17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice.
17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice.
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DOI：
10.14814/phy2.12628
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发表时间：
2015-12
影响因子：
2.5
通讯作者：
Okajima F
中科院分区：
文献类型：
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作者：
Yatomi M;Hisada T;Ishizuka T;Koga Y;Ono A;Kamide Y;Seki K;Aoki-Saito H;Tsurumaki H;Sunaga N;Kaira K;Dobashi K;Yamada M;Okajima F
特发性肺纤维化(IPF)是一种破坏性炎症性疾病，治疗选择有限。炎症在肺纤维化的发生发展中起着不可或缺的作用。未解决的炎症反应可导致严重的组织损伤、慢性炎症和纤维化。溶血素是一类内源性ω-3脂肪酸衍生的脂类介质，具有消炎作用。RvD1具有很强的抗炎、促分解活性，且不会引起免疫抑制。它的同分异构体17(R)-Resolvin D_1(17(R)-RvD_1)具有与RvD_1相同的功能。此外，17(R)-RvD1能抵抗二十烷类氧化还原酶的快速失活。在目前的研究中，我们验证了这样的假设，即17(R)-RvD1可以通过减少炎症和肺纤维化而在IPF中提供治疗益处，同时保持正常的免疫反应不变。通过微渗泵给予博莱霉素(BLM)诱导小鼠肺纤维化，然后给予17(R)-RvD_1或赋形剂腹腔注射。从博莱曼治疗开始给予17(R)-rvd1可减少中性粒细胞肺泡浸润、肺胶原含量和白细胞介素1β(IL-1β)、转化生长因子-β1(转化生长因子-β1)、结缔组织生长因子(CTGF1)和I型胶原的表达，并减少随后的组织学可检测到的纤维化。脂氧素A4受体/甲酰肽受体2(ALX/FPR2)拮抗剂可抑制17(R)-RvD1诱导的炎症细胞浸润。在肝纤维化后期给予17(R)-Rvd1也可改善肺衰竭。这些结果表明，17(R)-RvD1通过促进中性粒细胞炎症的消退来减轻肺纤维化，并提供肺恢复。这些数据突出了17(R)-Rvd1在治疗这种顽固性疾病方面的治疗潜力。
Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. Inflammation plays an integral role in the development of pulmonary fibrosis. Unresolved inflammatory responses can lead to substantial tissue injury, chronic inflammation, and fibrosis. The resolvins are a family of endogenous ω‐3 fatty acid derived‐lipid mediators of inflammation resolution. Resolvin D1 (RvD1) displays potent anti‐inflammatory, pro‐resolving activity, without causing immunosuppression. Its epimer, 17(R)‐resolvin D1 (17(R)‐RvD1), exhibits equivalent functionality to RvD1. In addition, 17(R)‐RvD1 is resistant to rapid inactivation by eicosanoid oxidoreductases. In the present study, we tested the hypothesis that 17(R)‐RvD1 can provide a therapeutic benefit in IPF by reducing inflammation and pulmonary fibrosis, while leaving the normal immune response intact. Mice were exposed to bleomycin (BLM) via micro‐osmotic pump to induce pulmonary fibrosis, and were then treated with 17(R)‐RvD1 or vehicle by intraperitoneal injection. Administration of 17(R)‐RvD1 from the start of BLM treatment attenuated neutrophil alveolar infiltration, lung collagen content, and Interleukin‐1β (IL‐1β), transforming growth factor‐β1 (TGF‐β1), connective tissue growth factor (CTGF), and type I collagen mRNA expression, along with subsequent reduction in histologically detectable fibrosis. The 17(R)‐RvD1‐induced infiltration of inflammatory cells was inhibited by an antagonist of lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2). The administration of 17(R)‐RvD1 at the later fibrotic stage also improved the lung failure. These results suggest that 17(R)‐RvD1 attenuates pulmonary fibrosis by promoting the resolution of neutrophilic inflammation and also provides pulmonary restoration. These data highlight the therapeutic potential of 17(R)‐RvD1 in the management of this intractable disease.