title: Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo.
abstract: 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.
authors: Department of Surgery, Clinical Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. kai.nowak@chir.ma.uni-heidelberg.de
authors: Kai
authors: K
authors: Nowak
authors: Sandra
authors: S
authors: Weih
authors: Roman
authors: R
authors: Metzger
authors: Ronald F
authors: RF
authors: Albrecht
authors: Stefan
authors: S
authors: Post
authors: Peter
authors: P
authors: Hohenberger
authors: Martha-Maria
authors: MM
authors: Gebhard
authors: Sergei M
authors: SM
authors: Danilov
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000276:immunology*; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000097:blood; D019332:Endothelin-1 / Q000097:blood; D004727:Endothelium / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000276:immunology*; D011651:Pulmonary Artery / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D013599:Systole / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D019332:Endothelin-1; D006454:Hemoglobins; D012333:RNA, Messenger; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; D007703:Peptidyl-Dipeptidase A; D010100:Oxygen