**Conflict of interest**

of rectal mucosal microvascular blood flow can result in a higher incidence of anastomotic

Although nicotine is considered to be the major mediator of CS effects on intestinal inflammation, there is a clear evidence for involvement of other smoke constituents in CS-dependent responses. Both UC and CD mouse models were affected by carbon monoxide (CO) inhalation [71–73, 142]. These studies suggested that the mechanism through which CO protected against intestinal inflammation involved promoting bactericidal activities of macrophages [142]. Nitric oxide (NO) was also suggested as contributing to beneficial CS effects, based on its relaxant effects on colonic smooth muscle from UC patients [143]. Moreover, physiological NO, derived from nicotine-stimulated intestinal neuronal cells, functioned as a mediator in

Smoking cigarettes is addictive and causes a number of serious diseases, including those of the respiratory and cardiovascular system [144], it also negatively impact on the gastrointestinal tract, such as CD [145]. Many of the adverse health effects of smoking are reversible and important health benefits are associated with smoking cessation [146]. With regard to the other major IBD form, a protective effect of cigarette smoking on the risk of UC development is well documented. However, whether CS constituents have beneficial effects on the course

CS inhalation studies in IBD mouse models would, ideally, reproduce the clinical effects of CS on colonic inflammation. This would facilitate identification of the mechanisms involved in the effects of CS on colitis and, eventually, lead to the characterisation of new anti-inflammatory processes involved in colon protection [22]. Nonetheless, so far, the results obtained using animal models of IBD following exposure to inhaled CS or to nicotine via non-inhalation routes, reflected the ambiguity of the clinical observations. These inconsistencies often reflect the high variability related to animal models (e.g. strains, IBD inducers, etc.) and inhalation methodologies. A more systematic and standardised approach is required to obtain consistent and reproducible data addressing the mechanisms by which CS interacts with the inflammatory processes in animal models of UC-like and CD-like colitis. Such systematic investigations could provide valuable insights into the possible anti-inflammatory effects of CS constituents in models related to UC. Corresponding studies in CD models would provide more mechanistic detail about how these compounds can enhance inflammation in CD.

We thank Edanz Group for editorial assistance and Stéphanie Boué for the artwork (**Figure 1**).

of the disease is less clear and the potential mechanisms are not understood.

smooth muscle relaxation in the colons of DSS-treated mice [137].

200 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

breakdown in chronic smokers [140].

*4.5.4. Non-nicotine-mediated effects*

**5. Conclusions**

**Acknowledgements**

Authors are employees of Philip Morris International. Philip Morris International is the sole source of funding and sponsor of this project. W.K. Schlage is contracted and paid by Philip Morris International.
