TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury

Abstract

Jordt S. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 307: L158 -L172, 2014. First published May 16, 2014; doi:10.1152/ajplung.00065.2014.-The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function. acute lung injury; chlorine; TRPV4 ACUTE LUNG INJURY (ALI) and its extreme manifestation, acute respiratory distress syndrome (ARDS), are associated with high levels of morbidity and mortality (28, 37). Major triggers of ALI and ARDS are pneumonia, sepsis, trauma, acid aspiration, inhalation of toxic gases or smoke, hyperoxia, high pressure ventilation, heart failure, or pancreatitis. A major hallmark of ALI and ARDS is the acute increase in permeability of the pulmonary vascular and epithelial barriers, resulting in edema and severe hypoxia (9). ALI and ARDS are often associated with exaggerated inflammatory responses due to neutrophil infiltration and increased macrophage activity in the injured lung (14,22). These inflammatory cells may aggravate injury through protease production, through generation of oxidative reactive species and proinflammatory cytokines and chemokines, and through prevention of inflammation resolution.The ion channel transient receptor potential vanilloid 4 (TRPV4) was recently identified as a major mediator of pulmonary dysfunction in animal models of ventilator-and heart failure-induced ALI, conditions associated with dramatic increases in pulmonary and vascular pressure (17,33). Among other ...

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…The TRPV4‐eNOS signaling achieves this feat by mediating the functional effect of TRPV4 channels, and by limiting the channel function through endothelial GC‐PKG signaling. While some pulmonary vascular disorders show reduced NO levels,10, 50, 51, 73 others show excessive TRPV4 channel activity 53, 54, 55, 74, 75. Thus, we propose that abnormalities in the NO‐PKG‐TRPV4 feedback mechanism may be involved in both types of pulmonary dysfunctions.…”

“…Inhibition of endothelial TRPV4 channels by inhaled NO may contribute to the negative outcome in pulmonary arterial hypertension. Inhibition of TRPV4 channel activity by NO‐GC‐PKG signaling will also have implications in the diseases characterized by excessive activation of TRPV4 channels, such as pulmonary edema and lung injury 53, 54, 55…”

Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

“…Mice were mechanically ventilated and challenged with increasing concentrations of methacholine as described previously (2,23,67). Briefly, air and Cl 2-exposed mice were anesthetized with pentobarbital (50 mg/kg ip; Vortech Pharmaceuticals, Dearborn, MI), paralyzed with pancuronium (4 mg/kg ip; Gensia Sicor Pharmaceuticals, Irvine, CA), intubated, connected to an FX-1 module of the flexiVent (SCIREQ, Montreal, PQ, Canada), and ventilated at a rate of 160 breaths per minute at a tidal volume of 0.2 ml with a positive end-expiratory pressure of 3 cmH 2O.…”

“…Increased airway resistance and airway hyperresponsiveness (AHR) are important pathological events of oxidative lung injury in general and Cl 2 toxicity in particular and result in persistent asthmalike symptoms and exacerbation of allergic airway inflammation (2,51,67), which may progress to lung fibrosis (54,55). The transient receptor potential family A1 (TRPA1) channels, present in sensory airway neurons, play an important role in the development of AHR in response to low (Ͻ50 ppm) concentrations of Cl 2 (6).…”

Novel regulators of endothelial barrier function

“…For example, endothelial knock-down or inhibition of calpains, a family of Ca 2ϩ -dependent, nonlysosomal cysteine proteases, reduces endothelial NO synthase (NOS3)-mediated NO production, subsequent phosphorylation of ICAM-1, and thereby, neutrophil recruitment as well as lung edema and protein extravasation (80). Similarly, deficiency in the polymodal cation channel TRPV4, which is highly expressed in pulmonary endothelial (95) and smooth muscle cells (29, 157) but seemingly absent in neutrophils (8), prevented both edema formation and neutrophil invasion in murine models of chlorine gas-and acid aspiration-induced lung injury (8). However, in conditions where stimuli and/or inhibitors act in parallel on both endothelial and immune cells, cause and effect in the interaction between these cell types are often hard to differentiate.…”