mobic and Fibrosis

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. In this study, we investigated the effects of a COX-2 inhibitor, meloxicam, on UUO-induced renal interstitial fibrosis in mice. Serum creatinine, blood urea nitrogen and urinary glucose were significantly increased by UUO. However, all of these changes were attenuated by meloxicam (1 mg/kg/day). Masson׳s trichrome staining showed that interstitial fibrosis was significantly increased by UUO, but that meloxicam also significantly diminished the area of UUO-induced fibrosis. Heat shock protein (HSP) 47 protein, a collagen-specific molecular chaperone essential for the biosynthesis of collagen molecules, and type IV collagen mRNA were increased in kidneys of UUO mice. Meloxicam reduced the expression of both HSP47 protein and type IV collagen mRNA. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) was increased by UUO, but these changes were inhibited by meloxicam. Collectively, these results suggest that COX-2 may be involved in the expression of HSP47 and type IV collagen through the phosphorylation of ERK and JNK, accelerating renal interstitial fibrosis.

Topics: Animals; Collagen; Cyclooxygenase 2 Inhibitors; Fibrosis; HSP47 Heat-Shock Proteins; Kidney; Kidney Diseases; Male; Meloxicam; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; RNA, Messenger; Thiazines; Thiazoles

Chagas disease is characterized by cardiac lesions and a high level of PGE2. Our objective was to investigate the role of PGE2 in cardiac lesions. BALB/c mice were infected with Trypanosoma cruzi (1x10(3) trypomastigote forms) and were treated daily with PBS, meloxicam (0.5 mg/kg) or etoricoxib (0.6 mg/kg). The animals were sacrificed on the 21st day of infection and we collected the cardiac tissue and spleen cells for tissue culture. We observed that treatment with COX-2 inhibitors was able to decrease synthesis of PGE2 by spleen cells. This reduction was accompanied by reduction of the inflammatory infiltrate, parasite nets, cardiac fibrosis and fewer COX-2 positive cells in cardiac tissue obtained from these animals. In conclusion, treatment with COX-2 inhibitors, and consequent inhibition of PGE2 synthesis, was able to reduce the cardiac damage observed during the acute phase of experimental Chagas disease, thus demonstrating the involvement of this mediator in the cardiac lesion.

Topics: Acute Disease; Animals; Cells, Cultured; Chagas Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Etoricoxib; Fibrosis; Male; Meloxicam; Mice; Mice, Inbred BALB C; Myocardium; Parasitemia; Prostaglandins; Pyridines; Spleen; Sulfones; Thiazines; Thiazoles; Trypanosoma cruzi

Both TGF-beta and cyclooxygenase-2 have been implicated in the pathogenesis of interstitial fibrosis in unilateral ureteral obstruction (UUO). Cyclic tensile stretch has been used in vitro to mimic the changes in intrarenal pressure in UUO. We sought to determine the effect of meloxicam (a selective cyclooxygenase-2 inhibitor) on extracellular matrix and TGF-beta synthesis in stretched renal fibroblasts (NRK-49F).. NRK-49F cells were subject to cyclic stretch (6 cycles/min, 15% elongation) using a Flexcell apparatus. Cells were stretched in the absence or presence of meloxicam for 48 h, and then cells and supernatants were isolated. Collagen was quantified by the Sircol assay; fibronectin and laminin were visualized using immunofluorescence. TGF-beta was quantified by ELISA, and protease activity determined by a colorimetric assay.. Both collagen and TGF-beta synthesis were increased following a 48-hour stretch of NRK-49F. Meloxicam significantly decreased the collagen and TGF-beta response to stretch. Stretch-induced fibronectin and laminin synthesis was also decreased by meloxicam. NRK-49F protease activity was decreased by stretch; this was unaffected by meloxicam.. Stretch of NRK-49F results in extracellular matrix synthesis, a process which may be activated in UUO and contribute to interstitial fibrosis. Inhibition of cyclooxygenase-2 may reduce fibrosis through a TGF-beta-dependent process.

Topics: Animals; Cell Culture Techniques; Collagen; Cyclooxygenase Inhibitors; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Fibroblasts; Fibrosis; Kidney; Meloxicam; Pressure; Rats; Tensile Strength; Thiazines; Thiazoles; Transforming Growth Factor beta; Ureteral Obstruction