STY39, a Novel Alpha-Melanocyte-Stimulating Hormone Analogue, Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice

Abstract

Various anti-inflammatory agents have been used to treat acute or chronic lung injury-induced pulmonary fibrosis (PF). However, the efficacy of the available treatments is disappointing, and new therapies are urgently needed. In the current study, we investigated the effect of a novel α-melanocyte-stimulating hormone analog, STY39, on bleomycin (BLM)-induced pulmonary inflammation and fibrosis in mice. C57BL/6 mice received an intratracheal injection of BLM before being treated with STY39 (0.625, 1.25, or 2.5 mg/kg, i.p.) once a day for 14 consecutive days. Various parameters, reflecting the inflammatory reaction, metabolism of extracellular matrix, myofibroblast proliferation, and degree of fibrosis in the lung, were evaluated. We found that STY39 significantly improved the survival of mice with lethal BLM-induced lung injury, limited body weight loss and the increase in the lung index, reduced the mRNA expression of types I and III procollagen and the production of hydroxyproline in the lung, diminished myofibroblast proliferation, and ultimately reduced BLM-induced lung damage. Further investigation revealed that, in a dose-dependent manner, STY39 treatment inhibited leukocyte migration into the lung; reduced the production of TNF-α, IL-6, macrophage inflammatory protein 2, and transforming growth factor β1 in the lung; and altered the ratio of matrix metalloproteinase 1 to tissue inhibitors of metalloproteinase 1. These findings suggest that STY39 attenuates BLM-induced experimental PF by limiting the inflammatory reaction through the inhibition of proinflammatory and profibrosis cytokines and by accelerating the metabolism of extracellular matrix. Therefore, STY39 may be an effective therapy for preventing PF. ABBREVIATIONS-ALI-acute lung injury; α-MSH-α-melanocyte-stimulating hormone; α-SMA-α-smooth muscle actin; BLM-bleomycin; BALF-bronchoalveolar lavage fluid; ECM-extracellular matrix; Hyp-hydroxyproline; IPF-idiopathic pulmonary fibrosis; L-LI-lethal lung injury; MMP-1-matrix metalloproteinase 1; MIP-2-macrophage inflammatory protein 2; NL-PF-nonlethal PF; PF-pulmonary fibrosis; TIMP-1-tissue inhibitors of metalloproteinases 1