Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis is a progressive scarring disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Recent studies support the hypothesis that these compositional and mechanical changes create a progressive feed-forward loop in which enhanced matrix deposition and tissue stiffening contribute to fibroblast and myofibroblast differentiation and activation, which further perpetuates matrix production and stiffening. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. Although our understanding of mechanotransduction pathways associated with pulmonary fibrosis remains incomplete, recent progress has allowed us to begin to elucidate the specific mechanisms supporting fibrotic feed-forward loops. The mechanosensors discussed here include integrins, Piezo channels, transient receptor potential channels, and nonselective ion channels. Also discussed are downstream transcription factors, including myocardin-related transcription factor and Yes-associated protein/transcriptional coactivator with PDZ-binding motif. This review describes mechanosensors and mechanotransduction pathways associated with fibrosis progression and highlights promising therapeutic insights.

Figure 1

Mechanoreceptors and signal transduction pathways activating profibrotic gene expression. Fibroblasts sense mechanical cues such as cellular stretch and extracellular matrix stiffening through stretch-activated ion channels, G protein–coupled receptors, and integrins. RGD (arginine-glycine-aspartate) integrin–linked focal adhesion complexes can activate Rho signaling leading to actin polymerization increasing α-smooth muscle actin (αSMA) and cellular contraction. Sensing of mechanical cues is followed by downstream activation of biochemical transduction pathways that converge on and regulate the nuclear translocation of myocardin-related transcription factor (MRTF) and Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). This leads to subsequent transcriptional regulation of profibrotic gene expression such as myofibroblast differentiation, extracellular matrix (ECM) deposition, and cellular contraction, further altering the mechanical microenvironment. In addition, application of externally applied force to the latency-associated peptide and latent transforming growth factor β (TGF-β)–binding protein 1 (LTBP1) activates TGF-β and canonical TGF-β/SMAD signaling. FAK, focal adhesion kinase; LINC, linker of nucleoskeleton and cytoskeleton; TGF-βR, TGF-β receptor; TRP, transient receptor potential.