High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

Jian, Ming; King, Judy; Al‐Mehdi, Abu‐Bakr; Liedtke, Wolfgang; Townsley, Mary I.

doi:10.1165/rcmb.2007-0192oc

Cited by 130 publications

(145 citation statements)

References 36 publications

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“…The role of TRPV4 in lung injury has been studied previously in animal models in which injury was induced by mechanical stress or pressure, including a ventilator-induced lung injury model, a model of heart failure induced by aortic banding, and a model of myocardial infarction induced by arterial ligation (17,21,33). Ventilator-induced lung injury is associated with subsequent inflammation driven by macrophages, and it was suggested that macrophage-expressed TRPV4 channels play a crucial role in activating these cells (16).…”

Section: Discussionmentioning

confidence: 99%

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

Balakrishna

Song

Achanta

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

186

224

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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 ...

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Section: Discussionmentioning

confidence: 99%

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

Balakrishna

Song

Achanta

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

186

224

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“…The observation that L-NAME converted the pulmonary vasodilator response to GSK1016790A to a biphasic response with a potent pulmonary vasoconstrictor component may suggest that in pathophysiological conditions characterized by increased oxidative stress, which can inactivate NO, TRPV4 channel activation could increase hydrostatic pressure in the lung and enhance edema formation (24). It has been suggested that TRPV4 channel activation plays a role in pulmonary edema induced by elevated pulmonary venous pressure (2,8,26). It has been reported that TRPV4 receptor blockade prevented the increase in lung permeability and pulmonary edema associated with increased pulmonary venous pressure (18).…”

Section: Discussionmentioning

confidence: 99%

Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat

Pankey

Zsombok

Lasker

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Pankey EA, Zsombok A, Lasker GF, Kadowitz PJ. Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat. Am J Physiol Heart Circ Physiol 306: H33-H40, 2014. First published November 1, 2013; doi:10.1152/ajpheart.00303.2013.-The transient receptor potential vanilloid 4 (TRPV4) channel is a nonselective cation channel expressed on many cell types, including the vascular endothelium and smooth muscle cells. TRPV4 channels play a role in regulating vasomotor tone and capillary permeability. The present study was undertaken to investigate responses to the TRPV4 agonist GSK101790A on the pulmonary and systemic vascular beds in the rat. Intravenous injection of GSK1016790A at doses of 2-10 g/kg produced dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and small increases in cardiac output, and responses were not altered by the cyclooxygenase inhibitor meclofenamate or the cytochrome P-450 inhibitor miconazole. Injection of GSK1016790A at a dose of 12 g/kg iv produced cardiovascular collapse that was reversible in some animals. GSK1016790A produced dose-related decreases in pulmonary and systemic arterial pressure when baseline tone in the pulmonary vascular bed was increased with U-46619. After treatment with the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester, GSK1016790A produced larger decreases in systemic arterial pressure and dose-dependent increases in pulmonary arterial pressure followed by a small decrease. These results demonstrate that GSK1016790A has vasodilator activity in pulmonary and systemic vascular beds and that when NOS is inhibited, GSK1016790A produced pulmonary vasoconstrictor responses that were attenuated by the L-type Ca 2ϩ channel antagonist isradipine. The presence of TRPV4 immunoreactivity was observed in small pulmonary arteries and airways. The present data indicate that responses to TRPV4 are modulated differently by NOS in pulmonary and systemic vascular beds and are attenuated by the TRPV4 antagonist GSK2193874. lung hydrostatic pressure; pulmonary vascular bed; transient receptor potential vanilloid 4 channels; vasodilation; hyperpolarization TRANSIENT RECEPTOR POTENTIAL VANILLOID 4 (TRPV4) is a member of the transient receptor potential ion channel superfamily that mediates the influx of cations into endothelial and smooth muscle cells with discrete selectivity for Ca 2ϩ (13,15,17,20,21). TRPV4 is expressed on vascular endothelial and smooth muscle cells and, when activated, promotes vasodilation by inducing membrane hyperpolarization (3,4,17,23). In addition to regulating vasomotor tone, TRPV4 regulates endothelial cell permeability in the lung (15,24). In isolated perfused lungs, TRPV4 activation increases endothelial permeability and promotes pulmonary edema formation in response to elevations in pulmonary venous pressure (7). TRPV4 activation decreases systemic arterial pressure in a variety of species, and it has been hypothesized that TRPV4 channel act...

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“…Our experiments rule out downregulation of eNOS or lack of eNOS substrate which have been shown to underlie endothelial dysfunction in pulmonary arterial hypertension, 31,32 and consequently suggest that lung endothelial dysfunction in CHF may be attributable to impaired posttranslational regulation of eNOS. 17,22 failed to elicit a [Ca 2ϩ ] i increase in CHF lungs. TRPV4 and TRPV2 were both downregulated in CHF, seemingly supporting the notion that downregulation of these cation channels may underlie the loss of endothelial mechanosensitivity.…”

Section: Lung Endothelial Dysfunction In Chfmentioning

confidence: 91%

Lung Endothelial Dysfunction in Congestive Heart Failure

Kerem

Yin

Kaestle

et al. 2010

Circulation Research

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Rationale: Congestive heart failure (CHF) frequently results in remodeling and increased tone of pulmonary resistance vessels. This adaptive response, which aggravates pulmonary hypertension and thus, promotes right ventricular failure, has been attributed to lung endothelial dysfunction. Objective: We applied real-time fluorescence imaging to identify endothelial dysfunction and underlying molecular mechanisms in an experimental model of CHF induced by supracoronary aortic banding in rats. Methods and Results: Endothelial dysfunction was evident in lungs of CHF rats as impaired endothelium-dependent vasodilation and lack of endothelial NO synthesis in response to mechanical stress, acetylcholine, or histamine. Key Words: congestive heart failure Ⅲ pulmonary hypertension Ⅲ endothelial dysfunction Ⅲ Ca 2ϩ regulation Ⅲ cytoskeletal dynamics C ongestive heart failure (CHF) is a major and growing cause of morbidity and mortality in most affluent countries, with a prevalence approaching 10 per 1000 among those older than 65 years of age. 1 Approximately 60% to 80% of patients with CHF of systolic or diastolic origin develop pulmonary hypertension owing to left heart disease (previously known as pulmonary venous hypertension). 2,3 Importantly, this form of pulmonary hypertension is not solely caused by a "passive" increase in pulmonary vascular pressures, but is frequently aggravated by a concomitant "reactive" increase in pulmonary vascular resistance (PVR). Incidence and magnitude of this "reactive" component vary from 20% to 100% and from supranormal to extreme PVR values, and seem to worsen with progressive duration and severity of the underlying heart disease. 4 -7 The "reactive" PVR increase in CHF results both from an elevated tone and extensive remodeling of lung resistance vessels. 8,9 The resulting increase in right ventricular afterload limits right ventricular output, and may ultimately cause fatal right ventricular failure. 2 The clinical relevance of this scenario is highlighted by epidemiological studies which identified reduced right ventricular ejection fraction as potent and independent predictor of mortality in CHF. 10 The results of several preclinical studies suggest that CHF may cause lung endothelial dysfunction, as indicated by an impaired endothelium-dependent relaxation of pulmonary artery segments in response to acetylcholine (ACh) in CHF rats. 11,12 Consequently, lung endothelial dysfunction has been Original

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High Vascular Pressure–Induced Lung Injury Requires P450 Epoxygenase–Dependent Activation of TRPV4

Cited by 130 publications

References 36 publications

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

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

Analysis of responses to the TRPV4 agonist GSK1016790A in the pulmonary vascular bed of the intact-chest rat

Lung Endothelial Dysfunction in Congestive Heart Failure

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