Mechanisms of myofibroblast survival in fibrosis

纤维化过程中肌成纤维细胞的存活机制

• 批准号: 6415989
• 负责人: David W. Riches
• 金额: $ 30.42万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-12 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415989
• 关键词: alveolar macrophages; apoptosis; cell adhesion; cell differentiation; cell growth regulation; cell proliferation; cellular pathology; collagen; cysteine endopeptidases; cytoprotection; enzyme activity; fibroblasts; growth factor; human tissue; idiopathic pulmonary fibrosis; inflammation; insulinlike growth factor; laboratory mouse; mitochondria; muscle cells; patient oriented research; platelet derived growth factor; respiratory epithelium; tissue /cell culture

Idiopathic pulmonary fibrosis/usual interstitial pneumonitis (IPF/UIP) is a fatal parenchymal lung disease characterized by interstitial and alveolar fibroproliferation and the appearance of myofibroblasts. Little is known about the mechanisms of myofibroblast accumulation in IPF/UIP or why they fail to be eliminated as occurs during normal wound repair. Previous studies from this and other laboratories have shown that survival factors, especially IGF-I, are abundantly expressed by macrophages and alveolar epithelial cells in IPF/UIP. In this proposal, we will test the hypothesis that the presence of survival factors, including IGF-I, in the parenchyma and airspaces of patients with IPF/UIP protect myofibroblasts from apoptosis. Under these conditions, myofibroblasts are proposed to accumulate in numbers and can thus contribute to parenchymal fibrosis for extended periods of time. The major goals of this proposal are three-fold: (1) to investigate the conditions and mechanisms that mediate myofibroblast apoptosis under conditions of growth factor and stretch withdrawal; (ii) to determine how IGF-I serves to protect myofibroblasts from undergoing apoptosis; and (iii) to investigate the mechanism of dysregulation of myofibroblast apoptosis in IPF/UIP. These goals will be addressed by four specific aims. Specific aim one will address the role of growth factors, physical forces and IGF-I in myofibroblast differentiation, reversion to a fibroblast phenotype and apoptosis. These studies will form a basis for determining the mechanisms that promote myofibroblast apoptosis with a focus on the mechanisms of caspase activation (specific aim two). The objective of specific aim three is to uncover the mechanisms through which IGF-I prevents the initiation of the death program. The focus of these studies will include the mechanism of inactivation of the effector capsases (3, 6 and 7) and the potential role of anti-apoptotic proteins. Lastly, in specific aim four, we propose to apply what has been learned from this studies conducted in this proposal to address the mechanisms that promote protection from apoptosis in the lungs of patients with IPF/UIP. The findings from this work are expected to provide new insights into the mechanism of myofibroblast apoptosis and how this process becomes dysregulated in IPF/UIP.

特发性肺间质纤维化/普通性间质性肺炎(IPF/UIP)是一种以肺间质和肺泡间质纤维增生和肌成纤维细胞的出现为特征的致命性肺病。对于肌成纤维细胞在IPF/UIP中聚集的机制以及为什么它们不能像正常伤口修复时那样被消除，人们知之甚少。该实验室和其他实验室以前的研究表明，在IPF/UIP中，巨噬细胞和肺泡上皮细胞大量表达生存因子，特别是IGF-I。在这个方案中，我们将检验这样的假设，即IPF/UIP患者的实质和空间中存在包括IGF-I在内的生存因子保护肌成纤维细胞免于凋亡。在这种情况下，肌成纤维细胞被认为是大量积累的，因此可以在较长时间内促进实质纤维化。本研究的主要目的有三个方面：(1)研究生长因子和牵张停用条件下肌成纤维细胞凋亡的条件和机制；(2)确定胰岛素样生长因子-I(IGF-I)如何保护肌成纤维细胞免受细胞凋亡的影响；(3)探讨IPF/UIP中肌成纤维细胞凋亡的调控机制。这些目标将通过四个具体目标来实现。具体目标一将阐述生长因子、物理力量和IGF-I在肌成纤维细胞分化、向成纤维细胞表型逆转和细胞凋亡中的作用。这些研究将为确定促进肌成纤维细胞凋亡的机制奠定基础，重点是caspase激活的机制(特定目标二)。具体目标三的目标是揭示IGF-I阻止死亡计划启动的机制。这些研究的重点将包括效应衣壳酶(3、6和7)的失活机制以及抗凋亡蛋白的潜在作用。最后，在特定的目标4中，我们建议应用从这项研究中获得的知识来解决促进IPF/UIP患者肺内细胞凋亡保护的机制。这项工作的发现有望为肌成纤维细胞凋亡的机制以及这一过程如何在IPF/UIP中变得失调提供新的见解。