Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis

Abstract

The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had a crucial role in the development of PF. Studies have demonstrated that about 16% of the fibroblasts in the lung tissue of fibrotic mice were derived from endothelial cells. Endothelial cells transdifferentiated into mesenchymal cells via the endothelial–mesenchymal transition (E(nd)MT), leading to the excessive proliferation of endothelial-derived mesenchymal cells and the accumulation of fibroblasts and ECM. This suggested that endothelial cells, a significant component of the vascular barrier, played an essential role in PF. Herein, this review discusses E(nd)MT and its contribution to the activation of other cells in PF, which could provide new ideas for further understanding the source and activation mechanism of fibroblasts and the pathogenesis of PF.

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“…In addition, a significantly decreased proportion of B cells ( P < 2.2 × 10 −16 ), neutrophils ( P < 2.2 × 10 −16 ), natural killer cells ( P < 2.2 × 10 −16 ), and T cells ( P = 0.043) were observed in BLM-induced mice ( Figure 2D ; see Table E4). Angiogenesis and impairment of the epithelial barrier had recently been implicated in lung fibrosis homeostasis and pathogenesis for a long time ( 26 ). Notably, after T 3 administration, fibrotic mice exhibited dramatic changes in the relative proportion of cell lineages, which were characterized by significant reduction of endothelial cells ( P = 0.005) and expansion of epithelial cells ( P = 0.009) and neutrophils ( P = 0.002) ( Figure 2D ; Table E4).…”

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“…We ensured SNPs independence by setting the linkage disequilibrium coefficient (r 2 = 0.001) and region width (kb = 1,000) to eliminate linkage disequilibrium and prevent bias. IPF is associated with various risk factors, including genetics, autoimmune deficiency, environmental exposure (such as smoking, diabetes, GERD), and viral infection, among others ( Reynolds et al, 2023 ; Zhao et al, 2023 ). Furthermore, GERD is associated with obesity, smoking, and genetics ( Maret-Ouda et al, 2020 ).…”

The contribution of endothelial cells to tissue fibrosis

“…In recent years, EndMT has emerged as an important player in the development of tissue fibrosis associated with a variety of diseases, as well as an attractive target for therapeutic purposes [ 3 , 5 – 9 ]. For instance, in a very recent study employing a rat model of Crohn's disease-related intestinal fibrosis, the traditional Chinese herb Xue-Jie-San has been shown to be effective in repressing EndMT, as reflected by the upregulation of CD31 and vascular endothelial-cadherin and the parallel downregulation of S100A4 and α-SMA expression in the colon of 2,4,6-trinitrobenzene sulfonic acid-treated animals [ 5 ].…”

“…By profoundly affecting tissue structure and eventually culminating into organ failure, pathological fibrosis represents an important cause of global morbidity and mortality [ 1 , 2 ]. Fibrotic disorders, comprising a wide spectrum of diseases, including kidney, cardiac and lung fibrosis, inflammatory bowel disease-associated intestinal fibrosis, as well as fibroproliferative vascular remodeling in pulmonary arterial hypertension (PAH) and multisystem fibrosis in systemic sclerosis (SSc, or scleroderma), represent a major health problem due to the great increasing number of affected individuals and the void of effective disease-modifying therapeutic approaches [ 3 – 9 ].…”