Preventive and therapeutic effects of thymosin β4 N-terminal fragment Ac-SDKP in the bleomycin model of pulmonary fibrosis

// Enrico Conte 1 , Evelina Fagone 1 , Elisa Gili 1 , Mary Fruciano 1 , Maria Iemmolo 1 , Maria Provvidenza Pistorio 1 , Daniela Impellizzeri 2 , Marika Cordaro 2 , Salvatore Cuzzocrea 2 , Carlo Vancheri 1 1 Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy 2 Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, 98166 Messina, Italy Correspondence to: Enrico Conte, email: econte@unict.it Keywords: Ac-SDKP, lung fibrosis, bleomycin, mouse, IPF Received: January 22, 2016 Accepted: March 04, 2016 Published: March 27, 2016 ABSTRACT In this study, the bleomycin model of pulmonary fibrosis was utilized to investigate putative anti-fibrotic activity of Ac-SDKP in vivo . Male CD-1 mice received intra-tracheal bleomycin (BLEO, 1 mg/kg) instillation in the absence or presence of Ac-SDKP (a dose of 0.6 mg/kg delivered intra-peritoneally on the day of BLEO treatment, d0, followed by bi-weekly additional doses). To evaluate therapeutic effects in a subset of mice, Ac-SDKP was administered one week after BLEO instillation (d7). Animals were sacrificed at one, two, or three weeks later. Measurement of fluid and collagen content in the lung, Broncho Alveolar Lavage Fluid (BALF) analysis, lung histology, immunohistochemistry (IHC), and molecular analysis were performed. Compared to BLEO-treated mice, animals that received also Ac-SDKP (at both d0 and d7) had significantly decreased mortality, weight loss, inflammation (edema, and leukocyte lung infiltration), lung damage (histological evidence of lung injury), and fibrosis (collagen histological staining and soluble collagen content in the lung) at up to 21 days. Moreover, IHC and quantitative RT-PCR results demonstrated a significant decrease in BLEO-induced IL-17 and TGF-β expression in lung tissue. Importantly, α-SMA expression, the hallmark of myofibroblast differentiation, was also decreased. This is the first report showing not only a preventive protective role of Ac-SDKP but also its significant therapeutic effects in the bleomycin model of pulmonary fibrosis, thus supporting further preclinical and clinical studies.