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16,16-Dimethyl Prostaglandin E₂ Efficacy on Prevention and Protection from Bleomycin-Induced Lung Injury and Fibrosis

¹ Department of Internal Medicine and Specialistic Medicine, Section of Respiratory Diseases, University of Catania, Catania, Italy; ² Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy; and ³ IRCCS Centro Neurolesi "Bonino-Pulejo," Messina, Italy

Correspondence and requests for reprints should be addressed to Carlo Vancheri, M.D., Ph.D., Department of Internal Medicine and Specialistic Medicine, Respiratory Diseases Section, University of Catania, Via Passo Gravina, 187, 95125, Catania, Italy. E-mail: vancheri{at}unict.it

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E₂ (PGE₂) synthetic analog 16,16-dimethyl-PGE₂ (dmPGE₂) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE₂ dose of 30 µg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE₂ co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE₂ treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE₂ also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE₂ is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

Key Words: lung fibrosis • bleomycin • 16,16-dimethyl-PGE₂ • mice • IPF

CLINICAL RELEVANCE We showed protective effects and therapeutic potentialities of 16,16-dimethyl–prostaglandin E2 in the lung fibroreparative processes. These results encourage further research to find new options for the treatment of pulmonary fibrosis.