Therapeutic Prospects of αv Integrins Inhibition in Fibrotic Lung Diseases and Carcinogenesis

Abstract

The uncontrolled fibrosis of lung tissue can lead to premature death in patients suffering from idiopathic pulmonary fibrosis (IPF), and it complicates the course of chronic obstructive pulmonary disease (COPD) and emphysema. It is also a risk factor for developing lung cancer. Antifibrotic drugs, such as nantedanib and pirfenidone, are able to slow down the progression of pulmonary fibrosis, but more effective treatment is still needed to reverse it. Studies on the pathogenesis of tissue fibrosis have demonstrated that integrins play a crucial role affecting the development of pulmonary fibrosis, for example, by activating transforming growth factor-β (TGF-β). Taking the above into consideration, targeting specific integrins could offer promising opportunities for managing fibroplastic changes in lung tissue. Integrins are a type of transmembrane molecule that mediate interactions between cells and extracellular matrix (ECM) molecules. This review discusses the role of integrins in the pathogeneses of respiratory diseases and carcinogenesis, as well as presents promising approaches to the drug therapy of pulmonary fibrosis of various etiologies based on integrin inhibition.

Keywords: chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; lung cancer; αv integrin.

Figure 1

Structures of integrins’ α and β subunits. α-I—inserted domain of α subunit; β-I—inserted domain of β subunit; Hyb—hybrid domain; PSI—plexin–semaphorin–integrin; EGF—epidermal growth factor-like domain; Thigh—thigh domain of α subunit; Calf-1 and-2—Calf-1 and -2 domains of α subunit; Intrinsic Glu—intrinsic glutamic acid molecule; MIDAS—metal ion-dependent adhesion site; ADMIDAS—adjacent to MIDAS site; SyMBS—synergistic metal ion-binding site.

Figure 2

Integrin-associated fibrotic and oncogenic pathways. TGF-β—transforming growth factor-β; MMP-2—matrix metalloproteinase 2; MMP-9—matrix metalloproteinase 9; P—phosphoric acid residue; SFKs—SRC family kinases; RTK—receptor tyrosine kinase; FAK—focal adhesion kinase; ERK—extracellular signal-regulated kinase; PI3K—phosphatidylinositol 3-kinase; AKT—protein kinase B; mTOR—mammalian target of rapamycin; PYK2—proline-rich tyrosine kinase 2; STAT—activator of transcription; RGD—arginyl–glycyl–aspartic acid; ADAM15—metalloproteinase 15.

Figure 3

An overview of the various activities of integrins and their potential inhibitors. TGF-β—transforming growth factor-β; LAP-TGF-β—latency-associated peptides in complex with TGF-β; IPF—idiopathic pulmonary fibrosis; CORD—chronic obstructive pulmonary disease; BG00011, Ab-31, B5, MORF-627, B6_Bp_dslf, GSK3335103, GSK3008348, PLN-74809, Cyclic octapeptide, Cilengitide—potential inhibitors of integrins, which are in different stages of clinical trials.