Ramiro Fernandez Lab

Lung recipients have the worst survival compared to all other solid organ recipients. The poor outcomes are largely driven by the high incidence of primary graft dysfunction (PGD), which results from lung ischemia reperfusion injury (IRI). Unfortunately, no specific therapies exist as the clinically actionable mechanisms associated with IRI remain unknown. We and others have identified a mechanism of mitochondrial-induced cell damage through low-grade mitochondrial outer membrane permeabilization (MOMP) termed “minority MOMP,” that is triggered by various cellular stressors. Our preliminary work has identified minority MOMP activation in pulmonary microvascular endothelial cells subjected to IRI. Along with minority MOMP activation, our lab has found IRI-induced global mitochondrial dysfunction and altered structural dynamics. In this project, we are testing whether modulating mitochondrial dynamics can preserve mitochondrial health in human lung allografts and reduce injury. The overall impact of this study is uncovering clinically actionable mitochondrial-based therapies for PGD to considerably enhance outcomes in lung transplantation.

Primary graft dysfunction (PGD) affects 30% of lung recipients and is the most common cause of early morbidity and mortality. Chronic lung allograft dysfunction (CLAD), characterized by end-stage fibrosis, is the most common cause of long-term death. PGD is strongly associated with the development of CLAD, suggesting a common underlying pathway however the mechanistic link remains unknown. PGD is characterized by a profound pro-inflammatory state induced by lung ischemia reperfusion injury (IRI). In prior work, we identified an innate immune cellular network responsible for the profound pro-inflammatory milieu leading to PGD. We also discovered activation of pro-fibrotic pathways through transcriptomic profiling of donor lungs after reperfusion. We hypothesize that by inhibiting the pro-inflammatory program of the innate immune system early post-transplant, we will ameliorate both lung IRI and its chronic sequelae, CLAD. We have developed a novel cell-based therapy that can be delivered locally through the airways for local production of anti-inflammatory cytokines. These “cytokine factories” can modulate the innate immune system to dampen the initial inflammatory insult and promote healing. This cell-based platform has been used in human trials and has been found to be safe. In this project, we will test whether this novel cell-based therapy can reduce lung IRI and inhibit the activation of pro-fibrotic pathways to prevent the development of CLAD. This represents a novel targeted treatment for the most significant clinical challenge in lung transplantation that has the potential to meaningfully improve outcomes for lung recipients.