Department of Anesthesiology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
Shock. 2011 Mar;35(3):308-14. doi: 10.1097/SHK.0b013e3181f8f15e.
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.
各种抗炎药物已被用于治疗急性或慢性肺损伤引起的肺纤维化（PF）。然而，可用治疗方法的疗效令人失望，迫切需要新的治疗方法。在目前的研究中，我们研究了新型α-黑色素细胞刺激激素类似物 STY39 对博莱霉素（BLM）诱导的小鼠肺炎症和纤维化的影响。C57BL/6 小鼠在接受 BLM 气管内注射后，每天腹腔注射 STY39（0.625、1.25 或 2.5 mg/kg），连续 14 天。评估了反映炎症反应、细胞外基质代谢、肌成纤维细胞增殖和肺纤维化程度的各种参数。我们发现，STY39 显著提高了致命 BLM 诱导的肺损伤小鼠的存活率，限制了体重减轻和肺指数的增加，降低了肺中 I 型和 III 型前胶原的 mRNA 表达和羟脯氨酸的产生，减少了肌成纤维细胞的增殖，并最终减轻了 BLM 诱导的肺损伤。进一步的研究表明，STY39 治疗以剂量依赖性方式抑制白细胞向肺内迁移；减少肺中 TNF-α、IL-6、巨噬细胞炎症蛋白 2 和转化生长因子β1 的产生；并改变基质金属蛋白酶 1 与组织抑制剂金属蛋白酶 1 的比值。这些发现表明，STY39 通过抑制促炎和促纤维化细胞因子来限制炎症反应，并通过加速细胞外基质的代谢来减轻 BLM 诱导的实验性 PF。因此，STY39 可能是预防 PF 的有效治疗方法。
