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  • br Materials and methods br


    Materials and methods
    Results The BUN and creatinine levels in the saline-treated CRF group were found to be significantly higher than those in the sham-operated control rats treated with either montelukast or saline (p<0.001; Table 1). Montelukast treatment in the CRF group reversed the serum creatinine level back to control levels, and significantly reduced the BUN level (p<0.001). Serum LDH activity showed a significant increase in the saline-treated CRF group, indicating a generalized tissue damage (p<0.01), while montelukast treatment in the CRF group suppressed the LDH activity (p<0.05; Table 1). On the other hand, the decreased plasma antioxidant capacity in the saline-treated CRF group (p<0.001) was elevated back to control levels by montelukast treatment (p<0.05). Chronic renal failure caused significant increases in the serum levels of leukotriene B4, and the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 (Fig. 1; p<0.001). When the CRF group was treated with montelukast, all of these pro-inflammatory mediators were significantly decreased (p<0.01–0.001). As compared with the sham-operated control group, apoptosis ratio of both neutrophils and lymphocytes was significantly increased in rats with CRF (p<0.05; Fig. 2). However, montelukast treatment reversed the apoptosis ratio of both white blood cells back to control ratios (p<0.05). The MDA levels, measured as a major degradation product of lipid peroxidation in the renal, pulmonary, cardiac and Refametinib tissues, were found to be significantly higher in the saline-treated CRF group as compared to those of the control group (p<0.001), while treatment with montelukast abolished these elevations (p<0.05–0.001; Fig. 3). In accordance with these findings, levels of the major cellular antioxidant GSH in all the studied tissues were significantly decreased in the saline-treated CRF group (p<0.01–0.001), while in the CRF group treated with montelukast, depleted GSH stores were replenished (p<0.05–0.01; Fig. 4). On the other hand, MPO activities in the renal, pulmonary, cardiac and brain tissues of saline-treated CRF group were significantly elevated, indicating enhanced tissue neutrophil infiltration (p<0.01–0.001; Fig. 5). Montelukast treatment abolished the elevations in lung, heart and brain tissue MPO activities (p<0.05–0.001) and significantly reduced the renal MPO activity (p<0.001). As a measure of enhanced fibrotic activity, collagen contents of all the studied tissues were increased in saline treated-CRF group (p<0.01–0.001). On the other hand, increased collagen levels were reversed back to control levels by montelukast treatment (p<0.05–0.001) (Fig. 6).
    Discussion As observed by increased lipid peroxidation, collagen content and myeloperoxidase activity and decreased GSH level, the present results demonstrate that CRF in rats yields to oxidative injury in the renal tissue, as well as in the lung, heart and brain tissues. These observed tissue damages were accompanied by elevated serum levels of pro-inflammatory mediators (LTB4, TNF-α, IL-1β and IL-6), while histological analyses verified the severity of CRF-induced systemic inflammatory response in all the studied tissues. The CysLT1 receptor antagonist montelukast administration protected against systemic oxidative injury and ameliorated the tissue injuries, while preserving the renal functions. Our results also demonstrate that CRF-induced organ toxicity is correlated with enhanced white blood cell apoptosis, while montelukast protected against leukocyte apoptosis and oxidative injury. Several studies have demonstrated that CysLTs increase in inflammatory conditions, such as ischemia/reperfusion or pyelonephritis [30], [31], [32], [33], [34]. Similarly, upregulation of the 5-lipoxygenase pathway of the arachidonate cascade in hemodialysis patients causes oxidative stress, lipid peroxidation and apoptosis in peripheral blood mononuclear cells [35]. In the present study, the elevation of serum LTB4, a bioactive metabolite of CysLT, suggests that this product has a pivotal role in the oxidative stress induced by uremia and might counteract with the progress of CRF [36]. On the other hand, antagonizing CysLT1 receptors with montelukast treatment prevented the elevation of cytokine production and the CRF-induced tissue injury, suggesting that leukotrienes may modulate the pro-inflammatory cytokines and the extent of oxidative injury.