Inhibition of LPA-LPAR1 and VEGF-VEGFR2 Signaling in IPF Treatment

Abstract

Due to the complex mechanism and limited treatments available for pulmonary fibrosis, the development of targeted drugs or inhibitors based on their molecular mechanisms remains an important strategy for prevention and treatment. In this paper, the downstream signaling pathways mediated by VEGFR and LPAR1 in pulmonary cells and the role of these pathways in pulmonary fibrosis, as well as the current status of drug research on the targets of LPAR1 and VEGFR2, are described. The mechanism by which these two pathways regulate vascular leakage and collagen deposition leading to the development of pulmonary fibrosis are analyzed, and the mutual promotion of the two pathways is discussed. Here we propose the development of drugs that simultaneously target LPAR1 and VEGFR2, and discuss the important considerations in targeting and safety.

Keywords: LPAR1; VEGFR2; idiopathic pulmonary fibrosis.

Figure 1

VEGFR2 related pathway diagram.

Figure 2

LPAR1 on the cell surface activates a downstream pathway that mediates a variety of cellular responses.

Figure 3

Relationship between VEGFR2 and LPAR1 and angiogenesis, lung epithelial cells, fibroblasts, and ECM. a: Type II alveolar epithelial cells (ATII) promote ECM accumulation through apoptotic pathways; b: fibroblasts promote fibrosis through angiogenesis and cooperation with TGF-β by resisting apoptosis, secreting collagen, and VEGF, thereby enhancing ECM production in fibroblasts; c: fibroblasts have the expression of LPAR1 and VEGFR2, the binding of LPA to LPAR1, VEGF to VEGFR2, and promoting fibroblast recruitment, vascular leakage, and endothelial barrier dysfunction; d, e: as a positive feedback loop, VEGF-A binds VEGFR1 and free TGF-β on ATII and regulates ATII cell injury as well as endothelial cell proliferation, migration, vascular permeability, secretion, microvessel formation, and other endothelial functions; f: VEGF from blood vessels may enhance epithelial cell proliferation and resistance to apoptosis in an autocrine manner; g: ATII transforms into fibroblasts; therefore, LPAR1 and VEGFR2 eventually lead to excessive ECM deposition and vascular leakage.

Figure 4

Diagram of the relationship between LPA-LPAR and VEGF-VEGFR pathways in disease states.