Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction
Michael Fricker, … , Simon Keely, Philip M. Hansbro
Michael Fricker, … , Simon Keely, Philip M. Hansbro
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e94040. https://doi.org/10.1172/jci.insight.94040.
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Research Article Gastroenterology Pulmonology

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Abstract

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract (GIT). Cigarette smoke (CS) exposure and chronic obstructive pulmonary disease (COPD) are risk factors for CD, although the mechanisms involved are poorly understood. We employed a mouse model of CS-induced experimental COPD and clinical studies to examine these mechanisms. Concurrent with the development of pulmonary pathology and impaired gas exchange, CS-exposed mice developed CD-associated pathology in the colon and ileum, including gut mucosal tissue hypoxia, HIF-2 stabilization, inflammation, increased microvasculature, epithelial cell turnover, and decreased intestinal barrier function. Subsequent smoking cessation reduced GIT pathology, particularly in the ileum. Dimethyloxaloylglycine, a pan-prolyl hydroxylase inhibitor, ameliorated CS-induced GIT pathology independently of pulmonary pathology. Prior smoke exposure exacerbated intestinal pathology in 2,4,6-trinitrobenzenesulfonic acid–induced (TNBS-induced) colitis. Circulating vascular endothelial growth factor, a marker of systemic hypoxia, correlated with CS exposure and CD in mice and humans. Increased mucosal vascularisation was evident in ileum biopsies from CD patients who smoke compared with nonsmokers, supporting our preclinical data. We provide strong evidence that chronic CS exposure and, for the first time to our knowledge, associated impaired gas exchange cause systemic and intestinal ischemia, driving angiogenesis and GIT epithelial barrier dysfunction, resulting in increased risk and severity of CD.

Authors

Michael Fricker, Bridie J. Goggins, Sean Mateer, Bernadette Jones, Richard Y. Kim, Shaan L. Gellatly, Andrew G. Jarnicki, Nicholas Powell, Brian G. Oliver, Graham Radford-Smith, Nicholas J. Talley, Marjorie M. Walker, Simon Keely, Philip M. Hansbro

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Figure 7

Smoking cessation alters pathology in the colon and ileum.

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Smoking cessation alters pathology in the colon and ileum. Mice were exp...
Mice were exposed to CS for 8 weeks to induce experimental COPD and then breathed normal air or continued CS exposure for 4 weeks. (A) qPCR assessment of mRNA showed that TNF-α expression increased, IFN-γ expression decreased, and TGF-β expression was unaltered in whole colons with smoking cessation (n = 5–6). (B) Smoking cessation resulted in nonsignificant decreases in the number of and volume of blood vessels, and a significant decrease in total MECA-32–positive mucosal area in colons compared with groups continually exposed to CS for 12 weeks (n = 4–6). (C) VEGF mRNA was increased in the colon following 12 weeks but not following smoking cessation, while iNOS was significantly increased in the colon following smoking cessation (n = 5–6). (D) mRNA levels of IFN-γ and TGF-β returned to baseline in the ileum following smoking cessation (n = 4–6). (E) Smoking cessation reversed the increased vascularization of ileal tissue (n = 4–6). (F) VEGF and iNOS expression were increased in the ileum of the 12-week CS-exposed group but not following smoking cessation (n = 4–6). *P ≤ 0.05, **P ≤ 0.01. Student’s unpaired 2-tailed t test used for comparisons of 2 groups, 1-way ANOVA with Tukey’s post-hoc was used whenever more than 2 experimental groups were compared.