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TRPV4 Channels Mediate Pulmonary Edema and Inflammation During Ischemia-Reperfusion Injury.

E. Charles, Y. Zhao, K. Hong, C. Marziano, J. Mehaffey, I. Kron, S. Sonkusare, V. Laubach, A. Sharma.

University of Virginia, Charlottesville, VA

Meeting: 2017 American Transplant Congress

Abstract number: 544

Keywords: Edema, Endothelial activation, Ischemia, Lung transplantation

Session Information

Session Name: Concurrent Session: Pathways in Ischemia Reperfusion

Session Type: Concurrent Session

Date: Tuesday, May 2, 2017

Session Time: 4:30pm-6:00pm

 Presentation Time: 4:30pm-4:42pm

Location: E351

Rationale: Lung ischemia-reperfusion (IR) injury remains a major challenge in post-transplant patients. Transient receptor potential vanilloid 4 (TRPV4) cation channels mediate cellular calcium influx, and this study investigates their role in regulation of endothelial permeability and epithelial activation during lung IR injury.

Methods: C57BL/6 wild-type (WT) and TRPV4-/- mice underwent sham surgery or lung IR (1hr left lung ischemia followed by 2hrs reperfusion) using an in vivo hilar-ligation model. In separate groups, WT mice were treated with GSK2193874 (TRPV4 specific antagonist; 1mg/kg) given i.v. 1hr before ischemia (n=5-8 mice/group). Lung function was measured using an isolated, buffer-perfused apparatus. Cytokine and myeloperoxidase levels were measured in bronchoalveolar lavage fluid, and lung injury was assessed by edema (wet/dry weight ratio) and neutrophil infiltration (immunohistochemistry). Murine alveolar type II epithelial cells (MLE12) and lung primary microvascular endothelial cells (PMVEC) were treated with either recombinant TNF-α (50[mu]M) or exposed to hypoxia/reoxygenation (HR; 3hrs/1hr) to quantify CXCL1, elementary calcium influx or neutrophil transendothelial migration.

Results: TRPV4-/- mice demonstrated a significant protection from lung dysfunction compared to WT mice after IR as seen by decreased airway resistance (1.6±0.1 vs. 2.1±0.2 cm H2O/[mu]l/sec; p=0.03) and pulmonary artery pressure (7.7±0.2 vs. 12.8±0.4 cm H2O; p<0.01) as well as increased pulmonary compliance (5.1±0.3 vs. 2.5±0.1 [mu]l/cm H2O; p<0.01). Lung injury was significantly attenuated in TRPV4-/- mice after IR as seen by significant mitigation of proinflammatory cytokines (IL-17, TNF-α, CXCL1, HMGB1), myeloperoxidase levels (57±7.9 vs. 114±9.5 ng/ml; p<0.01) and neutrophil infiltration. Treatment of WT mice with GSK2193874 significantly attenuated lung dysfunction and edema compared to untreated mice. In vitro experiments showed that TNF-α or HR induced a multifold increase in CXCL1 production from MLE12 cells which was markedly attenuated by pretreatment with GSK2193874. Also, neutrophil transendothelial migration and calcium influx events through PMVECs induced by TNF-α were significantly reduced by TRPV4 inhibitors.

Conclusions: Our results suggest that TRPV4 channels can modulate pulmonary inflammation and edema after IR, likely involving TRPV4-mediated signaling in both epithelial and endothelial cells.

CITATION INFORMATION: Charles E, Zhao Y, Hong K, Marziano C, Mehaffey J, Kron I, Sonkusare S, Laubach V, Sharma A. TRPV4 Channels Mediate Pulmonary Edema and Inflammation During Ischemia-Reperfusion Injury. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Charles E, Zhao Y, Hong K, Marziano C, Mehaffey J, Kron I, Sonkusare S, Laubach V, Sharma A. TRPV4 Channels Mediate Pulmonary Edema and Inflammation During Ischemia-Reperfusion Injury. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/trpv4-channels-mediate-pulmonary-edema-and-inflammation-during-ischemia-reperfusion-injury/. Accessed May 8, 2025.

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