Mechanisms of myofibroblast survival in fibrosis

特发性肺纤维化/普通型间质性肺炎（IPF/UIP）是一种致命的肺实质疾病，其特征是间质和肺泡纤维增生以及肌成纤维细胞的出现。 关于IPF/UIP中肌成纤维细胞蓄积的机制或它们在正常伤口修复过程中无法消除的原因知之甚少。本实验室和其他实验室的先前研究表明，IPF/UIP中的巨噬细胞和肺泡上皮细胞大量表达生存因子，特别是IGF-I。 在本提案中，我们将检验IPF/UIP患者的实质和气隙中存在的生存因子（包括IGF-I）保护肌成纤维细胞免于凋亡的假设。 在这些条件下，肌成纤维细胞被认为会大量积累，因此可能导致实质纤维化持续很长一段时间。 该提案的主要目标有三个方面：（1）研究在生长因子和牵拉撤回条件下介导肌成纤维细胞凋亡的条件和机制;（ii）确定IGF-I如何保护肌成纤维细胞免于凋亡;（iii）研究IPF/UIP中肌成纤维细胞凋亡失调的机制。 这些目标将通过四个具体目标来实现。 具体目标之一将解决的作用，生长因子，物理力量和IGF-I在肌成纤维细胞分化，逆转成纤维细胞表型和细胞凋亡。 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，重点是半胱天冬酶激活机制（具体目标二）。 具体目标三的目标是揭示IGF-I阻止死亡程序启动的机制。 这些研究的重点将包括效应衣壳蛋白酶（3，6和7）的失活机制和抗凋亡蛋白的潜在作用。 最后，在具体目标四中，我们建议应用本提案中进行的研究中所学到的知识，以解决促进IPF/UIP患者肺部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机制以及该过程如何在IPF/UIP中失调提供新的见解。

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.