Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

Hany H Arab,Muhammad Y Al-Shorbagy,Dalaal M Abdallah,Noha N Nassar,Rupesh Chaturvedi

doi:10.1371/journal.pone.0097193

Abstract

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.

Highlights

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, relapsing, immunologically mediated inflammatory disorders of the gastrointestinal tract that jeopardize the quality of life of patients suffering from these disorders [1]
Rats challenged with trinitrobenezene sulphonic acid (TNBS) suffered marked weight loss (.10%) as a result of colonic inflammation compared with vehicle-treated control group (Figure 1A)
These data were confirmed by the macroscopic examination of colon that revealed severe colonic injury characterized by mucosal mRNA species peroxisome proliferator activated receptor-gamma (PPAR-c) nuclear factor kappa B (NF-kB) p65 COX-2 inducible nitric oxide synthase (iNOS) Cytochrome C B cell lymphoma-2 (Bcl-2) associated x protein (Bax) Bcl-2 Caspase-3 GAPDH

Summary

Introduction

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, relapsing, immunologically mediated inflammatory disorders of the gastrointestinal tract that jeopardize the quality of life of patients suffering from these disorders [1]. Activation of intestinal immune system is associated with excessive generation of inflammatory cytokines such as tumor necrosis factor-a (TNF-a) which amplifies the inflammatory cascade by triggering the generation of other proinflammatory cytokines and enhancing the recruitment of macrophages and neutrophils [1,2]. The infiltration of neutrophils generates excessive amounts of reactive oxygen species (ROS), nitric oxide (NO) and prostaglandin E2 (PGE2) which provoke mucosal disruption [1]. Excessive generation of ROS and cytokines has been reported to activate several transcription factors that upregulate the inflammatory response. Increased levels of interleukin-10 (IL-10) have been reported in IBD patients [4] and experimental animals [5,6] where they attenuate the exaggerated inflammatory response [2]. The pathogenesis of IBD involves increased frequency of apoptosis with consequent loss of intestinal epithelial cells [7]

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