In this study, we evaluated the protective effect and therapeutic potential of the PGE2 synthetic analogue 16,16-dimethyl-PGE2 (dmPGE2) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intra-tracheal administration of bleomycin (1 mg/kg ) received a dmPGE2 dose of 30 micrograms/Kg/day by continuous sub-cutaneous infusion. Bronchoalveolar Lavage (BAL), immunohistochemical analysis for IL-1, TNF-alpha 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 to 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: (i) lung infiltration by leukocytes, ii) myeloperoxidase activity, (iii) IL-1, TNF-alpha and nitrotyrosine immunostaining (iv) lung edema, (v) histological 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, also delayed administration of dmPGE2 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.