Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo

• Published in: American journal of physiology. Lung cellular and molecular physiology 2007-07, Vol.293 (1), p.L162-L169
• Main Authors: Nowak, Kai, Weih, Sandra, Metzger, Roman, Albrecht, Ronald F., II, Post, Stefan, Hohenberger, Peter, Gebhard, Martha-Maria, Danilov, Sergei M
• Format: Article
• Language: English
• Subjects: ACE inhibitors; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Blood Pressure - drug effects; Catalase - immunology; Chemokine CXCL1; Chemokines, CXC - blood; Endothelin-1 - blood; Endothelium - enzymology; Endothelium - pathology; Enzymes; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Hemoglobins - metabolism; Lung - drug effects; Lung - enzymology; Lung - pathology; Lungs; Male; Monoclonal antibodies; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Organ Size - drug effects; Oxygen - metabolism; Peptidyl-Dipeptidase A - immunology; Pulmonary Artery - drug effects; Rats; Rats, Wistar; Reperfusion Injury - drug therapy; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Systole - drug effects
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00001.2007

1 Department of Surgery, Clinical Medical Faculty Mannheim and 2 Experimental Surgery, Faculty of Medicine, University of Heidelberg, Heidelberg, and 3 Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany; and 4 Department of Anesthesiology, University of Illinois, Chicago, Illinois Submitted 2 January 2007 ; accepted in final form 4 April 2007 Limitation of reactive oxygen species-mediated ischemia-reperfusion (I/R) injury of the lung by vascular immunotargeting of antioxidative enzymes has the potential to become a promising modality for extension of the viability of banked transplantation tissue. The preferential expression of angiotensin-converting enzyme (ACE) in pulmonary capillaries makes it an ideal target for therapy directed toward the pulmonary endothelium. Conjugates of ACE monoclonal antibody (MAb) 9B9 with catalase (9B9-CAT) have been evaluated in vivo for limitation of lung I/R injury in rats. Ischemia of the right lung was induced for 60 min followed by 120 min of reperfusion. Sham-operated animals (sham, n = 6) were compared with ischemia-reperfused untreated animals (I/R, n = 6), I/R animals treated with biotinylated catalase (CAT, n = 6), and I/R rats treated with the conjugates (9B9-CAT, n = 6). The 9B9-CAT accumulation in the pulmonary endothelium of injured lungs was elucidated immunohistochemically. Arterial oxygenation during reperfusion was significantly higher in 9B9-CAT (221 ± 36 mmHg) and sham (215 ± 16 mmHg; P < 0.001 for both) compared with I/R (110 ± 10 mmHg) and CAT (114 ± 30 mmHg). Wet-dry weight ratio of I/R (6.78 ± 0.94%) and CAT (6.54 ± 0.87%) was significantly higher than of sham (4.85 ± 0.29%; P < 0.05), which did not differ from 9B9-CAT (5.58 ± 0.80%). The significantly lower degree of lung injury in 9B9-CAT-treated animals compared with I/R rats was also shown by decreased serum levels of endothelin-1 (sham, 18 ± 9 fmol/mg; I/R, 42 ± 12 fmol/mg; CAT, 36 ± 11 fmol/mg; 9B9-CAT, 26 ± 9 fmol/mg; P < 0.01) and mRNA for inducible nitric oxide synthase (iNOS) [iNOS-GAPDH ratio: sham, 0.15 ± 0.06 arbitrary units (a.u.); I/R, 0.33 ± 0.08 a.u.; CAT, 0.26 ± 0.05 a.u.; 9B9-CAT, 0.14 ± 0.04 a.u.; P < 0.001]. These results validate immunotargeting by anti-ACE conjugates as a prospective and specific strategy to augment antioxidative defenses of the pulmonary endothelium in vivo. pulmonary endothelium; monoclonal antibodies Address for reprint requests and other correspondence: K. Nowak, Dept. of Surgery, Medica