TNF a major cytokine that is critical in

TNF-α, a major cytokine that is critical in acute and chronic inflammation, is responsible from chemotaxis, acute phase reactions and endothelial activation (Mahalingam and Karupiah, 1999). Our study showed that TNF-α is increased significantly in the pyelonephritic rats and montelukast displayed an inhibitory effect on TNF-α release along with the alleviation of neutrophil-mediated parenchymal destruction, suggesting that anti-inflammatory effect of montelukast in reducing the damaging effects of E. coli may be ascribed to an inhibition of TNF-α-mediated cytotoxicity. In the present study, malondialdehyde, which is a good indicator of the degree of lipid peroxidation (Gupta et al., 1996, Cherubini et al., 2005), was increased in the kidneys of E. coli-injected rats, indicating the presence of oxidative damage in exudative pyelonephritis. In accordance with that, GSH stores in the renal tissue were significantly depleted due to renal infection, indicating that GSH was used as an antioxidant for the detoxification of toxic oxygen metabolites. Reduced thiol agents, such as GSH, which are capable of interacting with free radicals to yield more stable elements, are known for their ability to repair membrane lipid peroxides (Rodriguez et al., 2004). As reported by Ross (1988), cell injury and enhanced cell susceptibility to toxic chemicals are related to the efflux of GSH precursors and hence to diminished GSH biosynthesis. In this sense, GSH and other antioxidants play a critical role in limiting the propagation of free-radical reactions, which would otherwise result in extensive lipid peroxidation. Due to its inhibitory effects on neutrophil infiltration, montelukast treatment reduced the oxidative injury of the kidney and restored the GSH levels significantly. Similarly, Noiri et al. (2000) have shown that the leukotriene CysLTs Aripiprazole antagonist provides a significant protective effect on acute renal failure. These data collectively support that cellular oxidative stress is a critical step in pyelonephritis-induced oxidative injury and leukotriene CysLTs are one of the principal mediators involved in the renal damage. Furthermore, the current findings demonstrate that the leukotriene CysLT1 receptor antagonist montelukast decreased the severity of kidney damage and renal scarring, by reversing the oxidative effects of E. coli infection, suggesting that antileukotriene drugs might have a future role in the treatment of acute pyelonephritis.
Introduction Asthma is an inflammatory condition of the airways characterized by bronchial hyperresponsiveness, airways obstruction, and epithelial damage.[1], [2], [3] Pathological changes are produced by the actions of various mediators, being released from inflammatory cells as a result of antigen recognition by IgE receptors. The inflammatory mediators have a variety of effects on target cells in the airways and may induce many of the pathological features found in asthma. Mediators produce their effects on target cells by the activation of specific cell surface receptors. Traditional asthma therapy mainly focused on relief of symptoms by the administration of mast cell stabilizers or bronchodilators.[5], [6] The attention for new therapeutic strategies has shifted to suppression of the inflammatory component, sometimes in combination with bronchodilation.[7], [8] For future development of antiasthmatics, one direction currently followed is blocking the actions of multiple inflammatory mediators. Leukotrienes were identified as inflammatory mediators in the late 1970s. Specific modulation of the effects of leukotrienes is possible by intervention of the biosynthesis or by blocking the specific leukotriene receptors. Three types of leukotriene receptors have been identified in humans: BLT, CysLT1, and CysLT2. The CysLT1 receptor, formerly LTD4, has been most thoroughly characterized.[10], [11], [12], [13] Radioligand binding studies classified this receptor as G-protein-coupled and photoaffinity labeling in guinea pig lung identified it as a single polypeptide with a molecular mass of 45kDa. In addition to respiratory tissues, CysLT1 receptors are located in ileum, gall bladder, stomach, cardiovascular system, and gastrointestinal tract.[10], [11], [13] Pharmacological studies revealed that the bronchoconstriction, mucus secretion, and possibly also the inflammatory condition of the airways are caused by an activation of the CysLT1 receptor.