Novel Strategies for Endothelial Preservation in Lung Transplant Ischemia-Reperfusion Injury

Abstract

Lung ischemia reperfusion (IR) injury inevitably occurs during lung transplantation. The pulmonary endothelium is the primary target of IR injury that potentially results in severe pulmonary dysfunction. Over the last decades, various molecules, receptors, and signaling pathways were identified in order to develop treatment strategies for the preservation of the pulmonary endothelium against IR injury. We here review the latest and most promising therapeutic strategies for the protection of the endothelium against IR injury. These include the stabilization of the endothelial glycocalyx, inhibition of endothelial autophagy, inhibition of adhesion molecules, targeting of angiotensin-converting enzyme, and traditional viral and novel non-viral gene transfer approaches. Though some of these strategies proved to be promising in experimental studies, very few of these treatment concepts made the transfer into clinical application. This dilemma underscores the need for more experimental evidence for the translation into clinical studies to invent therapeutic concepts against IR injury-mediated endothelial damage.

Keywords: endothelium; ischemia-reperfusion injury; lung; strategies; transplantation.

FIGURE 1

Endothelial glycocalyx degradation induced by ischemia-reperfusion injury and its restoration by Lidocaine and Sevoflurane. Upon IR injury, free radicals, among others, contribute to glycocalyx erosion. IR injury also leads to activation of leukocytes that in turn increase the secretion of chemokines and adhesion molecules, all damaging the endothelial layer. Heparan sulfate and syndecan-1 are shed into the blood when the glycocalyx is damaged by IR and could function as biomarkers of endothelial integrity. Both Lidocaine and Sevoflurane can restore and preserve damaged glycocalyx. IR, ischemia-reperfusion.

FIGURE 2

Mediators and strategies to protect the vascular endothelium from lung IR injury. Endothelial immunotargeting by a catalase-binding antibody to the angiotensin-converting-receptor on endothelium can reduce IR-reactive oxygen species. Erythropoietin exerts protective functions on endothelial cells by preventing apoptosis via endothelium-bound EPO receptors. Diannexin V mainly acts via preventing endothelial cell adhesion, and Kalium ATP-sensitive (ATP-sensitive potassium channels, KATP) channel agonists have the potential to prevent membrane depolarization thereby protecting the endothelium. Gene transfer of siRNA to the endothelium can reduced apoptosis, less production of adhesion molecules, and a reduced attraction of neutrophils. Finally, antibody-conjugated endothelial-targeted liposomes can inhibit the cytokine-induced inflammatory activation of the endothelium. IR, ischemia-reperfusion; ACE, angiotensin-converting enzyme; EPO, Erythropoetin; KATP, Kalium ATP-sensitive; siRNA, small interfering ribonucleic acid.

FIGURE 3

Viral and non-viral approaches to preserve IR-injured lung endothelium. One of the most commonly employed viral vectors is the adeno-associated virus. By such a virus, silicon microparticles can be delivered into inflammation-associated endothelium where it is internalized with the subsequent release of therapeutic nanoparticles. The virus becomes free within the cytoplasm, undergoes genetic cargo, and transfers into the nucleus for the transcription of endothelium-protective mediators. In contrast, non-viral approaches have advantages over the commonly used viral systems such as lower immunogenicity, reduced inflammation, and an overall better safety. A human Indoleamine-2,3-dioxygenase (IDO)–expressing plasmid can be delivered by a specific promoter into the endothelium and reduces cell apoptosis, vascular permeability, and leukocyte extravasation. Moreover, the mitochondrial function and ultrastructure of the endothelium is protected from oxidative stress. IDO, Indoleamine-2,3-dioxygenase.