Genetic control of apoptosis in developing pulmonary fibrosis

肺纤维化患者细支气管和肺泡上皮细胞Fas和FasL表达上调。在博来霉素治疗的实验动物中，肺组织中的凋亡通过Fas-FasL的相互作用而促进肺纤维化的发展。Fag是细胞表面分子，其在与特异性受体或抗体接合时触发细胞凋亡或炎症。FADD在这些受体激活后被募集到其胞质结构域，并作为共同的介体诱导细胞凋亡。基于这些知识，我们假设通过Fas修饰的细胞内信号为显性负性信号将抑制肺纤维化的发展。为了验证这一假设，我们构建了缺失死亡效应域的FADD缺失突变体重组腺病毒载体。肺内FADD显性负性转导可部分改善博莱霉素诱导的肺纤维化。这一结果将为肺纤维化的新治疗模式提供基础。

Upregulation of Fas and FasL expression in bronchiolar and alveolar epithelial cells Was found in patients with pulmonary fibrosis. In Bleomycin-treated experimental animal, apoptosis in lung tissue through the interaction of Fas-FasL contributes to development of pulmonary fibrosis. Fag are cell surface molecules that trigger apoptosis or inflammation upon engagement by specific receptor or antibody. FADD is recruited to the cytoplasmic domain of these receptors upon their activation and works as common mediator to induce apoptosis. Based upon these knowledge, we hypothesized that intracellular signals through Fas modified to be dominant-negative signal would suppress the development of pulmonary fibrosis. Tb evaluate this hypothesis, we constructed recombinant adenovirus vector coding FADD deletion mutant lacking the death effector domain. Bleomycin-induced pulmonary fibrosis was partially ameliorated by intratracheal FADD dominant negative transduction. This result would provide the basis for a novel therapeutic modality in pulmonary fibrosis.