Primary Graft Dysfunction in Lung Transplantation: An Overview of the Molecular Mechanisms

Abstract

Primary graft dysfunction (PGD) remains a major complication after lung transplantation. Donor lung ischemia followed by reperfusion drives oxidative stress and inflammatory responses. The pathophysiology is influenced by various donor-, procedure-, and recipient-related factors, which complicates the identification of biomarkers for evaluation of donor lung injury or therapeutic interventions to minimize PGD. This review provides an overview of the molecular pathways that contribute to PGD pathophysiology, including those involved in loss of endothelial-epithelial membrane integrity, neutrophil infiltration, and the development of pulmonary edema.

Keywords: inflammation; ischemia reperfusion injury; lung transplantation; neutrophils; oxidative stress; primary graft dysfunction.

Figure 1

An overview of the mechanisms of oxidative stress in LIRI. Ischemia can result in the depletion of ATP, which inactivates ATP-dependent ion channels. Na⁺ and Ca²⁺ accumulate in the cells, leading to cell swelling. Upon reperfusion, hypoxanthine, a breakdown product of ATP, is converted into superoxide by xanthine oxidase. Activation of NADPH oxidase contributes to the generation of ROS. Increased mitochondrial Ca²⁺ together with the presence of ROS triggers the opening of mPTPs and subsequent cell death. Cessation of flow and associated cell membrane depolarization lead to the inactivation of voltage-gated Ca²⁺ channels, contributing to intracellular Ca²⁺ retention. This stimulates the production of NO by eNOS, which reacts with ROS to form peroxynitrate. (Created in BioRender. Jennekens, J. (2025) https://BioRender.com/6et2zpu). Abbreviations: Ca²⁺ = calcium; mPTP = mitochondrial permeability transition pore; Na⁺ = sodium; eNOS = endothelial nitric oxide synthase; NO = nitric oxide; ROS = reactive oxygen species.

Figure 2

An overview of the mechanisms of innate immune activation in LIRI. DAMPs released by injured or dying cells can activate TLR4, which uses MyD88 to trigger the translocation of NF-κB from the cytosol into the nucleus where it activates the transcription of genes coding for pro-inflammatory cytokines and adhesion molecules in ECs. The NLRP3 inflammasome requires two specific activation signals. First, activation of NF-κB through TLR, NLR, or pro-inflammatory cytokine signaling and downstream upregulation of NLRP3, pro-IL-1β, and pro-IL-18 serves as the priming signal. Next, interaction between NLRP3 and a DAMP, such as eATP or ROS, is required, which results in activation of caspase-1 and cleavage of pro-IL-1β and pro-IL-18 into their mature forms (Created in BioRender. Jennekens, J. (2025) https://BioRender.com/h9my2qg). Abbreviations: DAMP = damage-associated molecular pattern; ECs = endothelial cells; NLRP3 = NOD-like receptor protein 3; eATP = extracellular ATP; ROS = reactive oxygen species. TLR4 = toll-like receptor 4.

Figure 3

Donor-, procedure-, and recipient-related factors influencing PGD pathophysiology. Donor type, warm ischemic time, preservation method, the use of cardiopulmonary bypass, red blood cell transfusion, and genetic predisposition of a recipient can contribute to donor lung injury prior to retrieval, during preservation, or upon reperfusion (Created in BioRender. de Heer, L. (2025) https://BioRender.com/9fkosgl). Abbreviations: DBD = donation after brain death; DCD = donation after circulatory death.