J Clin Invest. 2023 Sep 15;133(18):e172058. doi: 10.1172/JCI172058.
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
特发性肺纤维化（IPF）是一种肺部进行性瘢痕疾病，存活率低。IPF 的发病率和死亡率正在上升，但治疗仍然有限。目前，两种药物可以减缓瘢痕形成过程，但往往以无法忍受的副作用为代价，并且不会显著改变总体生存率。更好地了解 IPF 的发病机制可能会导致改善的治疗方法。目前的范式提出，在遗传引发的个体中，反复的肺泡上皮损伤由有害刺激引起，随后是异常的伤口愈合，包括细胞外基质分泌细胞的异常活性，导致组织纤维化和实质损伤。然而，这可能低估了血管对纤维化形成的重要性。肺接受 100%的心输出量，IPF 中的血管异常包括：（a）纤维化肺中整个血管形成不均匀，包括异常扩张血管和吻合的形成；（b）内皮细胞（EC）的异常空间分布群体；（c）内皮保护途径如前列环素信号的失调；和（d）常见血管和代谢合并症的频率增加。在这里，我们提出血管和 EC 异常在 IPF 的病理生物学中既是因果关系，也是后果关系，更全面地评估失调途径可能会导致针对这种毁灭性疾病的有效治疗方法和治愈方法。
