Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250000, China; The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Department of Respiration and Critical Care Medicine, Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, China.
Department of Clinical Laboratory Diagnostics, School of Laboratory Medicine, Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui, 233000, China.
Eur J Pharmacol. 2022 Sep 15;931:175184. doi: 10.1016/j.ejphar.2022.175184. Epub 2022 Aug 12.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-β1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-β1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-β1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.
特发性肺纤维化（IPF）是一种慢性、进行性、纤维性间质性肺炎，治疗选择有限。桉树脑是从桉树属植物中分离出来的萜氧化物，据报道具有多种生物学活性，如抗炎和抗氧化作用。在本研究中，我们旨在确定桉树脑是否能缓解博来霉素（BLM）诱导的肺纤维化，并抑制白细胞介素（IL）-13诱导的 M2 巨噬细胞极化。用桉树脑治疗后，BLM 诱导的肺纤维化和肺炎症明显减轻。肺中性粒细胞聚集和肺通透性降低，羟脯氨酸、α-平滑肌肌动蛋白和纤维连接蛋白的表达明显下调。桉树脑还显著抑制精氨酸酶-1、Ym-1、IL-13 和转化生长因子（TGF）-β1 的表达，减少 IL-13、IL-6、肿瘤坏死因子（TNF）-α 的产生，并减弱支气管肺泡灌洗液（BALF）中 TGF-β1 的活性。此外，体外实验表明，桉树脑干扰 M2 巨噬细胞极化，减少巨噬细胞介导的促纤维化因子 TGF-β1 的分泌。桉树脑抑制信号转导和转录激活因子 6（STAT6）和 p38 丝裂原激活蛋白激酶（p38 MAPK）的核定位，减少其下游转录因子 krupple 样因子 4（KLF4）和过氧化物酶体增殖物激活受体γ（PPAR-γ）的表达。这些发现表明，桉树脑通过调节 M2 巨噬细胞极化缓解 BLM 诱导的肺纤维化，从而抑制信号分子（如 STAT6 和 p38 MAPK）的激活和转录因子（如 KLF4 和 PPAR-γ）的表达。因此，桉树脑可能是 IPF 的一种潜在治疗药物。
