Resveratrol alleviates bleomycin-induced lung injury in rats
Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease with a high mortality rate and poor response to available medical therapy [1], [2]. It is characterized by an accumulation of alveolar macrophages and neutrophils in the lower respiratory tract, paranchymal cell injury and fibrosis of the alveolar walls [3].
Fibrosis is a feature of tissue remodeling that arises as a result of homeostatic repair mechanism but it may impact adversely the physiological function of the lungs [4]. It is well known that accumulated macrophages and neutrophils, releasing of toxic oxidants, are capable of inducing oxidant-mediated lung paranchymal cell toxicity [2], [5]. Activated neutrophils can also release myeloperoxidase (MPO), an enzyme that interacts with H2O2, to form the highly toxic hydroxyl radicals [6]. In this regard, it is reasonable to hypothesize that the alveolar epithelial cell injury that characterizes IPF may result, at least in part, from an enhanced oxidant burden that may exist in the lower respiratory tract of patients. Thus, supplementing patients with agents that have antioxidant and anti-inflammatory properties as an adjuvant therapy may have beneficial effects in the treatment of IPF.
Resveratrol (3,5,4′-trans-trihydroxystilbene), a natural phytoalexin present in grapes, peanuts, mulberries and red wine, has various pharmacological effects including anti-inflammatory properties, modulation of lipid metabolism and prevention of cancer [7], [8]. Its anti-inflammatory effect is related to inhibiting oxidation, leukocyte priming and expression of inflammatory mediators. Recently, it has been found to prevent and cure cardiovascular diseases [9] and improve microcirculatory disorders by protecting the vascular endothelium, modulation of lipid metabolism, increasing cellular nitric oxide levels, as well as inhibiting platelet aggregation [10]. Most of the studies have focused on the beneficial effects of resveratrol in the prevention of coronary hearth diseases and, cancer; however there are a limited number of studies considering its possible use as a therapeutic agent against drug induced oxidative organ damage. On the other hand, the use of alternative therapies, herbs, and supplements occurs at a very high rate among patients attending a variety of care settings [11].
Since bleomycin, one of the clinically important causative agents in pulmonary fibrosis, is widely used in experimental models of human disease resembling pulmonary fibrosis [12], in the present study we aimed to investigate the possible protective effect of resveratrol against bleomycin-induced oxidative lung injury in rats.
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Animals
Male Wistar albino rats (200–250 g) were housed in an air-conditioned room with 12-h light and dark cycles, where the temperature (22±2 °C) and relative humidity (65–70%) were kept constant. All experimental protocols were approved by the Marmara University School of Medicine Animal Care and Use Committee.
Experimental model for pulmonary fibrosis and treatment protocols
Following an overnight fasting, the rats were anesthetized (0.5 mg/kg ketamine hydrochloride and 1 mg/kg xylazine) and a midline incision was made in the neck and the trachea was exposed by blunt
Total and differential cell count in bronchoalveolar lavage fluid
Recovery rates of BALF ranged from 80 to 95 and were not significantly different between the groups. As shown in Table 1, bleomycin treatment caused significant increase in the total cell number and the percentage of neutrophils, while the percentage of lymphocytes and alveolar macrophages were significantly decreased. On the other hand, resveratrol treatment reversed these changes significantly.
Biochemical markers of lung injury and damage
In order to assess the pulmonary inflammation, proinflammatory cytokines, TGF-β, TNF-α, IL-1β, and
Discussion
Bleomycin, a glycopeptide antibiotic, is generally used in the treatment of lymphomas, squamous cell carcinoma and testicular tumors [19]. Due to its toxic effect on epithelial cells bleomycin is also used for the treatment of malignant pleural or pericardial effusions. However, the effective use of bleomycin in chemotherapy is greatly limited, since it causes a dose-dependent interstitial pneumonitis that often progresses to interstitial pulmonary fibrosis. In addition, several studies have
Acknowledgments
The authors are grateful to Ozgur Goknel, the Medical Director, in MICROGEN Pharmeceutical, for supplying us the resveratrol.
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