RATIONALE: Gastroesophageal reflux (GER) is common in patients with various airway diseases. Airway epithelial cells can release growth factors that promote fibroblast proliferation. Exposure of airway epithelium to bile acids may induce a fibrotic response. OBJECTIVES: To determine how bile acids interact with airway epithelium; particularly, whether transforming growth factor-beta1 secretion and fibroblast proliferation are affected. METHODS: Induced sputum from patients with asthma, GER, or asthma associated with GER symptoms, or from healthy control subjects was collected. Total bile acids were measured by a spectrophotometric enzymatic assay. The major components of bile acids, chenodeoxycholic acid (CD) and glycochenodeoxycholic acid (GCD), were used to stimulate primary airway epithelial cells. Quantitative polymerase chain reaction and Western blotting were applied for messenger RNA expression and signal pathway analysis, respectively. Conditioned medium following CD stimulation was coincubated with fibroblasts for proliferation study. RESULTS: The amount of total bile acids in induced sputum was significantly higher in patients with GER and asthma-associated GER symptoms compared to that of healthy control subjects (p<0.005). CD, but not GCD, significantly induced TGF-beta1 production. TGF-beta1 messenger RNA expression was 2.5-fold increased compared to unstimulated cells. This occurred via p38 mitogen-activated protein (MAP) kinase and activating transcription factor-2 activation. Pretreatment with dexamethasone inhibited TGF-beta1 production at both messenger RNA and protein levels by inhibiting p38 MAP kinase phosphorylation. Conditioned medium from CD-treated epithelial cells enhanced fibroblast proliferation. CONCLUSIONS: Aspiration of bile acids may induce airway fibrosis through the production of TGF-beta1 and fibroblast proliferation. Early intervention to attenuate these processes may reduce fibrogenesis in various airway diseases associated with GER.
RATIONALE: Gastroesophageal reflux (GER) is common in patients with various airway diseases. Airway epithelial cells can release growth factors that promote fibroblast proliferation. Exposure of airway epithelium to bile acids may induce a fibrotic response. OBJECTIVES: To determine how bile acids interact with airway epithelium; particularly, whether transforming growth factor-beta1 secretion and fibroblast proliferation are affected. METHODS: Induced sputum from patients with asthma, GER, or asthma associated with GER symptoms, or from healthy control subjects was collected. Total bile acids were measured by a spectrophotometric enzymatic assay. The major components of bile acids, chenodeoxycholic acid (CD) and glycochenodeoxycholic acid (GCD), were used to stimulate primary airway epithelial cells. Quantitative polymerase chain reaction and Western blotting were applied for messenger RNA expression and signal pathway analysis, respectively. Conditioned medium following CD stimulation was coincubated with fibroblasts for proliferation study. RESULTS: The amount of total bile acids in induced sputum was significantly higher in patients with GER and asthma-associated GER symptoms compared to that of healthy control subjects (p<0.005). CD, but not GCD, significantly induced TGF-beta1 production. TGF-beta1 messenger RNA expression was 2.5-fold increased compared to unstimulated cells. This occurred via p38 mitogen-activated protein (MAP) kinase and activating transcription factor-2 activation. Pretreatment with dexamethasone inhibited TGF-beta1 production at both messenger RNA and protein levels by inhibiting p38 MAP kinase phosphorylation. Conditioned medium from CD-treated epithelial cells enhanced fibroblast proliferation. CONCLUSIONS: Aspiration of bile acids may induce airway fibrosis through the production of TGF-beta1 and fibroblast proliferation. Early intervention to attenuate these processes may reduce fibrogenesis in various airway diseases associated with GER.
Authors: Joyce S Lee; Harold R Collard; Ganesh Raghu; Matthew P Sweet; Steven R Hays; Guilherme M Campos; Jeffrey A Golden; Talmadge E King Journal: Am J Med Date: 2010-04 Impact factor: 4.965
Authors: Michaela D Restivo; Anna Podolanczuk; Steven M Kawut; Ganesh Raghu; Peter Leary; R Graham Barr; David J Lederer Journal: Eur Respir J Date: 2017-05-19 Impact factor: 16.671
Authors: Anitra D Thomas; Kuei-Ying Su; Jui-Chih Chang; Jason H Leung; Sean M Lee; Zoie E Holzknecht; Mary Lou Everett; William Parker; R Duane Davis; Shu S Lin Journal: Surg Endosc Date: 2009-11-14 Impact factor: 4.584
Authors: Kuei-Ying Su; Anitra D Thomas; Jui-Chih Chang; Jason H Leung; Sean M Lee; Zoie E Holzknecht; Mary Lou Everett; W Michael Foster; Monica Kraft; William Parker; R Duane Davis; Shu S Lin Journal: Inflamm Res Date: 2012-05-08 Impact factor: 4.575