Mechanisms of lung ischemia-reperfusion injury

Abstract

Purpose of review: Lungs are extremely susceptible to injury, and despite advances in surgical management and immunosuppression, outcomes for lung transplantation are the worst of any solid organ transplant. The success of lung transplantation is limited by high rates of primary graft dysfunction because of ischemia-reperfusion injury characterized by robust inflammation, alveolar damage, and vascular permeability. This review will summarize major mechanisms of lung ischemia-reperfusion injury with a focus on the most recent findings in this area.

Recent findings: Over the past 18 months, numerous studies have described strategies to limit lung ischemia-reperfusion injury in experimental settings, which often reveal mechanistic insight. Many of these strategies involved the use of various antioxidants, anti-inflammatory agents, mesenchymal stem cells, and ventilation with gaseous molecules. Further advancements have been achieved in understanding mechanisms of innate immune cell activation, neutrophil infiltration, endothelial barrier dysfunction, and oxidative stress responses.

Summary: Methods for prevention of primary graft dysfunction after lung transplant are urgently needed, and understanding mechanisms of ischemia-reperfusion injury is critical for the development of novel and effective therapeutic approaches. In doing so, both acute and chronic outcomes of lung transplant recipients will be significantly improved.

Conflict of interest statement

CONFLICTS OF INTEREST

None

Figures

Figure 1. Inflammatory pathways contributing to lung IR injury

After IR, generation of reactive oxygen species (ROS) by endothelial cells (EC) via NADPH oxidase (NOX2) and nitric oxide (NO), and activation of integrin αvβ5, promotes vascular permeability. Alveolar macrophages (AM) are activated, in part via binding of damage-associated molecular patterns (DAMPs) to toll-like receptor 4 (TLR4), to secrete neutrophil chemokines (CXCL1 and CXCL2) via DAP12, pro-inflammatory cytokines (e.g. TNF-α), and high mobility group box 1 (HMGB1). HMGB1 binds to receptor for advanced glycation end products (RAGE) to induce IL-17 secretion by invariant natural killer T cells (iNKT). TNF-α induces the production of IL-8, another potent chemokine, by alveolar type 2 epithelial cells (AT2); a process augmented by IL-17. Elevated chemokine levels and adhesion molecule expression on ECs and neutrophils (PMN) leads to binding and infiltration of neutrophils, which can release cytokines, ROS and form neutrophil extracellular traps (NETs). AT1, alveolar type 1 epithelial cell.