Department of Anesthesiology, Institute of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Int J Mol Med. 2018 Dec;42(6):3083-3092. doi: 10.3892/ijmm.2018.3914. Epub 2018 Oct 2.
Pulmonary fibrosis is an aggressive end‑stage disease. Transforming growth factor‑β1 (TGF‑β1) mediates lung fibroblast activation and is essential for the progress of pulmonary fibrosis. BML‑111, a lipoxinA4 (LXA4) receptor (ALX) agonist, has been reported to possess anti‑fibrotic properties. The present study aimed to elucidate whether BML‑111 inhibits TGF‑β1‑induced mouse embryo lung fibroblast (NIH3T3 cell line) activation in vitro and bleomycin (BLM)‑induced pulmonary fibrosis in vivo. In vitro experiments demonstrated that BML‑111 treatment inhibits TGF‑β1‑induced NIH3T3 cell viability and the expression of smooth muscle α actin (α‑SMA), fibronectin and total collagen. Furthermore, this suppressive effect was associated with mothers against decapentaplegic homolog (Smad)2/3, extracellular signal‑regulated kinase (ERK) and Akt phosphorylation interference. In vivo experiments revealed that BML‑111 treatment markedly improved survival rate and ameliorated the destruction of lung tissue structure. It also reduced interleukin‑1β (IL‑1β), tumor necrosis factor‑α (TNF‑α) and TGF‑β1 expression in the BLM intratracheal mouse model. In addition, the expression ofα‑SMA and extracellular matrix (ECM) deposition (total collagen, hydroxyproline and fibronectin) were also suppressed following BML‑111 treatment. However, BOC‑2, an antagonist of ALX, partially weakened the effects of BML‑111. In conclusion, these results indicated that BML‑111 inhibits TGF‑β1‑induced fibroblasts activation and alleviates BLM‑induced pulmonary fibrosis. Therefore, BML‑111 may be used as a potential therapeutic agent for pulmonary fibrosis treatment.
肺纤维化是一种侵袭性的终末期疾病。转化生长因子-β1（TGF-β1）介导肺成纤维细胞的激活，是肺纤维化进展的关键。脂氧素 A4（LXA4）受体（ALX）激动剂 BML-111 已被报道具有抗纤维化特性。本研究旨在阐明 BML-111 是否能抑制 TGF-β1 诱导的体外小鼠胚胎肺成纤维细胞（NIH3T3 细胞系）激活和博来霉素（BLM）诱导的肺纤维化。体外实验表明，BML-111 处理可抑制 TGF-β1 诱导的 NIH3T3 细胞活力和平滑肌α肌动蛋白（α-SMA）、纤维连接蛋白和总胶原的表达。此外，这种抑制作用与母系对抗 decapentaplegic 同源物（Smad）2/3、细胞外信号调节激酶（ERK）和 Akt 磷酸化干扰有关。体内实验表明，BML-111 处理可显著提高存活率，改善肺组织结构破坏。它还降低了 BLM 气管内小鼠模型中的白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和 TGF-β1 的表达。此外，BML-111 处理还抑制了α-SMA 和细胞外基质（ECM）沉积（总胶原、羟脯氨酸和纤维连接蛋白）。然而，ALX 的拮抗剂 BOC-2 部分削弱了 BML-111 的作用。综上所述，这些结果表明 BML-111 抑制 TGF-β1 诱导的成纤维细胞激活并缓解 BLM 诱导的肺纤维化。因此，BML-111 可能被用作肺纤维化治疗的潜在治疗剂。
