Expanding the Role of the Mechanosensitive Ion Channel TRPV4 to Infection-Associated Acute Respiratory Distress Syndrome

By Rachel G. Scheraga, MD

Our laboratory has recently shown that the mechanosensitive, calcium-permeable, plasma membrane ion channel named transient receptor potential vanilloid 4 (TRPV4) plays a role in myofibroblast differentiation and in vivo lung fibrosis1.

The role of macrophages

The pathogenesis of pulmonary fibrosis depends on soluble factors and a mechanical signal (extracellular lung matrix stiffness). Similarly, effective macrophage engulfment of foreign particles (phagocytosis) requires orchestration of macrophage surface receptors, the particle itself and the extracellular matrix.

Acute respiratory distress syndrome (ARDS) from an infectious stimulus is a complex process characterized by endothelial and alveolar epithelial injury followed by recruitment and accumulation of inflammatory cells (i.e., macrophages) in the injured alveolus. Macrophages play a key role in lung injury and fibrosis by producing cytokines and other inflammatory remodeling factors. Hence, we sought to determine the role of TRPV4 in clearance of infection by macrophages (phagocytosis) and associated lung tissue injury.

Investigating TRPV4

We investigated the role of TRPV4 in integrating the dual signals provided by matrix stiffness and lipopolysaccharide (LPS), an important constituent on the surface of gram-negative bacteria, to control macrophage phagocytosis and cytokine production for host defense and resolution of lung injury.

In work recently published in the Journal of Immunology, we showed that inhibition of TRPV4 by pharmacologic agents or downregulation/deletion of TRPV4 resulted in almost complete blockage of LPS-stimulated macrophage phagocytosis in vitro and in vivo in a matrix stiffness-dependent manner. Moreover, TRPV4 mediated the LPS signal to release anti-inflammatory/ pro-resolution cytokines in macrophages.

Results

Taken together, these results implicate the mechanosensing channel, TRPV4, in the pathogenesis of gram-negative bacterial pneumonia and resolution of associated acute lung injury by integrating the LPS and the matrix stiffness signals for macrophage phagocytosis and pro-resolution cytokine release.

Pharmacologic agents targeting TRPV4 are currently under development and in Phase I clinical trials. Successful targeting of TRPV4 channel activity may lead to therapeutic approaches to treat bacterial pneumonia and associated ARDS.

Dr. Scheraga is an associate staff physician at the Respiratory Institute and holds a secondary appointment in the Lerner Research Institute Department of Pathobiology. For more information contact Dr. Scheraga at 216.444.4429 or scherar@ccf.org.