Abstract
Crohn's disease is a pathological condition of the gastro-intestinal tract, causing severe transmural inflammation in the ileum and/or colon. Cigarette smoking is one of the best known environmental risk factors for the development of Crohn's disease. Nevertheless, very little is known about the effect of prolonged cigarette smoke exposure on inflammatory modulators in the gut. We examined the effect of cigarette smoke on cytokine profiles in the healthy and inflamed gut of human subjects and in the trinitrobenzene sulphonic acid mouse model, which mimics distal Crohn-like colitis. In addition, the effect of cigarette smoke on epithelial expression of transient receptor potential channels and their concurrent increase with cigarette smoke-augmented cytokine production was investigated. Active smoking was associated with increased IL-8 transcription in ileum of controls (p < 0,001; n = 18-20/group). In the ileum, TRPV1 mRNA levels were decreased in never smoking Crohn's disease patients compared to healthy subjects (p <0,001; n = 20/group). In the colon, TRPV1 mRNA levels were decreased (p = 0,046) in smoking healthy controls (n = 20/group). Likewise, healthy mice chronically exposed to cigarette smoke (n = 10/group) showed elevated ileal Cxcl2 (p = 0,0075) and colonic Kc mRNA levels (p = 0,0186), whereas TRPV1 mRNA and protein levels were elevated in the ileum (p = 0,0315). Although cigarette smoke exposure prior to trinitrobenzene sulphonic acid administration did not alter disease activity, increased pro-inflammatory cytokine production was observed in the distal colon (Kc: p = 0,0273; Cxcl2: p = 0,104; Il1-β: p = 0,0796), in parallel with the increase of Trpv1 mRNA (p < 0,001). We infer that CS affects pro-inflammatory cytokine expression in healthy and inflamed gut, and that the simultaneous modulation of TRPV1 may point to a potential involvement of TRPV1 in cigarette smoke-induced production of inflammatory mediators.
Highlights
Crohn’s disease (CD) is characterized by severe gastro-intestinal inflammation and results from a complex interplay between genetic and environmental factors
We demonstrated that Trpv1 mRNA expression is induced in the distal colon of trinitrobenzene sulphonic acid (TNBS)-challenged Cigarette smoking (CS)-exposed mice compared to the air-exposed mice two days postTNBS (Fig 4G), which is in line with the CS-induced aggravation of TNBS-induced CXCL2, keratinocyte chemoattractant (KC) and IL-1β (Fig 4A–4F)
We demonstrate that CS exposure affects cytokine/chemokine profiles, in line with epithelial TRPV1 expression, in the healthy and inflamed gut
Summary
Crohn’s disease (CD) is characterized by severe gastro-intestinal inflammation and results from a complex interplay between genetic and environmental factors. In CD patients, a transmural and discontinuous inflammation affects mainly the ileum and colon, inflammatory lesions can extend to any part of the gastrointestinal tract [1, 2]. CD is mediated by a Th1 inflammatory response at the level of the gut mucosa [3]. Increased numbers of Th17 cells and the production of Th17-related cytokines are reported to be associated with active inflammation in CD patients [4]. Emerging evidence suggests that the development of CD in susceptible individuals is a consequence of a dysregulated dialogue between the intestinal microbiota and the immune system of the gut [5, 6]. Environmental factors affect the incidence and disease course of CD. Active smoking in particular is a very prominent risk factor [7]
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