Abstract
Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.
Highlights
Cigarette smoking (CS) is a major cause of mortality and disease, including chronic obstructive pulmonary disease (COPD)
The small intestinal length was unchanged after 2 months of CS; 6 months of CS exposure led to an increase in length (Figure 1D: 2 months sham 37.81 +− 0.47 cm vs CS 37.77 +− 0.33 cm, P=0.998; Figure 1I: 6 months sham 38.19 +− 0.47 cm vs CS 40.13 +− 0.59 cm, P=0.023)
Since the length of the colon could potentially be affected by the volume of faecal content due to widening of the colon in regions containing faecal pellets, we analysed the ratio of colon length to the number of faecal pellets
Summary
Cigarette smoking (CS) is a major cause of mortality and disease, including chronic obstructive pulmonary disease (COPD). CS is a major cause of COPD and extrapulmonary effects including those involving the gastrointestinal (GI) tract on patient health have been demonstrated [3,4]. CS exposure and COPD are risk factors for Crohn’s disease that is characterised by chronic mucosal inflammation and compromised intestinal barrier function [5]. Ex-smokers have an increased risk of developing UC and severe symptoms needing surgery [6]. Results from another population-based cohort study has revealed COPD as a risk factor for both UC and Crohn’s disease, suggesting that there is a significant interaction between both COPD and the structure and function of the GI tract [5]. CS exposure dose-dependently increased adenoma formation in mice with inflamed mucosa induced by 3% dextran sulphate sodium (DSS) [8]
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