Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction
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
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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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 5

Chronic CS exposure induces altered cellular turnover and increased barrier permeability in the colon.

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Chronic CS exposure induces altered cellular turnover and increased barr...
Mice were exposed to CS for 4, 8, or 12 weeks to drive development (4 weeks), establishment (8 weeks), and progression (12 weeks) of experimental COPD. (A) After 8 weeks, increased numbers of mitotic nuclei were observed in the colonic crypts of CS-exposed groups (n = 6). (B) TUNEL staining was performed to evaluate the extent of cell death, and increased numbers of TUNEL-positive cells were observed in the epithelial and mucosal layers of colons from CS-exposed groups (n = 6). (C) Representative fluorescent microscopy images of TUNEL-stained colon tissue. Notably, high numbers of TUNEL-positive cells were observed in the epithelial layer of the colons of CS-exposed groups (scale bar: 100 μM). (D) Increased colon barrier permeability was observed after 8 and 12 weeks of CS exposure (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.