma immunology, Hypersensitivity immunology, Inflammation immunology, Inflammation pathology, Th2 Cells immunology
- Abstract
Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4
+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation., (Copyright © 2016, American Association for the Advancement of Science.)- Published
- 2016
- Full Text
- View/download PDF
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