Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas-Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, CEP 30882-650-Pampulha, Belo Horizonte, MG, Brazil.
Am J Respir Cell Mol Biol. 2011 Jul;45(1):72-80. doi: 10.1165/rcmb.2009-0406OC. Epub 2010 Sep 10.
CC chemokines play an important role in the pathogenesis of idiopathic pulmonary fibrosis. Few studies have evaluated the efficacy of therapeutically targeting CC chemokines and their receptors during interstitial lung diseases. In the present study, the therapeutic effects of Evasin-1, a tick-derived chemokine-binding protein that has high affinity for CCL3/microphage inflammatory protein (MIP)-1α, was investigated in a murine model of bleomycin-induced lung fibrosis. CCL3/MIP-1α concentrations in lung homogenates increased significantly with time after bleomycin challenge, and this was accompanied by increased number of leukocytes and elevated levels of CCL2/monocyte chemoattractant protein (MCP)-1, CCL5/regulated upon activation, normal T cell expressed and secreted, TNF-α and transforming growth factor-β(1), and pulmonary fibrosis. Administration of evasin-1 on a preventive (from the day of bleomycin administration) or therapeutic (from Day 8 after bleomycin) schedule decreased number of leukocytes in the lung, reduced levels of TNF-α and transforming growth factor-β(1), and attenuated lung fibrosis. These protective effects were similar to those observed in CCL3/MIP-1α-deficient mice. In conclusion, targeting CCL3/MIP-1α by treatment with evasin-1 is beneficial in the context of bleomycin-induced lung injury, even when treatment is started after the fibrogenic insult. Mechanistically, evasin-1 treatment was associated with decreased recruitment of leukocytes and production of fibrogenic cytokines. Modulation of CCL3/MIP-1α function by evasin-1 could be useful for the treatment of idiopathic pulmonary fibrosis.
CC 趋化因子在特发性肺纤维化的发病机制中发挥着重要作用。很少有研究评估在间质性肺疾病期间治疗性靶向 CC 趋化因子及其受体的疗效。在本研究中，研究了 Evasin-1（一种源自蜱的趋化因子结合蛋白，对 CCL3/巨噬细胞炎症蛋白（MIP）-1α具有高亲和力）在博来霉素诱导的肺纤维化小鼠模型中的治疗效果。在博来霉素攻击后，肺匀浆中的 CCL3/MIP-1α 浓度随时间显著增加，并且伴随着白细胞数量增加和 CCL2/单核细胞趋化蛋白（MCP）-1、CCL5/调节正常 T 细胞表达和分泌、TNF-α 和转化生长因子-β(1) 水平升高，以及肺纤维化。预防性（从博来霉素给药之日起）或治疗性（从博来霉素给药后第 8 天起）给予 Evasin-1 可减少肺中的白细胞数量，降低 TNF-α 和转化生长因子-β(1) 的水平，并减轻肺纤维化。这些保护作用与 CCL3/MIP-1α 缺陷小鼠观察到的相似。总之，用 Evasin-1 治疗靶向 CCL3/MIP-1α 在博来霉素诱导的肺损伤情况下是有益的，即使在纤维化损伤后开始治疗也是如此。从机制上讲，Evasin-1 治疗与白细胞募集和纤维生成细胞因子产生减少有关。Evasin-1 对 CCL3/MIP-1α 功能的调节可能对特发性肺纤维化的治疗有用。
