The endothelium in lung fibrosis: a core signaling hub in disease pathogenesis?

Abstract

Pulmonary fibrosis is a progressive chronic lung disease characterized by excessive deposition of extracellular matrix and structural destruction, associated with a severe five year mortality rate. The onset of the disease is thought to be triggered by chronic damage to the alveolar epithelium. Since the pulmonary endothelium is an important component of the alveolar-capillary niche, it is also affected by the initial injury. In addition to ensuring proper gas exchange, the endothelium has critical functional properties, including regulation of vascular tone, inflammatory responses, coagulation and maintenance of vascular homeostasis and integrity. Recent single-cell analyses have shown that shifts in endothelial cell subtypes occur in pulmonary fibrosis. Furthermore, the increased vascular remodeling associated with pulmonary fibrosis leads to deteriorated outcomes for patients, underscoring the importance of the vascular bed in pulmonary fibrosis. To date, the causes and consequences of endothelial and vascular involvement in pulmonary fibrosis are poorly understood. Therefore, it is of great importance to investigate the involvement of endothelial cells and the vascular system in the pathogenesis of the disease. In this review, we will outline the current knowledge on the role of the pulmonary vasculature in pulmonary fibrosis, in terms of abnormal cellular interactions, hyperinflammation, vascular barrier disorders and an altered basement membrane composition. Finally, we will summarize recent advances in extensive therapeutic research and discuss the significant value of novel therapies targeting the endothelium.