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  • The levels of circulating pro inflammatory cytokines are mar


    The levels of circulating pro-inflammatory cytokines are markedly elevated in ESRD, and have been speculated to play an important role as causative factors in a number of uremic complications [37]. The impairment of phagocyte functions and deregulated cytokine productions are highly prevalent in CRF. It might be due to underlying uremic condition, reduced renal clearance of cytokines, or co-morbidity, such as chronic moles to mass calculator failure [38]. However, the information on the oxidant status of patients with chronic renal failure mostly comes from patients on hemodialysis. Since uremia-related factors (e.g. hyperhomocysteinemia or inflammation), or dialysis-related factors (e.g. bioincompatible membranes or endotoxin-contaminated dialysate), may contribute to the genesis of oxidative stress in CRF patients [39], [40], its pathogenesis in these patients remains poorly defined. Recently, the presence of oxidative stress was previously demonstrated in patients with chronic kidney disease, who were not yet exposed to renal replacement therapy [41], [42]. Similarly, the results of the present study reveal that chronic renal failure with apparent uremic features presents with elevated levels of circulating inflammatory mediators (IL-1β, IL-6 and TNF-α levels) and oxidative injury of the kidney and remote organs. The pro-inflammatory cytokines activate neutrophils, macrophages or monocytes, platelets and mastocytes, which release large amounts of the toxic oxidizing reactive oxygen metabolites (ROMs), causing cellular injury via several mechanisms including the peroxidation of membrane lipids, and the oxidative damage of proteins and DNA [43], [44], [45]. In the present study, increased tissue MDA levels indicate the presence of enhanced lipid peroxidation due to CRF, while the declined levels of tissue glutathione demonstrate the depletion of the antioxidant pool. Montelukast, on the other hand, reduced the oxidative injury of cellular structures, while the expenditure of the intracellular antioxidant glutathione was prevented by montelukast. Moreover, CRF-induced reduction in plasma total antioxidant capacity was also reversed by montelukast treatment, with a concomitant reduction in the serum LDH activity. In accordance with these biochemical changes that verify the antioxidant effect of montelukast, both the morphologic evaluation and the renal function tests revealed that montelukast was also effective in protecting the kidney against CRF-induced degenerative changes. Furthermore, the remote organs that were targeted by the CRF-induced systemic inflammation, were also protected by the CysLT antagonist. In accordance with our results, in a study by Patel et al. [46], the degree of renal dysfunction, and inflammation caused by ischemia–reperfusion was significantly reduced in 5-lipoxygenase knockout mice as compared to wild type mice. Moreover, administration of 5-lipoxygenase inhibitor before ischemia–reperfusion, significantly reduced the degree of renal dysfunction and injury. The cellular sources of inflammatory cytokines enhanced in chronic renal failure patients are mainly neutrophils and monocytes [10]. Although the distinct mechanisms for the induction of leukocyte apoptosis remain uncertain, oxidant stress has been suggested as a major triggering factor. Our results demonstrate that CRF-induced oxidative injury is correlated with enhanced leukocyte apoptosis, while montelukast protected against leukocyte apoptosis and oxidative injury. In many diseases and acute inflammatory disorders, important components of the pathological processes are linked to the ability of neutrophils to release a complex assortment of agents that can destroy normal cells and dissolve connective tissues [47]. It has been shown that free radicals trigger the accumulation of leukocytes in the tissues and activated neutrophils secrete enzymes (e.g., MPO, elastase, proteases) and liberate more free radicals. ROMs can generate hypocholorus acid (HOCl) in the presence of neutrophil-derived MPO and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage [48]. Therefore, MPO plays a fundamental role in oxidant production by neutrophils, which are a potential source of oxygen free radicals [49] and are considered to be a major effector cell in the tissue damage. Accumulated evidence has shown that MPO activity is elevated in many renal diseases [50]. In the present study, elevated levels of MPO activity in CRF were inhibited by montelukast treatment, indicating that the protective effect of montelukast involves an inhibitory effect on neutrophil activity. In support of our findings, Matsui et al. have found that a 5-lipoxygenase inhibitor could improve hepatic functions in hepatic I/R by reducing tissue MPO activity [51]. Similarly, Takamatsu et al. [31] have studied the role of leukotrienes in hepatic I/R and suggested that these lipid mediators enhanced the vascular permeability and recruitment of neutrophils. Similarly, Noiri et al. [52] have shown that the CysLTs receptor antagonist provides a significant protective effect in acute renal failure. In accordance with the aforementioned studies, the results of the present study indicate that oxidative injury and associated organ dysfunction can be ameliorated by blocking the CysLTs receptors, which are responsible of increased permeability, and thus, recruitment of neutrophils and macrophages, which are producers of the pro-inflammatory mediators. Moreover, in an animal model of human membranous nephropathy, the synthesis of CysLTs from macrophages was increased by an ischemic challenge in the renal tissue [30]. Thus, CysLT receptor antagonist montelukast may have acted as an antioxidant not only by blocking the recruitment of neutrophils and macrophages, but the effect may also involve an interaction with the receptors expressed on the neutrophils and macrophages.