Autotaxin(ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid(LPA) pro...Autotaxin(ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid(LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors(LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysi-ological situations in vivo and in human diseases.展开更多
高迁移率族蛋白B1(high-mobility group box 1,HMGB1)是一种保守的核蛋白,对维持核小体稳定、DNA重组、复制、修复及转录有重要作用。其可由坏死的细胞被动释放,或在适宜刺激下主动分泌至胞外。近年的研究显示:HMGB1信号的活化与肺损伤...高迁移率族蛋白B1(high-mobility group box 1,HMGB1)是一种保守的核蛋白,对维持核小体稳定、DNA重组、复制、修复及转录有重要作用。其可由坏死的细胞被动释放,或在适宜刺激下主动分泌至胞外。近年的研究显示:HMGB1信号的活化与肺损伤、肺纤维化、肺癌等肺部疾病的发展密切相关,而阻断HMGB1信号可抑制其病理进程,说明HMGB1的抑制对这类疾病有潜在治疗价值。该文就HMGB1在呼吸系统疾病中的作用及其机制作一综述,以期为上述疾病的诊断和治疗提供新的理论依据。展开更多
低氧促有丝分裂因子(hypoxia-induced mitogenic factor,HIMF)是近年来新发现的一种分泌蛋白,其作用与多种肺部疾病的发生发展息息相关。HIMF具有促有丝分裂、血管生成性、血管收缩性、趋化因子特性等多种生物学功功能,并能通过诱导细胞...低氧促有丝分裂因子(hypoxia-induced mitogenic factor,HIMF)是近年来新发现的一种分泌蛋白,其作用与多种肺部疾病的发生发展息息相关。HIMF具有促有丝分裂、血管生成性、血管收缩性、趋化因子特性等多种生物学功功能,并能通过诱导细胞内Ca2+浓度升高、促进炎症因子及生长因子的产生等机制影响细胞活动。目前研究发现HIMF能调节PLC-IP3、PI3K-Akt、BTK、Notch等多条信号通路,引起炎症发生、气道重塑、血管收缩及增厚等病理过程,从而诱导疾病的发生。H I M F参与发病机制的进一步研究能为今后疾病的防治提供新的线索和靶点。本文就近年来对HIMF介导的信号通路及其在肺部疾病中的研究进展做一综述。展开更多
Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cel...Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.展开更多
基金Supported by National Grants from the Hellenic Ministry of Education,Lifelong Learning and Religious Affairs,No.09SYN-12-679/680
文摘Autotaxin(ATX or ENPP2) is a secreted glycoprotein widely present in biological fluids. ATX primarily functions as a plasma lysophospholipase D and is largely responsible for the bulk of lysophosphatidic acid(LPA) production in the plasma and at inflamed and/or malignant sites. LPA is a phospholipid mediator produced in various conditions both in cells and in biological fluids, and it evokes growth-factor-like responses, including cell growth, survival, differentiation and motility, in almost all cell types. The large variety of LPA effector functions is attributed to at least six G-protein coupled LPA receptors(LPARs) with overlapping specificities and widespread distribution. Increased ATX/LPA/LPAR levels have been detected in a large variety of cancers and transformed cell lines, as well as in non-malignant inflamed tissues, suggesting a possible involvement of ATX in chronic inflammatory disorders and cancer. In this review, we focus exclusively on the role of the ATX/LPA axis in pulmonary pathophysiology, analysing the effects of ATX/LPA on pulmonary cells and leukocytes in vitro and in the context of pulmonary pathophysi-ological situations in vivo and in human diseases.
文摘高迁移率族蛋白B1(high-mobility group box 1,HMGB1)是一种保守的核蛋白,对维持核小体稳定、DNA重组、复制、修复及转录有重要作用。其可由坏死的细胞被动释放,或在适宜刺激下主动分泌至胞外。近年的研究显示:HMGB1信号的活化与肺损伤、肺纤维化、肺癌等肺部疾病的发展密切相关,而阻断HMGB1信号可抑制其病理进程,说明HMGB1的抑制对这类疾病有潜在治疗价值。该文就HMGB1在呼吸系统疾病中的作用及其机制作一综述,以期为上述疾病的诊断和治疗提供新的理论依据。
文摘低氧促有丝分裂因子(hypoxia-induced mitogenic factor,HIMF)是近年来新发现的一种分泌蛋白,其作用与多种肺部疾病的发生发展息息相关。HIMF具有促有丝分裂、血管生成性、血管收缩性、趋化因子特性等多种生物学功功能,并能通过诱导细胞内Ca2+浓度升高、促进炎症因子及生长因子的产生等机制影响细胞活动。目前研究发现HIMF能调节PLC-IP3、PI3K-Akt、BTK、Notch等多条信号通路,引起炎症发生、气道重塑、血管收缩及增厚等病理过程,从而诱导疾病的发生。H I M F参与发病机制的进一步研究能为今后疾病的防治提供新的线索和靶点。本文就近年来对HIMF介导的信号通路及其在肺部疾病中的研究进展做一综述。
基金Supported by Grants from Pulmonary Hypertension Association and American Lung Association to Dr.Guofei Zhou
文摘Von Hippel-Lindau protein(p VHL) was first identified as a tumor suppressor gene as mutations in the VHL gene predispose individuals to systemic benign or malignant tumors and cysts in many organs, including renal cell carcinoma of the clear-cell type and hemangioblastoma. Although p VHL is best known to act as a component of ubiquitin protein ligase for the proteasomal degradation of hypoxia inducible factor(HIF)-α, p VHL also interacts with extracellular matrix proteins and cytoskeleton, regulating extracellular matrix assembly, cell signaling, and many other cellular functions. Recent studies suggest that p VHL contributes to many lung diseases, including pulmonary arterial hypertension, lung cancer, pulmonary fibrosis, and acute respiratory distress syndrome. Mutation or loss of function of p VHL activates HIF and induced expression of vascular endothelial growth factor, endothelin-1, and Fox M1, leading to pulmonary arterial hypertension. Loss of p VHL in lung cancer cells promotes epithelial-mesenchymal transition and cancer migration and invasion while decreasing lung cancer cell proliferation and colonization. In patients of idiopathic pulmonary fibrosis, elevated expression of p VHL induces expression of fibronectin/integrin α5β1/focal adhesion kinase signaling, resulting in fibroproliferation and fi-brosis. In alveolar epithelial cells, p VHL mediates Na, K-ATPase degradation in an HIF independent pathway, causing decreased edema clearance during hypoxia. These studies suggest that p VHL plays key roles in the pathogenesis of many lung diseases, and further investigations are warranted to elucidate the underlying molecular mechanisms.
