CFTR dysfunction in smooth muscle drives TGFβ dependent airway hyperreactivity

Autor: Elizabeth L. Kramer, Kristin M. Hudock, Cynthia R. Davidson, John P. Clancy
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Respiratory Research, Vol 24, Iss 1, Pp 1-11 (2023)
Druh dokumentu: article
ISSN: 1465-993X
DOI: 10.1186/s12931-023-02495-2
Popis: Abstract Background The primary underlying defect in cystic fibrosis (CF) is disrupted ion transport in epithelia throughout the body. It is unclear if symptoms such as airway hyperreactivity (AHR) and increased airway smooth muscle (ASM) volume in people with CF are due to inherent abnormalities in smooth muscle or are secondary to epithelial dysfunction. Transforming Growth Factor beta 1 (TGFβ) is an established genetic modifier of CF lung disease and a known driver of abnormal ASM function. Prior studies have demonstrated that CF mice develop greater AHR, goblet cell hyperplasia, and ASM hypertrophy after pulmonary TGFβ exposure. However, the mechanism driving these abnormalities in CF lung disease, specifically the contribution of CFTR loss in ASM, was unknown. Methods In this study, mice with smooth muscle-specific loss of CFTR function (Cftr fl/fl ; SM-Cre mice) were exposed to pulmonary TGFβ. The impact on lung pathology and physiology was investigated through examination of lung mechanics, Western blot analysis, and pulmonary histology. Results Cftr fl/fl ; SM-Cre mice treated with TGFβ demonstrated greater methacholine-induced AHR than control mice. However, Cftr fl/fl ; SM-Cre mice did not develop increased inflammation, ASM area, or goblet cell hyperplasia relative to controls following TGFβ exposure. Conclusions These results demonstrate a direct smooth muscle contribution to CF airway obstruction mediated by TGFβ. Dysfunction in non-epithelial tissues should be considered in the development of CF therapeutics, including potential genetic therapies.
Databáze: Directory of Open Access Journals
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