Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury

Haywood, Nathan; Ta, Huy Q.; Zhang, Aimee; Charles, Eric J.; Rotar, Evan P.; Noona, Sean W; Salmon, Morgan; Daneva, Zdravka; Sonkusare, Swapnil K.; Laubach, Victor E.

doi:10.1016/j.athoracsur.2021.04.052

Cited by 13 publications

(16 citation statements)

References 36 publications

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“…On the basis of our findings that Trpv4 ECKO mice are protected against lung IRI ( 16 ), we hypothesized that increased Ca 2+ influx through endothelial TRPV4 channels mediates lung IRI. To test this notion, we used a well-established left-lung hilar-ligation model of IRI in mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1A) involving 1 hour of ligation (ischemia) followed by 2 hours of reperfusion ( 9 , 20 ). After IR, mice display substantial lung dysfunction, neutrophil infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage (BAL) fluid ( 16 ). Control mice underwent sham surgery with no hilar ligation.…”

Section: Resultsmentioning

confidence: 99%

“…Transient receptor potential vanilloid 4 (TRPV4) channels, which constitute a major Ca 2+ entry pathway in pulmonary endothelium ( 8 , 10 , 11 ), have emerged as central players in the pathogenesis of different forms of lung injury ( 12 – 15 ). We provided evidence that endothelial TRPV4-knockout ( Trpv4 ECKO ) mice are protected against increased vascular permeability, lung inflammation, and edema after lung IR ( 16 ), suggesting that endothelial TRPV4 channels are critical mediators of lung IRI. However, whether increased activity of pulmonary endothelial TRPV4 channels contributes to lung IRI is not known.…”

Section: Introductionmentioning

confidence: 99%

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Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Kuppusamy,

Ta,

Davenport

et al. 2023

Sci. Signal.

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Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR–induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca 2+ influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI–induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Kuppusamy,

Ta,

Davenport

et al. 2023

Sci. Signal.

Self Cite

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“…Fernandez et al 13 Mouse clamp-IRI Adenosine receptor agonism ameliorated lung IRI Lau et al 14 Mouse clamp-IRI Fibrinolysis enhanced by PAI-1 inhibition attenuated lung IRI Lan et al 15 In situ mouse lung perfusion NKCC1 inhibition improved lung IRI Sharma et al 16 Mouse clamp-IRI Antagonism of pannexin-1, an eATP channel, ameliorated IRI Haywood et al 17 Mouse clamp-IRI TRPV4 cation channel activation mediated endothelial permeability Li et al 18 Mouse transplant Necroptosis inhibition through RIPK inhibition reduced neutrophil infiltration Chatterjee et al 19 Mouse and rat ex vivo perfusion; in vitro endothelial cells…”

Section: Study Model Mechanismmentioning

confidence: 99%

“…Once activated, the pulmonary endothelium undergoes a calcium influx, which in turn activates cellular pathways that disrupt tight junctions and cause endothelial barrier dysfunction. 46 Haywood et al 17 showed that genetic endothelial-specific transient receptor potential vanilloid 4 deficiency and pharmacological inhibition could improve lung function and compliance. They also found lower proinflammatory cytokines levels in the bronchoalveolar lavage and attenuated neutrophil infiltration.…”

Section: Endothelial and Epithelial Cell Transmembrane Fluxmentioning

confidence: 99%

Primary Graft Dysfunction in Lung Transplantation: A Review of Mechanisms and Future Applications

et al. 2023

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Lung allograft recipients have worse survival than all other solid organ transplant recipients, largely because of primary graft dysfunction (PGD), a major form of acute lung injury affecting a third of lung recipients within the first 72 h after transplant. PGD is the clinical manifestation of ischemia–reperfusion injury and represents the predominate cause of early morbidity and mortality. Despite PGD’s impact on lung transplant outcomes, no targeted therapies are currently available; hence, care remains supportive and largely ineffective. This review focuses on molecular and innate immune mechanisms of ischemia–reperfusion injury leading to PGD. We also discuss novel research aimed at discovering biomarkers that could better predict PGD and potential targeted interventions that may improve outcomes in lung transplantation.

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Endothelial TRPV4 channels in lung edema and injury

Sonkusare

Laubach

2022

Current Topics in Membranes

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Endothelial Transient Receptor Potential Vanilloid 4 Channels Mediate Lung Ischemia-Reperfusion Injury

Cited by 13 publications

References 36 publications

Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Purinergic P2Y2 receptor–induced activation of endothelial TRPV4 channels mediates lung ischemia-reperfusion injury

Primary Graft Dysfunction in Lung Transplantation: A Review of Mechanisms and Future Applications

Endothelial TRPV4 channels in lung edema and injury

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