Immunotargeting of catalase to ACE or ICAM-1 protects perfused rat lungs against oxidative stress.
The pulmonary endothelium is susceptible to oxidative insults. Catalase conjugated with monoclonal antibodies (MAbs) against endothelial surface antigens, angiotensin-converting enzyme (MAb 9B9) or intercellular adhesion molecule-1 (MAb 1A29), accumulates in the lungs after systemic injection in rats (V. Muzykantov, E. Atochina, H. Ischiropoulos, S. Danilov, and A. Fisher. Proc. Natl. Acad. Sci. USA 93: 5213-5218, 1996). The present study characterizes the augmentation of antioxidant defense by these antibody-catalase conjugates in isolated rat lungs perfused for 1 h with catalase conjugated with either MAb 9B9, MAb 1A29, or control mouse IgG. Approximately 20% of the injected dose of Ab-125I-catalase accumulated in the perfused rat lungs (vs. <5% for IgG-125I-catalase). After elimination of nonbound material, the lungs were perfused further for 1 h with 5 mM hydrogen peroxide (H2O2). H2O2 induced an elevation in tracheal and pulmonary arterial pressures (126 +/- 7 and 132 +/- 5%, respectively, of the control level), lung wet-to-dry weight ratio (7.1 +/- 0.4 vs. 6.0 +/- 0.01 in the control lungs), and ACE release into the perfusate (436 +/- 20 vs. 75 +/- 7 mU in the control perfusates). Both MAb 9B9-catalase and MAb 1A29-catalase significantly attenuated the H2O2-induced elevation in 1) angiotensin-converting enzyme release to the perfusate (215 +/- 14 and 217 +/- 38 mU, respectively), 2) lung wet-to-dry ratio (6.25 +/- 0.1 and 6.3 +/- 0.3, respectively), 3) tracheal pressure (94 +/- 4 and 101 +/- 4%, respectively, of the control level), and 4) pulmonary arterial pressure (103 +/- 3 and 104 +/- 7%, respectively, of the control level). Nonconjugated catalase, nonconjugated antibodies, nonspecific IgG, and IgG-catalase conjugate had no protective effect, thus confirming the specificity of the effect of MAb-catalase. These results support a strategy of catalase immunotargeting for protection against pulmonary oxidative injury.
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6068, USA.
E N
EN
Atochina
I V
IV
Balyasnikova
S M
SM
Danilov
D N
DN
Granger
A B
AB
Fisher
V R
VR
Muzykantov
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology; D019921:Biotinylation; D002374:Catalase / Q000378:metabolism* / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007074:Immunoglobulin G / Q000494:pharmacology; D000922:Immunotoxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*; D007457:Iodine Radioisotopes; D008168:Lung / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000276:immunology / Q000502:physiology*; D011652:Pulmonary Circulation / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D018799:Intercellular Adhesion Molecule-1; D006861:Hydrogen Peroxide; D002374:Catalase; D007703:Peptidyl-Dipeptidase A