Primary graft dysfunction after Lung transplantation: unveiling the role of innate immunity.

Abstract

Primary graft dysfunction (PGD) represents a clinical acute lung injury syndrome occurring within 72 hours after lung transplantation, remaining the main cause of early mortality after lung transplantation. However, very few effective and specific therapies are available, except for supportive treatment. Broad cellular and molecular mechanisms contribute to PGD, yet the precise mechanism remains poorly understood. The major underlying pathophysiology of PGD is ischemia-reperfusion injury (IRI), which inevitably occurs during lung transplantation. Ischemia and subsequent reperfusion of donor lungs commonly trigger cellular and molecular dysfunction, causing disorders of metabolism and ionic homeostasis, release of reactive oxygen species (ROS), dysfunction of mitochondria, secretion of inflammatory cytokines, and activation of innate immunity. These events induce both programmed and non-programmed cell death, leading to vascular and alveolar epithelial damage, pulmonary edema, and impaired gas exchange. Innate immune activation during lung ischemia-reperfusion unfolds in two distinct phases, with the early phase primarily driven by donor-derived immune cells and the late phase mainly driven by recipient-derived immune cells. This review systematically summarizes the pathophysiology of PGD from the perspective of cellular and molecular aspects, especially emphasizing the process of programmed cell death and dynamic innate immune cell migration, which might potentially provide novel insights into the prevention and targeted therapy for IRI and PGD after lung transplantation.