Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Fricker, Michael, Goggins, Bridie J., Mateer, Sean, Jones, Bernadette, Kim, Richard Y., Gellatly, Shaan L., Jarnicki, Andrew G., Powell, Nicholas, Oliver, Brian G., Radford-Smith, Graham, Talley, Nicholas J., Walker, Marjorie M., Keely, Simon and Hansbro, Philip M. (2018) Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction. JCI Insight, 3 3: 1-19. doi:10.1172/jci.insight.94040

Author Fricker, Michael
Goggins, Bridie J.
Mateer, Sean
Jones, Bernadette
Kim, Richard Y.
Gellatly, Shaan L.
Jarnicki, Andrew G.
Powell, Nicholas
Oliver, Brian G.
Radford-Smith, Graham
Talley, Nicholas J.
Walker, Marjorie M.
Keely, Simon
Hansbro, Philip M.
Title Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction
Journal name JCI Insight   Check publisher's open access policy
ISSN 2379-3708
Publication date 2018-02-08
Year available 2018
Sub-type Article (original research)
DOI 10.1172/jci.insight.94040
Open Access Status Not yet assessed
Volume 3
Issue 3
Start page 1
End page 19
Total pages 19
Place of publication ANN ARBOR
Language eng
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.
Keyword COPD
Inflammatory bowel disease
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Medicine Publications
Version Filter Type
Citation counts: Google Scholar Search Google Scholar
Created: Wed, 14 Feb 2018, 11:06:34 EST