The regulatory role of TGF-beta in airway remodeling in asthma.
The regulatory role of TGF-beta in airway remodeling in asthma.
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DOI：
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发表时间：
2007
影响因子：
4
通讯作者：
T. Makinde;R. Murphy;D. Agrawal
中科院分区：
文献类型：
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作者：
T. Makinde;R. Murphy;D. Agrawal
结构细胞和炎性细胞都能够分泌转化生长因子（TGF）-β并表达TGF-β受体。TGF-β可以诱导多种细胞应答，包括分化、凋亡、存活和增殖，并且已经涉及包括癌症和哮喘在内的几种致病性病症的发展。据报道，哮喘气道中TGF-β水平升高。TGF-β与其受体复合物结合并激活涉及蛋白质如Sma和Mad同源物、磷脂酰肌醇-3激酶和促分裂原活化蛋白激酶的多种途径，导致若干基因的转录。细胞类型、细胞条件和微环境都在决定哪种途径被激活方面发挥作用，这反过来又是哪种基因被转录的指示。TGF-β已显示诱导气道上皮细胞的凋亡。还报道了TGF-β在调节上皮细胞粘附特性中的可能作用。TGF-β增强杯状细胞增殖表明在粘液分泌过多中起作用。TGF-β水平升高与上皮下纤维化相关。TGF-β诱导成纤维细胞增殖，并在上皮下纤维化发展过程中分化为肌成纤维细胞和细胞外基质（ECM）蛋白合成。TGF-β还诱导气道平滑肌细胞（ASMC）的增殖和存活以及ECM分泌，这表明气道组织厚度增加的可能原因。TGF-β还诱导血管内皮细胞生长因子和纤溶酶原激活物抑制剂的产生和释放，有助于哮喘气道中的血管重塑。阻断TGF-β活性可抑制哮喘小鼠模型中的上皮脱落、粘液高分泌、血管生成、ASMC肥大和增生。减少TGF-β的产生和控制TGF-β的作用将有利于慢性哮喘气道重塑的治疗干预的发展。
Both structural and inflammatory cells are capable of secreting transforming growth factor (TGF)-beta and expressing TGF-beta receptors. TGF-beta can induce multiple cellular responses including differentiation, apoptosis, survival and proliferation, and has been implicated in the development of several pathogenic conditions including cancer and asthma. Elevated levels of TGF-beta have been reported in the asthmatic airway. TGF-beta binds to its receptor complex and activates multiple pathways involving proteins such as Sma and Mad homologues, phosphatidylinositol-3 kinase and the mitogen-activated protein kinases, leading to the transcription of several genes. Cell type, cellular condition, and microenvironment, all play a role in determining which pathway is activated, which, in turn, is an indication of which gene is to be transcribed. TGF-beta has been shown to induce apoptosis in airway epithelial cells. A possible role for TGF-beta in the regulation of epithelial cell adhesion properties has also been reported. Enhancement of goblet cell proliferation by TGF-beta suggests a role in mucus hyper-secretion. Elevated levels of TGF-beta correlate with subepithelial fibrosis. TGF-beta induces proliferation of fibroblast cells and their differentiation into myofibroblasts and extracellular matrix (ECM) protein synthesis during the development of subepithelial fibrosis. TGF-beta also induces proliferation and survival of and ECM secretion in airway smooth muscle cells (ASMCs), suggesting a possible cause of increased thickness of airway tissues. TGF-beta also induces the production and release of vascular endothelial cell growth factor and plasminogen activator inhibitor, contributing to the vascular remodeling in the asthmatic airway. Blocking TGF-beta activity inhibits epithelial shedding, mucus hyper-secretion, angiogenesis, ASMC hypertrophy and hyperplasia in an asthmatic mouse model. Reduction of TGF-beta production and control of TGF-beta effects would be beneficial in the development of therapeutic intervention for airway remodeling in chronic asthma.