Key role of the endothelium in lung ischemia-reperfusion injury: What the clinician needs to know

Lung transplantation remains the definitive treatment for selected patients with end-stage respiratory failure; however, outcomes are limited by significant early morbidity and mortality. Primary graft dysfunction (PGD), occurring within the first 72 hours after transplantation, is the most severe early complication and is largely driven by pulmonary ischemia-reperfusion (IR) injury. Growing evidence identifies the pulmonary endothelium as a primary target of IR, with endothelial dysfunction playing a central role in increased vascular permeability, pulmonary edema, impaired gas exchange, and altered pulmonary vascular tone. During ischemia, endothelial metabolic alterations, oxidative stress priming, and glycocalyx degradation sensitize the pulmonary microvasculature to reperfusion injury. Reperfusion then triggers a marked inflammatory response characterized by reactive oxygen species generation, calcium overload, mitochondrial dysfunction, leukocyte recruitment, and disruption of intercellular junctions, leading to endothelial barrier breakdown and microvascular leakage. The endothelial glycocalyx, a critical regulator of vascular permeability and mechanotransduction, is particularly vulnerable to IR injury, and its degradation further amplifies inflammation and capillary leakage. This narrative review summarizes the key mechanisms involved in pulmonary IR injury, with a focus on endothelial and glycocalyx dysfunction and their contribution to PGD after lung transplantation. We discuss major pathways involved in vasomotor dysregulation, oxidative stress, and inflammatory signaling, as well as the influence of graft preservation strategies, including cold storage temperature and ex vivo lung perfusion. Finally, we review emerging therapeutic approaches aimed at preserving endothelial integrity and glycocalyx structure. Targeting endothelial and glycocalyx protection represents a promising strategy to reduce IR-related lung injury and improve post-transplant outcomes.