Chest
Volume 132, Issue 5, November 2007, Pages 1548-1556
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Original Research
GERD AND LUNG DISEASE
Exposure of Airway Epithelium to Bile Acids Associated With Gastroesophageal Reflux Symptoms: A Relation to Transforming Growth Factor-β1 Production and Fibroblast Proliferation

https://doi.org/10.1378/chest.07-1373Get rights and content

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-β1 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-β1 production. TGF-β1 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-β1 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-β1 and fibroblast proliferation. Early intervention to attenuate these processes may reduce fibrogenesis in various airway diseases associated with GER.

Section snippets

Study Subjects

Patients with asthma (eight female and six male; age, 52.5 ± 17.5 years; FEV1 percentage of predicted, 79.9 ± 16% [mean ± SD]), GER (nine female and three male; age, 47.8 ± 14.6 years; FEV1 percentage of predicted, 86.3 ± 17.7), or asthma with associated GER symptoms (nine female and two male; age, 50.8 ± 15.3 years; FEV1 percentage of predicted, 76.9 ± 14) were recruited from Asthma Clinic of Taipei Veterans General Hospital. Asthma was diagnosed according to guidelines.20 Asthma was newly

Bile Acids in the Airways

Induced sputum was collected from healthy control subjects, and from patients with asthma, GER, or asthma associated with GER symptoms. The amount of total bile acids in induced sputum is demonstrated in Figure 1. Mean values of total bile acids were 0.5 ± 0.1, 0.6 ± 0.1, 1.8 ± 0.2, and 5.4 ± 1.6 nmol/g of sputum for healthy subjects, and patients with asthma, GER, and asthma associated with GER symptoms, respectively.

Effect of CD and GCD on TGF-β1 Release

The effect of CD on the generation of TGF-β1 from HAECs is shown in Figure 2,

Discussion

GER symptoms are common in various chronic airway disorders.123456 The present study demonstrates that the amount of total bile acids is significantly higher in the airways of patients with GER or asthma with associated GER symptoms compared to those of healthy subjects and asthmatic patients without GER symptoms. Although GER and bile acid aspiration has been linked to the development of bronchiolitis obliterans after lung transplant, the mechanism of pathogenesis remains unclear.17 We have

References (31)

  • MatikainenM et al.

    Bile acid composition and esophagitis after total gastrectomy

    Am J Surg

    (1982)
  • HsuJY et al.

    Abnormal acid reflux in asthmatic patients in a region with low GERD prevalence

    J Gastroenterol

    (2005)
  • CasanovaC et al.

    Increased gastro-oesophageal reflux disease in patients with severe COPD

    Eur Respir J

    (2004)
  • RaghuG et al.

    High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis

    Eur Respir J

    (2006)
  • TobinRW et al.

    Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (1998)
  • Cited by (0)

    This study was supported by the National Science Council, Taiwan (grant NSC 94-2314-B-075-096).

    The authors have no conflicts of interest to disclose.

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