Possible Modulatory Role of Nitric Oxide in Lung Toxicity Induced in Rats by Chronic Administration of Bleomycin

Abstract

Background: The present study was undertaken to evaluate whether stimulation or inhibition of nitric oxide (NO) synthesis could affect lung toxicity induced by chronic administration of bleomycin (BLM). L-arginine (ARG) and N^G-nitro-L-arginine methyl ester (L-NAME) were employed as NO precursor and NO synthesis inhibitor, respectively. Methods: BLM was administered intraperitoneally to male Wistar rats at a dose of 15 mg/kg, 3 times a week, for a total period of 4 weeks. ARG (500 mg/kg/day) and L-NAME (100 mg/kg/day) were given in drinking water, the treatments commenced with BLM and continued up to the end of the experiment. Appropriate controls were performed. Results: BLM treatment resulted in a pronounced fall in the average body weight of animals, together with a rise in the lung weight/body weight ratio. In the lung tissue, elevated levels of hydroxyproline (HP) and lipid peroxides (LP) as well as decreased activity of angiotensin converting enzyme (ACE) further evidenced the toxicity. Pulmonary level of NO end products, nitrite and nitrate, tended to rise but did not reach a significant level. Glutathione (GSH) content and GSH-peroxidase activity measured in the lung remained unaltered. In animals given concurrent treatment of BLM and ARG, a remarkable rise in the pulmonary level of nitrite and nitrate was observed. Average body weight was still decreased when compared with the untreated control group, but the decrease was significantly less than that observed in the BLM group. In addition, ARG decreased the extent of BLM-induced elevations of lung HP and LP levels. Meanwhile, ARG failed to significantly affect the BLM-evoked decrease in pulmonary ACE activity and increase in lung weight/body weight ratio. In animals given simultaneous treatment of BLM and L-NAME, noticeable reductions in the pulmonary levels of nitrite/nitrate and GSH were detected. BLM-induced decrease in body weight and increase in lung weight/body weight ratio were accentuated by L-NAME co-treatment. Furthermore, administration of L-NAME led to more profound elevations in lung HP and LP levels, without affecting the decrease in pulmonary ACE activity elicited by BLM. Conclusion: In principle, the present findings indicate that the lung toxicity exerted by chronic administration of BLM is alleviated by ARG, but exacerbated by L-NAME supplementation. This could indicate a possible protective role of NO.

Inhibition or knock out of Inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury

“…Pharmacological inhibitors of NOS, and also ablation of the gene for iNOS has been shown to reduce the development of the inflammatory response [47-49]. In addition, various studies have point out that iNOS play an important role in the pulmomary fibrosis induced by bleomycin [50-52]. Therefore, some study have also demonstrated that non-selective and partial selective iNOS inhibitor like aminoguanidine exert beneficial effect against lung injury induced by bleomycin [53-57].…”

Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats

“…Bleomycin-induced pulmonary injury and lung fibrosis have been documented in studies using several animal models [4, 5]. These models have been widely used for studying the mechanisms involved in the progression of human pulmonary fibrosis and the impact of various drugs on this progression [6, 7]. The bleomycin induces the genesis of reactive oxygen species upon binding to DNA and iron, which in turn causes DNA damage [8].…”

Antifibrosis effects of total glucosides of Danggui–Buxue–Tang in a rat model of bleomycin-induced pulmonary fibrosis

“…This model has been widely used for studying the mechanisms involved in the progression of human pulmonary fibrosis and the impact of various drugs on this progression (Yara et al, 2001;El-Khatib, 2002).…”