This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christofidou-Solomidou, M. Articles by Muzykantov, V. R. Search for Related Content PubMed PubMed Citation Articles by Christofidou-Solomidou, M. Articles by Muzykantov, V. R.

(American Journal of Pathology. 2002;160:1155-1169.)
© 2002 American Society for Investigative Pathology

Animal Model

Vascular Immunotargeting of Glucose Oxidase to the Endothelial Antigens Induces Distinct Forms of Oxidant Acute Lung Injury

Targeting to Thrombomodulin, But Not to PECAM-1, Causes Pulmonary Thrombosis and Neutrophil Transmigration

Melpo Christofidou-Solomidou^*, Stephen Kennel, Arnaud Scherpereel^*, Rainer Wiewrodt^*, Charalambos C. Solomides, Giuseppe G. Pietra, Juan-Carlos Murciano^¶, Sayed A. Shah^*, Harry Ischiropoulos^||, Steven M. Albelda^* and Vladimir R. Muzykantov^¶**

From the Department of Medicine,^*
Pulmonary CriticalCare Division, the Institute of EnvironmentalMedicine,^¶
and the Departments ofPharmacology^**
andPathology,
University of Pennsylvania MedicalCenter, Philadelphia, Pennsylvania; the Department ofPathology,
Temple University,Philadelphia, Pennsylvania; the Children’s Hospital,^||
Philadelphia, Pennsylvania; and the Oak Ridge NationalLaboratories,
Oak Ridge, Tennessee

Oxidative endothelial stress, leukocyte transmigration, and pulmonary thrombosis are important pathological factors in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Vascular immunotargeting of the H₂O₂-generating enzyme glucose oxidase (GOX) to the pulmonary endothelium causes an acute oxidative lung injury in mice.¹ In the present study we compared the pulmonary thrombosis and leukocyte transmigration caused by GOX targeting to the endothelial antigens platelet-endothelial cell adhesion molecule (PECAM) and thrombomodulin (TM). Both anti-PECAM and anti-TM delivered similar amounts of ¹²⁵I-GOX to the lungs and caused a dose-dependent, tissue-selective lung injury manifested within 2 to 4 hours by high lethality, vascular congestion, polymorphonuclear neutrophil (PMN) sequestration in the pulmonary vasculature, severe pulmonary edema, and tissue oxidation, yet at an equal dose, anti-TM/GOX inflicted more severe lung injury than anti-PECAM/GOX. Moreover, anti-TM/GOX-induced injury was accompanied by PMN transmigration in the alveolar space, whereas anti-PECAM/GOX-induced injury was accompanied by PMN degranulation within vascular lumen without PMN transmigration, likely because of PECAM blockage. Anti-TM/GOX caused markedly more severe pulmonary thrombosis than anti-PECAM/GOX, likely because of TM inhibition. These results indicate that blocking of specific endothelial antigens by GOX immunotargeting modulates important pathological features of the lung injury initiated by local generation of H₂O₂ and that this approach provides specific and robust models of diverse variants of human ALI/ARDS in mice. In particular, anti-TM/GOX causes lung injury combining oxidative, prothrombotic, and inflammatory components characteristic of the complex pathological picture seen in human ALI/ARDS.

This article has been cited by other articles:

				C. M. Costello, K. Howell, E. Cahill, J. McBryan, M. Konigshoff, O. Eickelberg, S. Gaine, F. Martin, and P. McLoughlin Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L272 - L284. [Abstract] [Full Text] [PDF]

				A. L. Lagan, D. D. Melley, T. W. Evans, and G. J. Quinlan Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L161 - L174. [Abstract] [Full Text] [PDF]

				K. Nowak, S. Weih, R. Metzger, R. F. Albrecht II, S. Post, P. Hohenberger, M.-M. Gebhard, and S. M. Danilov Immunotargeting of catalase to lung endothelium via anti-angiotensin-converting enzyme antibodies attenuates ischemia-reperfusion injury of the lung in vivo Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L162 - L169. [Abstract] [Full Text] [PDF]

				K. Danielyan, B.-S. Ding, C. Gottstein, D. B. Cines, and V. R. Muzykantov Delivery of Anti-Platelet-Endothelial Cell Adhesion Molecule Single-Chain Variable Fragment-Urokinase Fusion Protein to the Cerebral Vasculature Lyses Arterial Clots and Attenuates Postischemic Brain Edema J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 947 - 952. [Abstract] [Full Text] [PDF]

				T. Nakagomi, O. Kitada, K. Kuribayashi, H. Yoshikawa, K. Ozawa, S. Ogawa, and T. Matsuyama The 150-Kilodalton Oxygen-Regulated Protein Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice Am. J. Pathol., October 1, 2004; 165(4): 1279 - 1288. [Abstract] [Full Text] [PDF]

				A. Pagano, Y. Donati, I. Metrailler, and C. Barazzone Argiroffo Mitochondrial cytochrome c release is a key event in hyperoxia-induced lung injury: protection by cyclosporin A Am J Physiol Lung Cell Mol Physiol, February 1, 2004; 286(2): L275 - L283. [Abstract] [Full Text] [PDF]

				M. Christofidou-Solomidou, A. Scherpereel, R. Wiewrodt, K. Ng, T. Sweitzer, E. Arguiri, V. Shuvaev, C. C. Solomides, S. M. Albelda, and V. R. Muzykantov PECAM-directed delivery of catalase to endothelium protects against pulmonary vascular oxidative stress Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L283 - L292. [Abstract] [Full Text] [PDF]

				J.-C. Murciano, S. Muro, L. Koniaris, M. Christofidou-Solomidou, D. W. Harshaw, S. M. Albelda, D. N. Granger, D. B. Cines, and V. R. Muzykantov ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface Blood, May 15, 2003; 101(10): 3977 - 3984. [Abstract] [Full Text] [PDF]