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 8

DMOG treatment during chronic CS exposure prevents pathology in the colon.

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DMOG treatment during chronic CS exposure prevents pathology in the colo...
Mice were exposed to CS for 8 weeks to induce experimental COPD and were treated with DMOG throughout. (A) Tissue hypoxia was measured using hypoxyprobe, and DMOG treatment partially prevented the mucosal hypoxic phenotype in colons of CS-exposed mice (n = 3–4). (B) DMOG treatment partly prevented increases in TNF-α and TGF-β mRNA expression in the colon (n = 4–6). (C) DMOG treatment inhibited increases in vasculature (n = 5–6). (D and E) DMOG treatment increased the mRNA expression of HIF target genes VEGF, iNOS, CD73, and gravin in the colons of CS-exposed groups (n = 4–6). (F) DMOG treatment completely inhibited increases in crypt mitoses (n = 5–6). (G) DMOG treatment completely inhibited the CS-induced increases in colon barrier permeability in CS-exposed mice (n = 4–6). *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. 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.