Nitrite attenuates mitochondrial impairment and vascular permeability induced by ischemia-reperfusion injury in the lung

Am J Physiol Lung Cell Mol Physiol. 2020 Apr 1;318(4):L580-L591. doi: 10.1152/ajplung.00367.2018. Epub 2020 Feb 19.


Primary graft dysfunction (PGD) is directly related to ischemia-reperfusion (I/R) injury and a major obstacle in lung transplantation (LTx). Nitrite (NO2-), which is reduced in vivo to form nitric oxide (NO), has recently emerged as an intrinsic signaling molecule with a prominent role in cytoprotection against I/R injury. Using a murine model, we provide the evidence that nitrite mitigated I/R-induced injury by diminishing infiltration of immune cells in the alveolar space, reducing pulmonary edema, and improving pulmonary function. Ultrastructural studies support severe mitochondrial impairment in the lung undergoing I/R injury, which was significantly protected by nitrite treatment. Nitrite also abrogated the increased pulmonary vascular permeability caused by I/R. In vitro, hypoxia-reoxygenation (H/R) exacerbated cell death in lung epithelial and microvascular endothelial cells. This contributed to mitochondrial dysfunction as characterized by diminished complex I activity and mitochondrial membrane potential but increased mitochondrial reactive oxygen species (mtROS). Pretreatment of cells with nitrite robustly attenuated mtROS production through modulation of complex I activity. These findings illustrate a potential novel mechanism in which nitrite protects the lung against I/R injury by regulating mitochondrial bioenergetics and vascular permeability.

Keywords: endothelial barrier function; ischemia-reperfusion injury; lung transplantation; mitochondrial dysfunction; nitrite; primary graft dysfunction; vascular permeability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Capillary Permeability / drug effects*
  • Cell Line, Tumor
  • Cytoprotection / drug effects
  • Electron Transport Complex I / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Humans
  • Hypoxia / drug therapy
  • Hypoxia / metabolism
  • Lung / drug effects*
  • Lung / metabolism
  • Lung Transplantation / methods
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Nitrites / pharmacology*
  • Primary Graft Dysfunction / drug therapy
  • Primary Graft Dysfunction / metabolism
  • Pulmonary Edema / drug therapy
  • Pulmonary Edema / metabolism
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / metabolism


  • Nitrites
  • Reactive Oxygen Species
  • Electron Transport Complex I