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An RGS4-mediated phenotypic switch of bronchial smooth muscle cells promotes fixed airway obstruction in asthma.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (1), pp. e28504. Date of Electronic Publication: 2012 Jan 12. - Publication Year :
- 2012
-
Abstract
- In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma.
- Subjects :
- Airway Obstruction complications
Airway Obstruction physiopathology
Asthma physiopathology
Bronchoconstriction drug effects
Carbachol pharmacology
Cell Proliferation drug effects
Excitation Contraction Coupling drug effects
Female
Humans
In Vitro Techniques
Male
Middle Aged
Mitogens pharmacology
Models, Biological
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle enzymology
Phenotype
Phosphatidylinositol 3-Kinases metabolism
Platelet-Derived Growth Factor pharmacology
Proto-Oncogene Proteins c-akt metabolism
Sputum drug effects
Sputum metabolism
Airway Obstruction pathology
Asthma complications
Asthma pathology
Bronchi pathology
Myocytes, Smooth Muscle metabolism
Myocytes, Smooth Muscle pathology
RGS Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22253691
- Full Text :
- https://doi.org/10.1371/journal.pone.0028504