Immunotargeting of glucose oxidase to endothelium in vivo causes oxidative vascular injury in the lungs
| Autor: | David W. Harshaw, Evgenia Arguiris, Giuseppe G. Pietra, Steven M. Albelda, Melpo Christofidou-Solomidou, Vladimir R. Muzykantov, Garret A. FitzGerald, Charalambos C. Solomides |
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| Rok vydání: | 2000 |
| Předmět: |
Pulmonary and Respiratory Medicine
Lung Diseases Pathology medicine.medical_specialty Pulmonary Circulation Endothelium Physiology Oxidative phosphorylation Pharmacology In Vitro Techniques medicine.disease_cause Antibodies Glucose Oxidase Mice In vivo Physiology (medical) medicine Animals Glucose oxidase Tissue Distribution Vascular Diseases biology business.industry Cell Biology Rats Endothelial stem cell Platelet Endothelial Cell Adhesion Molecule-1 Oxidative Stress medicine.anatomical_structure Drug delivery Gene Targeting cardiovascular system biology.protein Endothelium Vascular business Oxidative stress Blood vessel |
| Zdroj: | American journal of physiology. Lung cellular and molecular physiology. 278(4) |
| ISSN: | 1040-0605 |
| Popis: | Vascular immunotargeting is a novel approach for site-selective drug delivery to endothelium. To validate the strategy, we conjugated glucose oxidase (GOX) via streptavidin with antibodies to the endothelial cell surface antigen platelet endothelial cell adhesion molecule (PECAM). Previous work documented that 1) anti-PECAM-streptavidin carrier accumulates in the lungs after intravenous injection in animals and 2) anti-PECAM-GOX binds to, enters, and kills endothelium via intracellular H2O2 generation in cell culture. In the present work, we studied the targeting and effect of anti-PECAM-GOX in animals. Anti-PECAM-GOX, but not IgG-GOX, accumulated in the isolated rat lungs, produced H2O2, and caused endothelial injury manifested by a fourfold elevation of angiotensin-converting enzyme activity in the perfusate. In intact mice, anti-PECAM-GOX accumulated in the lungs (27 ± 9 vs. 2.4 ± 0.3% injected dose/g for IgG-GOX) and caused severe lung injury and 95% lethality within hours after intravenous injection. Endothelial disruption and blebbing, elevated lung wet-to-dry ratio, and interstitial and alveolar edema indicated that anti-PECAM-GOX damaged pulmonary endothelium. The vascular injury in the lungs was associated with positive immunostaining for iPF2α-III isoprostane, a marker for oxidative stress. In contrast, IgG-GOX caused a minor lung injury and little (5%) lethality. Anti-PECAM conjugated with inert proteins induced no death or lung injury. None of the conjugates caused major injury to other internal organs. These results indicate that an immunotargeting strategy can deliver an active enzyme to selected target cells in intact animals. Anti-PECAM-GOX provides a novel model of oxidative injury to the pulmonary endothelium in vivo. |
| Databáze: | OpenAIRE |
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