Chronic cigarette smoke exposure induces systemic hypoxia that drives intestinal dysfunction
| Autor: | Andrew G. Jarnicki, Sean W. Mateer, Philip M. Hansbro, Bernadette Jones, Graham L. Radford-Smith, Marjorie M. Walker, Brian G. Oliver, Simon Keely, Nicholas J. Talley, Bridie J. Goggins, Shaan L. Gellatly, Richard Kim, Nick Powell, Michael Fricker |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Time Factors Angiogenesis Biopsy Inflammatory bowel disease Mice Pulmonary Disease Chronic Obstructive Crohn Disease Risk Factors Smoke Intestinal Mucosa Lung COPD Smoking General Medicine Colonoscopy Middle Aged Cell Hypoxia Amino Acids Dicarboxylic medicine.anatomical_structure Disease Progression Female medicine.symptom Research Article Adult Colon Inflammation Ileum Prolyl Hydroxylases 03 medical and health sciences Tobacco medicine Animals Humans Pulmonary pathology Colitis Aged business.industry Pulmonary Gas Exchange Prolyl-Hydroxylase Inhibitors Hypoxia (medical) medicine.disease Mice Inbred C57BL Disease Models Animal Oxidative Stress 030104 developmental biology Trinitrobenzenesulfonic Acid Immunology Smoking Cessation business |
| Zdroj: | JCI insight. 3(3) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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