Resveratrol alleviates bleomycin-induced lung injury in rats

Abstract

Antioxidant therapy may be useful in diseases with impaired oxidant–antioxidant balance such as pulmonary fibrosis. This study was designed to examine the effects of resveratrol, an antioxidant agents, against bleomycin-induced pulmonary fibrosis and oxidative damage. Wistar albino rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) followed by either saline or resveratrol (10 mg/kg; orally) for 14 days. The effect of resveratrol on pulmonary oxidative damage was studied by cell count and analysis of cytokine levels (TGF-β, TNF-α, IL-1β and IL-6) in the bronchoalveolar lavage fluid (BALF) and biochemical measurements of malondialdehyde (MDA), an end product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the lung tissue. Bleomycin-induced lung fibrosis was determined by lung collagen contents and also microscopically.

Bleomycin caused a significant decrease in lung GSH, which was accompanied with significant increases in MDA level, MPO activity, and collagen contents of the lung tissue concomitant with increased levels of the pro-inflammatory mediators and cell count in BALF. On the other hand, resveratrol treatment reversed all these biochemical indices as well as histopathological alterations induced by bleomycin. The results demonstrate the role of oxidative mechanisms in bleomycin-induced pulmonary fibrosis, and resveratrol, by its antioxidant properties, ameliorates oxidative injury and fibrosis due to bleomycin. Thus, an effective supplement with resveratrol as an adjuvant therapy may be a very promising agent in alleviating the side effects of bleomycin, an effective chemotherapeutic agent.

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.