巨噬细胞STAT3磷酸化在吸烟引起的呼吸道上皮细胞恶性化转变中的作用及其机制

Harmful substances from cigarette smoke are the main pathogenesis of various lung diseases including chronic obstructive pulmonary disease (COPD) and lung cancer. Cigarette smoke contains at least 400 toxic substances in the gaseous and particulate phases. Variation of immune function caused by smoking is a critical factor in the respiratory diseases. Macrophages are the important immune cells in the lung tissues. They are highly versatile and multifunctional, whose function depends on their biological microenvironment. Two distinct polarized phenotypes of macrophages have been described for M1 and M2. The M1 phenotype is the pro-inflammatory macrophage with microbicidal and tumoricidal activities and characterized by the release of inflammatory cytokines, reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI). M2 macrophages, in contrast, show an immunosuppressive function and promote tumor growth and metastasis in established tumors. However, the role and mechanism of M2 phenotype in the early transformation of lung tissues is still unclear. It has been reported that immunity abnormality usually existed in COPD and lung cancer patients. Immune functions are severely impaired during the COPD exacerbation, and patients with COPD are much easier to develop lung cancer. It has also been proved that M1 phenotype progressively decreased in COPD smokers accompanied with a gradual increase of M2 phenotype, suggesting that M2 polarized macrophages probably take part in the early malignant transformation of lung tissues. Our preliminary studies showed that smoking promoted the polarization of macrophages to the M2 phenotype, and their changes are associated with STAT3 phosphorylation. Some researchers have also reported that inflammatory cytokines derived from STAT3 activation may in turn stimulate activation of STAT3 in normal tissue cells and then lead to their malignant changes. Accordingly, we hypothesize that malfunction of macrophages caused directly by smoking or indirectly by the progress or exacerbation of COPD is closely related to lung malignant transformation, and the activation of STAT3 signaling pathway is involved in its mechanism. We will use cell culture and animal models to explore the relationship between macrophage functional changes caused by smoking and lung malignant transformation, to reveal the role of STAT3 phosphorylation of macrophages in pulmonary malignant transformation on the level of the molecular, cellular, and animal overall, and to provide ideas for the prevention of smoking-induced lung tumor via immune system.

烟草的有害物质是引起肺部疾病的主要原因之一，免疫功能的改变在其中起着关键作用。巨噬细胞是肺部最丰富的免疫群体，有不同的极化状态，M2型在已形成的肿瘤中普遍存在且有促肿瘤发展的作用，但它在肺部早期转化中的作用和机制尚不清楚。慢性阻塞性肺病多数可继发肺癌，其中的吸烟者肺部M1型巨噬细胞数量持续减少，M2型相应增加。因此，M2型巨噬细胞可能参与肺部的早期转化。我们发现，吸烟可使巨噬细胞向M2型极化，其变化与STAT3磷酸化相关。已知STAT3激活所产生的某些因子可诱导正常细胞STAT3激活而导致其恶性化改变。据此我们提出假说，吸烟直接或间接导致的巨噬细胞M2型极化可促进肺部恶性化转变，且由STAT3信号通路介导。我们拟采用细胞培养和模式动物探索吸烟造成的巨噬细胞改变与肺部癌变的相关性，从分子、细胞和整体水平揭示巨噬细胞STAT3磷酸化在肺部恶性转变中的作用，为有效预防吸烟引起的肺部恶变提供思路。

肺癌和肺纤维化是严重威胁人类健康和生命的疾病，其发病率逐年上升，临床上尚无有效治疗措施。吸烟被认为是上述疾病的主要诱导因素之一。巨噬细胞是肺部最丰富的免疫群体，有不同的极化状态，M2型在已形成的肿瘤中普遍存在且有促肿瘤发展的作用，但它在肺部早期转化中的作用和机制尚不清楚。慢性阻塞性肺病多数可继发肺癌，其中的吸烟者肺部M1型巨噬细胞数量持续减少，M2型相应增加。因此，M2型巨噬细胞可能参与肺部的早期转化。此外，特发性肺纤维化患者体内M2型肺泡巨噬细胞比例显著升高，提示M2型的极化与IPF发生存在密切的相关性。基于以上事实，我们研究了以下内容：吸烟对肺泡巨噬细胞M2型极化的作用；STAT3信号通路在巨噬细胞M2型极化中的作用；M2型巨噬细胞对肺泡上皮细胞恶变的影响；M2型巨噬细胞对肺纤维化的作用。研究结果显示：吸烟通过激活STAT3信号通路促进巨噬细胞M2型极化；M2型巨噬细胞能够促进肺癌细胞的增殖、迁移和侵袭；M2型巨噬细胞能够促进肺纤维化的进展。此外，我们还发现miR-497-5p能够促进肺纤维化的进展。本研究阐明了巨噬细胞在肺癌和肺纤维化中的作用及其相关机制，为临床寻求有效的肺癌和肺纤维化的干预措施提供了理论依据。