Modeling, pathogenesis and treatment of idiopathic pulmonary fibrosis

特发性肺纤维化(IPF)是一种以成纤维细胞病灶为特征的顽固性间质性肺疾病， 肺泡重塑和闭塞，中位生存期为3~4年。唯一有效的治疗方法是 肺移植，一种由于供体器官可用性低而受阻的干预措施，以及严重的手术和 免疫并发症。因此，迫切需要创新的方法。我们确定了三个主要的 在改善IPF预后方面的挑战，并建议在三个方面应对这些挑战 我们联盟的研究中心：(1)应该建立细胞源来研究IPF的发病机制和 最终预防或逆转纤维化。在Hub 1中，我们建议定向分化人类多能干细胞 细胞(HPSCs)进入肺组织，以研究发病机制并建立药物发现平台。(2)单元格 需要移除/递送方法来替换不可逆转的受损的肺组织或携带 特发性肺纤维化的发病机制。在枢纽2，我们将开发必要的生物工程模式，这将需要 HPSCs定向分化为肺组织的优势。(3)该领域需要一个大型动物模型来 特发性肺间质纤维化发病机制的验证和新治疗方法的临床前验证 由前两个研究中心开发。因此，我们建议建立IPF的小型猪模型。 验证Hub1中发现的致病机制，以及在 中心2.这项提议的首要目标是对IPF的发病机制进行迫切需要的深入了解 (中心1)，并利用这些见解为IPF新治疗方法的开发提供信息(中心2)。 由于IPF目前是一种无法治疗的疾病，无法预测哪些方法将是有益的，以及 治疗方法可视病情分期而定。药理学方法可能针对纤维化过程 或启动这一过程的上皮细胞发出的通路，在早期可能是有用的 阶段性疾病或遗传易感性的患者。可再生的方法可以包括 细胞疗法，特别是针对ATII细胞，最有可能在疾病早期或易患 IPF，但可能扩展到终末期疾病的再细胞肺支架移植。这两种类型的 再生方法将需要生物工程技术，这些技术将被开发中心2并被告知 通过在Hub 1中实现对IPF发病机制的更深入理解。最终，对疾病的验证 治疗方法的机制和临床前测试需要大型动物模型，这是重点 集线器3。

Idiopathic pulmonary fibrosis (IPF) is an intractable interstitial lung disease characterized by fibroblastic foci, remodeling and obliteration of alveoli, and a median survival of 3 to 4 years. The only definitive treatment is lung transplantation, an intervention hampered by low availability of donor organs, and severe surgical and immunological complications. Innovative approaches are therefore urgently needed. We identified three major challenges towards improving the prognosis of IPF, and propose to address these challenges in the three research hubs of our consortium: (1) Cell sources should be established to study pathogenesis of IPF and to eventually prevent or reverse fibrosis. In Hub 1, we propose directed differentiation of human pluripotent stem cells (hPSCs) into lung tissue to investigate pathogenesis and establish platforms for drug discovery. (2) Cell removal/delivery methods are needed to either replace irreversibly damaged lung tissue, or the cells that carry pathogenesis of IPF. In Hub 2, we will develop the necessary bioengineering modalities that will take advantage of directed differentiation of hPSCs into lung tissue. (3) The field requires a large animal model for the validation of pathogenetic mechanisms and preclinical validation of novel therapeutic modalities for IPF developed by the first two research hubs. We therefore propose to establish a miniature swine model for IPF to validate pathogenetic mechanisms discovered in Hub1, and cellular replacement approaches developed in Hub 2. The overarching goal of this proposal is to gain desperately needed insight into the pathogenesis of IPF (Hub 1) and to use these insights to inform the development of novel therapeutic approaches for IPF (Hub 2). As IPF is currently an untreatable disease, it is not possible to predict which approaches will be beneficial, and the therapy may be dictated by disease stage. Pharmacological approaches may target the fibrotic process itself, or pathways emanating from epithelial cells that initiate this process and would likely be useful in early stage disease or in patients that are genetically predisposed. Regenerative approaches could consist of cellular therapies, in particular targeting ATII cells, most likely early in disease or in patients predisposed to IPF, but may extend to transplantation of recellularized lung scaffolds in end-stage disease. Both types of regenerative approaches will require bioengineering technologies that will be developed Hub 2 and informed by a deeper understanding of IPF pathogenesis achieved in Hub 1. Ultimately, verification of disease mechanism and preclinical testing of therapeutic approaches requires a large animal model, which is the focus of Hub 3.