Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Fricker, M; Goggins, BJ; Mateer, S; Jones, B; Kim, RY; Gellatly, SL; Jarnicki, AG; Powell, N; Oliver, BG; Radford-Smith, G; Talley, NJ; Walker, MM; Keely, S; Hansbro, PM

Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction

Fricker, M

Goggins, BJ Mateer, S Jones, B

Kim, RY

Gellatly, SL Jarnicki, AG Powell, N

Oliver, BG

Radford-Smith, G Talley, NJ Walker, MM Keely, S

Hansbro, PM

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Publication Type:: Journal Article
Citation:: JCI insight, 2018, 3 (3)
Issue Date:: 2018-02-08

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Field	Value	Language
dc.contributor.author	Fricker, M https://orcid.org/0000-0002-8587-1774	en_US
dc.contributor.author	Goggins, BJ	en_US
dc.contributor.author	Mateer, S	en_US
dc.contributor.author	Jones, B https://orcid.org/0000-0003-4613-7865	en_US
dc.contributor.author	Kim, RY https://orcid.org/0000-0002-8709-5270	en_US
dc.contributor.author	Gellatly, SL	en_US
dc.contributor.author	Jarnicki, AG	en_US
dc.contributor.author	Powell, N https://orcid.org/0000-0003-3231-6950	en_US
dc.contributor.author	Oliver, BG https://orcid.org/0000-0002-7122-9262	en_US
dc.contributor.author	Radford-Smith, G	en_US
dc.contributor.author	Talley, NJ	en_US
dc.contributor.author	Walker, MM	en_US
dc.contributor.author	Keely, S https://orcid.org/0000-0002-1248-9590	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.date.available	2018-01-10	en_US
dc.date.issued	2018-02-08	en_US
dc.identifier.citation	JCI insight, 2018, 3 (3)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128668
dc.description.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.	en_US
dc.relation.ispartof	JCI insight	en_US
dc.relation.isbasedon	10.1172/jci.insight.94040	en_US
dc.subject.mesh	Intestinal Mucosa	en_US
dc.subject.mesh	Colon	en_US
dc.subject.mesh	Ileum	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Tobacco	en_US
dc.subject.mesh	Crohn Disease	en_US
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Disease Progression	en_US
dc.subject.mesh	Trinitrobenzenesulfonic Acid	en_US
dc.subject.mesh	Amino Acids, Dicarboxylic	en_US
dc.subject.mesh	Colonoscopy	en_US
dc.subject.mesh	Pulmonary Gas Exchange	en_US
dc.subject.mesh	Biopsy	en_US
dc.subject.mesh	Risk Factors	en_US
dc.subject.mesh	Smoking	en_US
dc.subject.mesh	Smoking Cessation	en_US
dc.subject.mesh	Smoke	en_US
dc.subject.mesh	Cell Hypoxia	en_US
dc.subject.mesh	Oxidative Stress	en_US
dc.subject.mesh	Time Factors	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Prolyl-Hydroxylase Inhibitors	en_US
dc.subject.mesh	Prolyl Hydroxylases	en_US
dc.title	Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	3	en_US

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/128668