Understanding the Role of TRPV4 in Mechanosensing, Myofibroblast Differentiation and Pulmonary Fibrosis

By Mitchell A. Olman, MD

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with marginally effective medical treatment. Myofibroblasts are critical to the fibrogenic lung repair process through their ability to produce collagen, secrete pro-fibrotic cytokines and contract tissue. Although myofibroblasts require active transforming growth factor-β (TGF-β) and a mechanical signal for their generation, the nature of the mechanical signal and the mechanism by which the mechanical signal is sensed have remained elusive.

A role for TRPV4?

In a search through the literature, my team noted that a calcium-permeable cell membrane ion channel named transient receptor potential vanilloid 4 (TRPV4) was activated upon plasma membrane stretch and thus could act as a mechanosensor. Thus, we investigated whether TRPV4 plays a role in myofibroblast differentiation and/or in vivo lung fibrosis.

Inhibition of TRPV4 blocks key responses to TGF-β

In work recently published in the Journal of Clinical Investigation, we show that inhibition of TRPV4 by small molecule inhibitors and/or downregulation/deletion of TRPV4 using molecular or genetic techniques resulted in an almost complete blockade of both the calcium influx response as well as the myofibroblast differentiation response to TGF-β

Moreover, TRPV4 exhibited its mechanosensing and myofibroblast differentiating effect under conditions of matrix stiffness in the range of normal and fibrotic lung (1-25 kPa), suggesting it can sense changes in matrix stiffness during the fibrogenic process. Using a model assay system developed in our laboratory, we also noted that TRPV4 blocked the myofibroblast differentiation response to actual fibrotic lung tissue. Furthermore, TRPV4 deficiency protects mice from in vivo lung fibrosis in an experimental murine model.

A promising therapeutic approach across multiple disorders

These data identify TRPV4 as a long-elusive mechanosensor/transducer that mediates myofibroblast differentiation and in vivo pulmonary fibrogenesis. Successful manipulation of TRPV4 channel activity may be a novel therapeutic approach for fibrotic diseases of the lung and other organs. TRPV4 has also recently been shown to be involved in other disorders associated with pulmonary parenchymal stretch including ventilator-induced lung injury, and a TRPV4 inhibitor for pulmonary edema due to pulmonary venous hypertension is undergoing Phase I trials.

In other work in our group, we are studying the role of TRPV4 in macrophage function (with Rachel Scheraga, MD), and the role of nonmuscle myosin in inducing the pro-fibrotic fibroblast phenotype (with Brian Southern, MD).

Dr. Olman is a staff physician in the Respiratory Institute with a primary appointment in the Department of Pathobiology.