Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury

Ashish K. Sharma, Eric J. Charles, Yunge Zhao, Adishesh K. Narahari, Pranav K. Baderdinni, Miranda E. Good, Ulrike M. Lorenz, Irving L. Kron, Douglas A. Bayliss, Kodi S. Ravichandran, Brant E. Isakson, Victor E. Laubach

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after I/R and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was used whereby left lungs underwent 1 h of ischemia and 2 h of reperfusion. Treatment of wild-type mice with Panx1 inhibitors (carbenoxolone or probenecid) significantly attenuated I/R-induced pulmonary dysfunction, edema, cytokine production, and neutrophil infiltration versus vehicle-treated mice. In addition, VE-Cad-CreERT2+/Panx1fl/fl mice (tamoxifen-in-ducible deletion of Panx1 in vascular endothelium) treated with tamoxifen were significantly protected from IRI (reduced dysfunction, endothelial permeability, edema, proinflammatory cytokines, and neutrophil infiltration) versus vehicle-treated mice. Furthermore, extracellular ATP levels in bronchoalveolar lavage fluid is Panx1-mediated after I/R as it was markedly attenuated by Panx1 antagonism in wild-type mice and by endothelial-specific Panx1 deficiency. Panx1 gene expression in lungs after I/R was also significantly elevated compared with sham. In vitro experiments demonstrated that TNF-α and/or hypoxia-reoxygenation induced ATP release from lung microvascular endothelial cells, which was attenuated by Panx1 inhibitors. This study is the first, to our knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R. Pharmacological antagonism of Panx1 activity may be a novel therapeutic strategy to prevent IRI and primary graft dysfunction after lung transplantation.

Original languageEnglish (US)
Pages (from-to)L301-L312
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume315
Issue number2
DOIs
StatePublished - Aug 2018
Externally publishedYes

Keywords

  • Danger-associated molecular pattern
  • Inflammation
  • Ischemia-reperfusion injury
  • Pannexin
  • Purinergic signaling

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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  • Cite this

    Sharma, A. K., Charles, E. J., Zhao, Y., Narahari, A. K., Baderdinni, P. K., Good, M. E., Lorenz, U. M., Kron, I. L., Bayliss, D. A., Ravichandran, K. S., Isakson, B. E., & Laubach, V. E. (2018). Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury. American Journal of Physiology - Lung Cellular and Molecular Physiology, 315(2), L301-L312. https://doi.org/10.1152/ajplung.00004.2018