Annexin V homodimer protects against ischemia reperfusion–induced acute lung injury in lung transplantation

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 151; no. 3; pp. 861 - 869
• Main Authors: Hashimoto, Kohei, MD, Kim, Hyunhee, MSc, Oishi, Hisashi, MD, PhD, Chen, Manyin, MD, Iskender, Ilker, MD, Sakamoto, Jin, MD, Ohsumi, Akihiro, MD, Guan, Zehong, MSc, Hwang, David, MD, PhD, Waddell, Thomas K., MD, PhD, Cypel, Marcelo, MD, MSc, Liu, Mingyao, MD, MSc, Keshavjee, Shaf, MD, MSc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2016
• Subjects: Acute Lung Injury - etiology; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute Lung Injury - physiopathology; Acute Lung Injury - prevention & control; Animals; Annexin A5 - pharmacology; apoptosis; Apoptosis - drug effects; Cardiothoracic Surgery; Cytokines - metabolism; Cytoprotection; diannexin; Disease Models, Animal; Fibrin - metabolism; Inflammation Mediators - metabolism; ischemia reperfusion injury; Keratin-18 - metabolism; Lung - blood supply; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung - physiopathology; Lung - surgery; Lung Transplantation - adverse effects; Male; Peptide Fragments - metabolism; primary graft dysfunction; Protective Agents - pharmacology; Rats, Inbred Lew; Reperfusion Injury - etiology; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Reperfusion Injury - prevention & control; IRI; Diannexin group; CK18-M30; apoptosis; ischemia reperfusion injury; mRNA; terminal deoxynucleotidyl transferase dUTP nick end labeling; PGD; diannexin; plasminogen activator inhibitor-1; TUNEL; caspase-cleaved cytokeratin 18; PAI-1; messenger ribonucleic acid; DN group; primary graft dysfunction
• ISSN: 0022-5223; 1097-685X
• DOI: 10.1016/j.jtcvs.2015.10.112

Abstract Objective We hypothesized that administration of a homodimer of recombinant annexin V, diannexin, could shield phosphatidylserine on the endothelium, and inhibit leukocyte and platelet adhesion, thereby potentially reducing ischemia reperfusion injury (IRI) in lung transplantation. This hypothesis was tested using a rat syngeneic single left-lung transplant model. Methods Rats were randomly assigned to receive diannexin (DN group; n = 10) or normal saline (control group; n = 10). Diannexin (1000 μg/kg) was administered to the donor lung in the pulmonary flush solution, and to the recipient intravenously, 5 minutes after initiation of reperfusion. Grafts were reperfused for 2 hours. Results The transplanted grafts in the DN group performed significantly better in gas exchange with higher partial pressure of oxygen (control group: 179 ± 121 vs DN group: 330 ± 54 mm Hg; P  = .007) and lower partial pressure of carbon dioxide (control: 55.1 ± 26 vs DN: 34.2 ± 11 mm Hg; P  = .04), as well as lower peak airway pressure (control: 20.5 ± 8.5 vs DN: 12.0 ± 7.9 cm H2 O; P  = .035) after 2 hours of reperfusion. Wet-to-dry lung weight ratio ( P  = .054), and alveolar fibrin deposition score ( P  = .04), were reduced in the DN group. Caspase-cleaved cytokeratin 18 in plasma (a marker of epithelial apoptosis) was significantly reduced in the DN group ( P  = .013). Furthermore, gene-expression levels of proinflammatory cytokines in the transplanted graft, including interleukin-6 ( P  = .04) and macrophage inflammatory protein 2 ( P  = .03) were significantly decreased in the DN group. Conclusions A homodimer of recombinant annexin V reduced ischemia reperfusion injury in a lung transplant animal model, by reducing cell death and tissue inflammation.