title: Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury.
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-alpha 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-alpha 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.
authors.affiliation: Department of Internal Medicine and Specialistic Medicine, Section of Respiratory Diseases, University of Catania, Catania, Italy. marcofailla@yahoo.it
authors.forename: Marco
authors.initials: M
authors.lastname: Failla
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Elisa
authors.initials: E
authors.lastname: Gili
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sortino
authors.forename: Nunzio
authors.initials: N
authors.lastname: Crimi
authors.forename: Achille P
authors.initials: AP
authors.lastname: Caputi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Carlo
authors.initials: C
authors.lastname: Vancheri
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D004195:Disease Models, Animal; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice
chemical_list: D020024:Leukotriene Antagonists; D015289:Leukotrienes; D001761:Bleomycin