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Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats.
Eur J Pharmacol. 2007 May 21; 562(3):247-58.EJ

Abstract

Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a highly nuclear receptor expressed in the colon, may participate in the control of inflammation, especially in regulating the production of immunomodulatory and inflammatory mediators, cellular proliferation and apoptosis. In order to delve into the anti-inflammatory mechanisms and signalling pathways of PPARgamma agonists, we have studied the effects of rosiglitazone, a PPARgamma agonist on the extent and severity of acute ulcerative colitis caused by intracolonic administration of 2,4,6-trinitribenzene sulfonic acid (TNBS) in rats. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-alpha) levels and a histological study of the lesions. We determined prostaglandin E2 production as well as the cyclooxygenases (COX)-1 and -2 expressions by immunohistochemistry and Western blotting. The nuclear factor kappa (NF-kappaB) p65 and p38 mitogen-activated protein kinase (MAPK) expression levels were also measured by Western blotting. Finally, since PPARgamma agonists modulate apoptosis, we tried to clarify its effects under early acute inflammatory conditions. Inflammation following TNBS induction was characterized by increased colonic wall thickness, edema, diffuse inflammatory cells infiltration, necrosis reaching an ulcer index (UI) of 9.66+/-0.66 cm(2) and increased MPO activity and TNF-alpha colonic levels. Rosiglitazone treatment significantly reduced the morphological alteration associated with TNBS administration and the UI with the highest dose. In addition, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Rosiglitazone significantly reduced the rise in the prostaglandin (PG) E(2) generation compared with TNBS group. The COX-1 levels remained stable throughout the treatment in all groups. The COX-2 expression was elevated in TNBS group; however rosiglitazone administration reduced the COX-2 overexpression. A high expression of NF-kappaB p65 and p38 MAPK proteins appeared in colon mucosa from control TNBS-treated rats; nevertheless, PPARgamma agonist treatment drastically decreased them. There were no significant changes in apoptosis after rosiglitazone treatment when compared to TNBS group. In conclusion, rosiglitazone seems to modulate the acute colitis through NF-kappaB p65 and p38 MAPK signalling pathways.

Authors+Show Affiliations

Department of Pharmacology, University of Sevilla, Profesor García González Street 2, 41012 Seville, Spain.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17343846

Citation

Sánchez-Hidalgo, Marina, et al. "Rosiglitazone, a PPARgamma Ligand, Modulates Signal Transduction Pathways During the Development of Acute TNBS-induced Colitis in Rats." European Journal of Pharmacology, vol. 562, no. 3, 2007, pp. 247-58.
Sánchez-Hidalgo M, Martín AR, Villegas I, et al. Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats. Eur J Pharmacol. 2007;562(3):247-58.
Sánchez-Hidalgo, M., Martín, A. R., Villegas, I., & de la Lastra, C. A. (2007). Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats. European Journal of Pharmacology, 562(3), 247-58.
Sánchez-Hidalgo M, et al. Rosiglitazone, a PPARgamma Ligand, Modulates Signal Transduction Pathways During the Development of Acute TNBS-induced Colitis in Rats. Eur J Pharmacol. 2007 May 21;562(3):247-58. PubMed PMID: 17343846.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rosiglitazone, a PPARgamma ligand, modulates signal transduction pathways during the development of acute TNBS-induced colitis in rats. AU - Sánchez-Hidalgo,Marina, AU - Martín,Antonio Ramon, AU - Villegas,Isabel, AU - de la Lastra,Catalina Alarcón, Y1 - 2007/02/01/ PY - 2006/08/16/received PY - 2007/01/09/revised PY - 2007/01/10/accepted PY - 2007/3/9/pubmed PY - 2007/6/22/medline PY - 2007/3/9/entrez SP - 247 EP - 58 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 562 IS - 3 N2 - Recent studies have shown that peroxisome proliferator-activated receptor gamma (PPARgamma), a highly nuclear receptor expressed in the colon, may participate in the control of inflammation, especially in regulating the production of immunomodulatory and inflammatory mediators, cellular proliferation and apoptosis. In order to delve into the anti-inflammatory mechanisms and signalling pathways of PPARgamma agonists, we have studied the effects of rosiglitazone, a PPARgamma agonist on the extent and severity of acute ulcerative colitis caused by intracolonic administration of 2,4,6-trinitribenzene sulfonic acid (TNBS) in rats. The inflammatory response was assessed by gross appearance, myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-alpha) levels and a histological study of the lesions. We determined prostaglandin E2 production as well as the cyclooxygenases (COX)-1 and -2 expressions by immunohistochemistry and Western blotting. The nuclear factor kappa (NF-kappaB) p65 and p38 mitogen-activated protein kinase (MAPK) expression levels were also measured by Western blotting. Finally, since PPARgamma agonists modulate apoptosis, we tried to clarify its effects under early acute inflammatory conditions. Inflammation following TNBS induction was characterized by increased colonic wall thickness, edema, diffuse inflammatory cells infiltration, necrosis reaching an ulcer index (UI) of 9.66+/-0.66 cm(2) and increased MPO activity and TNF-alpha colonic levels. Rosiglitazone treatment significantly reduced the morphological alteration associated with TNBS administration and the UI with the highest dose. In addition, the degree of neutrophil infiltration and the cytokine levels were significantly ameliorated. Rosiglitazone significantly reduced the rise in the prostaglandin (PG) E(2) generation compared with TNBS group. The COX-1 levels remained stable throughout the treatment in all groups. The COX-2 expression was elevated in TNBS group; however rosiglitazone administration reduced the COX-2 overexpression. A high expression of NF-kappaB p65 and p38 MAPK proteins appeared in colon mucosa from control TNBS-treated rats; nevertheless, PPARgamma agonist treatment drastically decreased them. There were no significant changes in apoptosis after rosiglitazone treatment when compared to TNBS group. In conclusion, rosiglitazone seems to modulate the acute colitis through NF-kappaB p65 and p38 MAPK signalling pathways. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17343846/Rosiglitazone_a_PPARgamma_ligand_modulates_signal_transduction_pathways_during_the_development_of_acute_TNBS_induced_colitis_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00095-7 DB - PRIME DP - Unbound Medicine ER -