tri-n-butylstannylmethacrylate and Colitis

Although neutrophils are strongly implicated in eliminating pathogens, excessive recruitment may cause tissue damage. Therefore, reducing cell influx during an inflammatory process may be a potential target for treating inflammatory bowel diseases (IBD). As CXCR2 is involved in neutrophil migration, this study aimed to evaluate whether the systemic therapeutic treatment with selective CXCR2 antagonist SB225002 ameliorates experimental colitis, which was induced in mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). After colitis establishment (24 h), mice were treated with SB225002. At later time-points, up to 72 h, mice were monitored for body weight loss and overall mortality. At the time of sacrifice, colonic tissues were scored for macro- and microscopic damage, and cytokine levels, myeloperoxidase (MPO) activity, and protein expression were analyzed. TNBS administration induced macro- and microscopic damage in colon tissue, leading in most cases to animal death. Curative treatment with SB225002 significantly reduced all of the parameters analyzed, leading to an improvement of inflammatory signs. SB225002 reduced neutrophil influx, MPO activity, IL-1beta, MIP-2, and keratinocyte-derived chemokine (KC) levels and the expression of vascular endothelial growth factor, inducible NO synthase, and cyclooxygenase-2 proteins into the colon tissue. Levels of IL-4 and IL-10 were increased significantly in the colons of animals treated with SB225002. Additionally, curative treatment with mouse anti-KC significantly reduced MPO activity and colonic damage. These results taken together demonstrate that a selective blockade of CXCR2 consistently reduced TNBS-induced colitis, suggesting that the use of SB225002 is a potential therapeutic approach for the treatment of IBD and other related inflammatory disorders.

Topics: Acute Disease; Animals; Colitis; Disease Models, Animal; Interleukin-1; Interleukin-10; Male; Methacrylates; Mice; Mice, Inbred BALB C; Phenylurea Compounds; Receptors, Interleukin-8B

Colonic inflammation has profound effects on the urinary bladder physiology and produces hypersensitivity of bladder afferent neurons and neurogenic bladder overactivity. Calcitonin gene-related peptide (CGRP) expressed in dorsal root ganglia (DRG) plays an important role in mediating sensory perception following visceral inflammation. In the present study, we determined that the expression of CGRP was increased in bladder afferent neurons in lumbosacral DRG following tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in rat. After colitis, the percentage of bladder afferent neurons expressing CGRP was increased in L1 (61.2+/-2.9% in colitis vs. 37.7+/-5.1% in controls; p<0.05) and S1 DRG (26.3+/-2.3% in colitis vs. 15.5+/-1.9% in controls; p<0.01). We also demonstrated that the expression of tyrosine kinase receptor TrkB was increased in L1 (39.7+/-2.9% in colitis vs. 25.2+/-4.3% in controls; p<0.05) and S1 DRG (45.6+/-3.8% in colitis vs. 38.3+/-3.6% in controls; p<0.01) following colitis. CGRP and TrkB were co-stored in a subpopulation of DRG neurons in control and colitic animals and the number of DRG cells co-expressing CGRP and TrkB was significantly increased in L1 (2.7-fold, p<0.01) and S1 DRG (2.4-fold, p<0.01) following colitis. In cultured DRG, exogenous BDNF application significantly increased CGRP expression, which was blocked by TrkB selective inhibitor K252a. These results suggest that up-regulation of CGRP and TrkB in bladder afferent neurons may play a role in colon-to-bladder cross-sensitization following colitis.

Topics: Amidines; Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Carbocyanines; Cells, Cultured; Colitis; Ganglia, Spinal; Gene Expression Regulation; Male; Methacrylates; Neurons, Afferent; Rats; Rats, Sprague-Dawley; Receptor, trkB; Up-Regulation; Urinary Bladder