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

Marco Failla^*¹ , Tiziana Genovese^*²^,3 , Emanuela Mazzon²^,3 , Elisa Gili¹ , Carmelo Muià²^,3 , Mariangela Sortino⁴ , Nunzio Crimi¹ , Achille P Caputi²^,3 , Salvatore Cuzzocrea^*²^,3 and Carlo Vancheri¹

¹Department of Internal Medicine and Specialistic Medicine, Section of Respiratory Diseases, University of Catania, Catania, Italy

²Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy

³Centro per lo Studio e il Trattamento dei Neurolesi Lungodegenti, University of Messina, Messina, Italy

⁴Department of Clinical and Experimental Medicine and Pharmacology, Catania, Italy

author email corresponding author email* Contributed equally

Respiratory Research 2006, 7:137doi:10.1186/1465-9921-7-137


Published:	21 November 2006

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.