December 8, 2015/Pulmonary/News & Insight

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

Discovery may lead to novel therapies

15-PUL-2463-TRPV4-CQD-650×450

By Rachel G. Scheraga, MD

Advertisement

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

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.

Advertisement

Related Articles

Doctor talking with patient
March 21, 2024/Pulmonary/News & Insight
COVID-19: A Management Update

A review of IDSA and NIH guidelines

Clinician performing bronchoscopy
February 16, 2024/Pulmonary/News & Insight
Program Implemented to Standardize Diagnostic Bronchoscopy Data Ensures Quality Care

Caregivers are provided with real-time bronchoscopy patient findings

Community Lung Clinic
January 16, 2024/Pulmonary/News & Insight
Providing Culturally Competent Care Through Cleveland Clinic’s Community Lung Clinic

New program sets out to better support underserved patient populations

physician-scientist
October 18, 2023/Pulmonary/News & Insight
Cleveland Clinic Selected By the NIH as a Training Site for the Scientist Leaders of Tomorrow

As the U.S. has seen an increase in respiratory-related morbidity and mortality, supporting future respiratory researchers has become imperative

Chronic Cough
The Chronic Cough Conundrum

Diagnosing the cause of a chronic cough can be challenging and timely, but multidisciplinary collaboration and the development of new treatments are improving the process

physician shaking hands with professional colleague
Cleveland Clinic’s Respiratory Therapy Training Program

Despite a decline in numbers, the demand for respiratory therapists continues to rise

Pulmonary fibrosis
A New Approach to Progressive Pulmonary Fibrosis

A mindset shift has changed the way pulmonologists both treat and define PFF

Tired patient
February 21, 2023/Pulmonary/News & Insight
Cleveland Clinic Joins NIH’s COVID-19 Recovery Research Consortium

Will enable patients with long COVID to enroll in national clinical trials

Ad