Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury

Marco Failla,Elisa Gili,Achille P Caputi,Salvatore Cuzzocrea,Tiziana Genovese,Mariangela Sortino,Emanuela Mazzon,Carmelo Muià,Nunzio Crimi,Carlo Vancheri

doi:10.1186/1465-9921-7-137

Marco Failla, Elisa Gili + Show 8 more

Open Access

https://doi.org/10.1186/1465-9921-7-137

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Abstract

Leukotrienes are increased locally in idiopathic pulmonary fibrosis. Furthermore, a role for these arachidonic acid metabolites has been thoroughly characterized in the animal bleomycin model of lung fibrosis by using different gene knock-out settings.We investigated the efficacy of pharmacological inhibition of leukotrienes activity in the development of bleomycin-induced lung injury by comparing the responses in wild-type mice with mice treated with zileuton, a 5-lipoxygenase inhibitor and MK-571, a cys-leukotrienes receptor antagonist.Mice were subjected to intra-tracheal administration of bleomycin or saline and were assigned to receive either MK-571 at 1 mg/Kg or zileuton at 50 mg/Kg daily. One week after bleomycin administration, BAL cell counts, lung histology with van Gieson for collagen staining and immunohistochemical analysis for myeloperoxidase, IL-1 and TNF-α were performed.Following bleomycin administration both MK-571 and zileuton treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i) loss of body weight, (ii) mortality rate, (iii) lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts), (iv) lung edema, (v) histological evidence of lung injury and collagen deposition, (vi) lung myeloperoxidase, IL-1 and TNF-α staining.This is the first study showing that the pharmacological inhibition of leukotrienes activity attenuates bleomycin-induced lung injury in mice. Given our results as well as those coming from genetic studies, it might be considered meaningful to trial this drug class in the treatment of pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial pneumonias of unknown origin and one of the most aggressive interstitial lung diseases
When compared to lung sections taken from saline-treated animals, histological examination of WT mice treated with bleomycin were characterized by extensive inflammatory infiltration by neutrophils, lymphocyte and plasma cells extending through the lung epithelium, fibrosis and granulomas were seen in perivascular region (Fig. 1a and 1b)
Lung fibrosis grading [17] revealed a moderate to severe fibrosis reaction after one week of bleomycin administration, which was significantly reduced in animals treated with MK-571 and Zileuton (6.1+/-0.5 vs. 2.1+/-0.3 and 1.7+/-0.6, p < 0.01, Fig. 1e)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial pneumonias of unknown origin and one of the most aggressive interstitial lung diseases. It is characterized by a chronic and progressive course leading to respiratory failure with a median survival under 3 years [1,2,3]. A number of studies suggest a causal role for leukotrienes (LT) in lung fibrosis [5]. These are lipid mediators derived by the hydrolysis from membrane phospholipids of arachidonic acid by the phospholipase A2 and 5-lipoxygenase[6]. Increased LT levels have been demonstrated in mice lungs following intra-tracheal administration of bleomycin [10]

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