Role of EETs in regulation of endothelial permeability in rat lung

Alvarez, Diego F.; Gjerde, Eli-Anne B.; Townsley, Mary I.

doi:10.1152/ajplung.00150.2003

Cited by 50 publications

(66 citation statements)

References 47 publications

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“…Isolated perfused lungs were prepared as previously described and equilibrated so that a baseline isogravimetric period was established, where lung pressures and weight remained stable. 30 Under these conditions, mean pulmonary artery pressure was 9 AE 1 and 48 AE 6.23 cm H 2 O in normotensive and pulmonary arterial hypertensive wild-type lungs, respectively (P < 0.01). Mean pulmonary artery pressures were comparable between hypertensive wild-type (48 AE 6.23) and TRPC4-knockout rats (43 AE 4.69) ( Figure 1B).…”

Section: Store Depletion Enhances Endothelial Permeability In Pulmonamentioning

confidence: 79%

“…DNA was extracted from tail snips, as described previously, 29 and 2 mL of the resulting DNA solution was subjected to PCR analysis using three primers (primer A, Filtration coefficient (K f ) values were measured as previously described, using zone 3 conditions. 30 Baseline K f was calculated as the rate of weight gain obtained 13 to 15 minutes after a 10 cm H 2 O increase in pulmonary venous pressure, normalized per 100 g predicted wet lung weight. A dose of 75 nmol/L thapsigargin was added to the perfusate reservoir and circulated for 10 minutes, and a second K f was determined after the treatment in both the wild-type and TRPC4-knockout groups under normotensive and pulmonary arterial hypertensive conditions.…”

Section: Genotyping Of the Trpc4-knockout Ratsmentioning

confidence: 99%

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Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

Francis

Zhou

et al. 2016

The American Journal of Pathology

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The canonical transient receptor potential channel 4 (TRPC4) comprises an endothelial storeeoperated Ca 2þ entry channel, and TRPC4 inactivation confers a survival benefit in pulmonary arterial hypertension (PAH). Endothelial Ca 2þ signals mediated by TRPC4 enhance vascular permeability in vitro, but the contribution of TRPC4-dependent Ca 2þ signals to the regulation of endothelial permeability in PAH is poorly understood. We tested the hypothesis that TRPC4 increases vascular permeability and alters the frequency of endothelial Ca 2þ transients in PAH. We measured permeability in isolated lungs, and found that TRPC4 exaggerated permeability responses to thapsigargin in Sugen/hypoxia-treated PAH rats. We compared endothelial Ca 2þ activity of wild-type with TRPC4-knockout rats using confocal microscopy, and evaluated how Ca 2þ signals were influenced in response to thapsigargin and sequential treatment with acetylcholine. We found that thapsigargin-stimulated Ca 2þ signals were increased in PAH, and recovered by TRPC4 inactivation. Store depletion revealed bimodal Ca 2þ responses to acetylcholine, with both shortand long-duration populations. Our results show that TRPC4 underlies an exaggerated endothelial permeability response in PAH. Furthermore, TRPC4 increased the frequency of endothelial Ca 2þ transients in severe PAH, suggesting that TRPC4 provides a Ca 2þ source associated with endothelial dysfunction in the pathophysiology of PAH. This phenomenon represents a new facet of the etiology of PAH, and may contribute to PAH vasculopathy by enabling inflammatory mediator flux across the endothelial barrier. The current model of the endothelium extends beyond the concept of a homogeneous cell monolayer in contact with the blood.1e6 Recent advances in high-resolution microscopy have enabled the measurement of individual cellular behavior rather than tissue-wide averaged responses, and we are now beginning to understand the heterogeneous nature of local endothelia and their major impact on physiology and disease.7e10 Endothelial dysfunction underlies the pathogenesis of pulmonary arterial hypertension (PAH), a deadly disease of high pulmonary artery pressure culminating in right-sided heart failure. Endothelial dysfunction in PAH is characterized by the aberrant production of endothelial-dependent vasoconstrictors and vasodilators within pulmonary arterioles, leading to sustained elevation of pulmonary artery pressure, and the initiation of endothelial hyperproliferation, leading to occlusive lesion formation within the microcirculation.

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Section: Store Depletion Enhances Endothelial Permeability In Pulmonamentioning

confidence: 79%

Section: Genotyping Of the Trpc4-knockout Ratsmentioning

confidence: 99%

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

Francis

Zhou

et al. 2016

The American Journal of Pathology

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“…or EpETrEs according to LIPIDMAPS nomenclature) are a class of important lipid mediators with critical physiological functions that include vasodilation, antiinflammation, antihypertension, organ protection, and analgesic effects (4). Specifically in lung health and lung disease, EETs are reported to affect lung epithelial ion transport (5-7), relax precontracted bronchi (8), reduce inflammation (9,10), regulate endothelial permeability in the lung (11), and regulate pulmonary vascular pressures (12,13). Thus, modulation of endogenous EETs is an attractive approach to potentially control the symptoms of asthma, which include chronic airway inflammation and airway hyperresponsiveness (AHR).…”

Section: Clinical Relevancementioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

Yang¹,

Bratt

Franzi

et al. 2015

Am J Respir Cell Mol Biol

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Control of airway inflammation is critical in asthma treatment. Soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. We hypothesized that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. BALB/c mice were sensitized and exposed to OVA over 6 weeks. A sEH inhibitor (sEHI) was administered for 2 weeks. Respiratory system compliance, resistance, and forced exhaled nitric oxide were measured. Lung lavage cell counts were performed, and selected cytokines and chemokines in the lung lavage fluid were measured. A LC/MS/MS method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. The pharmacological inhibition of sEH increased concentrations of the antiinflammatory epoxy eicosatrienoic acids and simultaneously decreased the concentrations of the proinflammatory dihydroxyeicosatrienoic acids and dihydroxyoctadecenoic acids. All monitored inflammatory markers, including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVA-exposed mice were reduced by sEHI. The type 2 T helper cell (Th2) cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after sEHI administration. Resistance and dynamic lung compliance were also improved by sEHI. We demonstrated that sEHI administration attenuates allergic airway inflammation and airway responsiveness in a murine model. sEHI may have potential as a novel therapeutic strategy for allergic asthma.Keywords: soluble epoxide hydrolase; asthma; inflammation; lipid mediators; type 2 T helper cell cytokines Clinical RelevanceWe demonstrated that inhibition of soluble epoxide hydrolase attenuates allergic airway inflammation and airway responsiveness in a murine model. Therefore, sEH inhibitors may have potential as a novel therapeutic strategy for allergic asthma.Three hundred million people worldwide suffer from episodic or persistent asthma (1). The cornerstones of treatment for persistent asthma are inhaled corticosteroids and b-agonist bronchodilators; however, a significant minority of patients with asthma does not respond well to these therapies (2). Thus, there are ongoing efforts to develop novel treatment strategies (3), such as specific antagonists of type 2 T helper cell (Th2) cytokines and mediators.

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“…Thus, we compared the pressure threshold for a HiPv-induced permeability increase at perfusate temperatures of 26 (n 5 7) and 33 (n 5 9) 8C. (7,8) to identify whether the permeability increase was dependent upon extracellular Ca 21 (n 5 5) and using ruthenium red to block TRPV channels (n 5 4). HiPv challenge was also evaluated in lungs from TRPV4 2/2 mice (n 5 7).…”

Section: Clinical Relevancementioning

confidence: 99%

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

Jian¹,

King²,

Al‐Mehdi³

et al. 2008

Am J Respir Cell Mol Biol

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129

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High vascular pressure targets the lung septal network, causing acute lung injury. While calcium entry in septal endothelium has been implicated, the channel involved is not known. This study tested the hypothesis that the vanilloid transient receptor potential channel, TRPV4, is a critical participant in the permeability response to high vascular pressure. Isolated lungs from TRPV4 1/1 or TRPV4 2/2 mice were studied at baseline or during high pressure challenge. Permeability was assessed via the filtration coefficient. Endothelial calcium transients were assessed using epifluorescence microscopy of the lung subpleural network. Light microscopy and point counting were used to determine the alveolar fluid volume fraction, a measure of alveolar flooding. Baseline permeability, calcium intensity, and alveolar flooding were no different in TRPV4 1/1 versus TRPV4 2/2 lungs. In TRPV4 1/1 lungs, the high pressure-induced permeability response was significantly attenuated by low calcium perfusate, the TRPV antagonist ruthenium red, the phospholipase A 2 inhibitor methyl arachidonyl fluorophosphonate, or the P450 epoxygenase inhibitor propargyloxyphenyl hexanoic acid. Similarly, the high pressure-induced calcium transient in TRPV4 1/1 lungs was attenuated with ruthenium red or the epoxygenase inhibitor. High vascular pressure increased the alveolar fluid volume fraction compared with control. In lungs from TRPV4 2/2 mice, permeability, calcium intensity, and alveolar fluid volume fraction were not increased. These data support a role for P450-derived epoxyeicosatrienoic aciddependent regulation of calcium entry via TRPV4 in the permeability response to high vascular pressure.Keywords: epoxyeicosatrienoic acid; capillary permeability; respiratory distress syndrome; TRPV cation channels In lung, high vascular pressure (HiPv) exceeding a threshold of 30 to 50 cm H 2 O increases endothelial permeability (1-4). While mechanical stress failure of the alveolar septal barrier can occur at higher pressures, leading to overt alveolar flooding (5), the molecular mechanisms underlying the early HiPv-induced increase in endothelial permeability are not well understood. Kuebler and colleagues (6) have reported that moderate HiPv promotes Ca 21 entry into lung endothelium, and acute lung injury is often dependent upon such Ca 21 transients (7-10). Although HiPv-induced lung injury could plausibly be dependent upon Ca 21 entry, this has not been experimentally confirmed nor has a candidate channel been identified.The Ca 21 permeable channel TRPV4, a member of the vanilloid subfamily of transient receptor potential (TRP) channels, is expressed in the alveolar septal compartment (8). The notion that TRPV4 might subserve HiPv-induced Ca 21 entry in lung endothelium is based on the observation that the channel can be activated by mechanical stress, such as hypotonic cell swelling or shear stress (11-13). In vitro studies have shown that activation of TRPV4 with mechanical stress requires hydrolysis of membrane phospholipids via phospholipas...

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Role of EETs in regulation of endothelial permeability in rat lung

Cited by 50 publications

References 47 publications

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca2+ Transients in Severe Pulmonary Arterial Hypertension

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

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

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