Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis
Introduction
Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, which catalyzes the hydrolysis of cGMP and has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum [1], [2]. The data of a recent study have shown that sildenafil, acting via nitric oxide (NO)-dependent mechanism, prevented indomethacin-induced gastropathy, possibly through a reduction of leukocyte adhesion and maintenance of gastric blood flow [3].
Bleomycin is an anti-cancer agent with limited therapeutic use in the clinics due to its toxicities [4]. Bleomycin-induced pulmonary fibrosis is a widely used animal model of idiopathic pulmonary fibrosis [5]. Intratracheal administration of bleomycin into the lungs of the rats has shown to cause alveolar damage, fibroblast proliferation, inflammatory cell accumulation and collagen deposition all of which contribute to the development of lung fibrosis. The reactive oxygen metabolites were found to have a significant role in the development of lung injury in this model. Indeed, several observations demonstrated that antioxidant regimen including N-acetylcysteine and erdosteine attenuated the extent of tissue injury [5], [6], [7], [8], [9]. Moreover, excess nitric oxide production was also shown to be involved in the bleomycin-induced toxicity in rats [5].
In the light of the above-mentioned findings, this study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant–antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis.
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Animals
Sprague–Dawley rats of either sex (200–250 g; n = 7–8 per group) were kept in a room at a constant temperature (22 ± 1 °C) with 12 h light/dark cycles and fed standard pellet chow and water ad libitum. The study protocol was approved by Marmara University, School of Medicine, Animal Care and Use Committee.
Induction of lung fibrosis
After an overnight fasting, lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia with 60 mg/kg ketamine hydrochloride
Microscopic evaluation of the lung samples
The microscopic lesion score (4.7 ± 0.2) of the group with bleomycin-induced lung fibrosis was reduced by treatment with sildenafil citrate (4.2 ± 0.2), however, this effect did not reach a statistically significant level. Interestingly, in l-NAME-treated sildenafil group, the microscopic lesion score showed a significant decrease when compared to the group that was not treated with l-NAME (3.6 ± 0.2; p < 0.05) (Fig. 1).
The histopathological analysis of the lung tissues from either untreated or
Discussion
The results of the present study demonstrate that daily sildenafil citrate treatment of rats markedly improves bleomycin-induced lung fibrosis as confirmed by biochemical assays.
Recently, experiments have shown the involvement of oxidative mechanisms in the pathogenesis of bleomycin-induced toxicity. It has generally been hypothesized that activated inflammatory cells which accumulate in the lungs release reactive oxygen species that result in lung injury, and proliferation of fibroblasts in
Acknowledgments
Sildenafil citrate was a generous gift of Fako Pharmaceutical Company, Istanbul, Turkey for research use.
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