In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis

Abstract

Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF-κB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.

The Role of Transient Receptor Potential Vanilloid 4 in Pulmonary Inflammatory Diseases

“…In the setting of pulmonary inflammation, TRPV4 has been found to be highly expressed and upregulated in airway smooth muscle, vascular endothelial cells, alveolar epithelial cells, and immune cells such as macrophages and neutrophils (12, 16, 21, 26–28). TRPV4 has been implicated in the pathogenesis of asthma, CF, and sterile and infection-associated ARDS (4–10, 29). …”

“…TRPV4-dependent calcium influx in response to hypotonicity is reduced in human CF epithelial cells (34). Furthermore, other hypotonicity-induced TRPV4 chemical activators (5,6-, 8,9-, 11,12-, and 14,15-EET) and their metabolites (5,6 DHET) have been measured in the sputum of CF patients (10). Although the current consensus suggests that dehydration of airway mucous is the predominant cause of impaired mucociliary clearance in CF, recent considerations have been put forth to increase ciliary function or ciliary beat frequency (CBF) as a means to improve mucociliary clearance (35, 36).…”

“…In this regard, TRPV4 activation induces epithelial cell secretion of pro-inflammatory cytokines/chemokines and active lipid mediators (e.g., IL-8, cytosolic PLA2, prostaglandin E2, NF-κB, AA, etc.) in response to lipopolysaccharide (LPS) (10). Secretion of IL-8/KC, in both bronchial epithelial cells and in intact mice lungs in response to TPRV4 activation, was increased upon inhibition of CFTR (10).…”

“…in response to lipopolysaccharide (LPS) (10). Secretion of IL-8/KC, in both bronchial epithelial cells and in intact mice lungs in response to TPRV4 activation, was increased upon inhibition of CFTR (10). These data demonstrate that TRPV4 has pleotropic effects on CF pathogenesis.…”

“…Dysregulation of channel function and/or expression can lead to organ dysfunction and disease (1–3). Recent studies have shown that a transient receptor potential (TRP) channel family member, transient receptor potential vanilloid 4 (TRPV4), is implicated in inflammatory lung diseases such as asthma, cystic fibrosis (CF), acute lung injury/acute respiratory distress syndrome (ARDS), and pulmonary fibrosis (4–10). In fact, these studies show that TRPV4 can regulate inflammatory cytokines that play key roles in orchestrating lung tissue homeostasis and inflammatory lung disease (4, 7, 10–14).…”