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Immunotargeting of catalase to the pulmonary endothelium alleviates oxidative stress and reduces acute lung transplantation injury

Nature Biotechnology volume 21, pages 392–398 (2003)Cite this article

Abstract

Vascular immunotargeting may facilitate the rapid and specific delivery of therapeutic agents to endothelial cells. We investigated whether targeting of an antioxidant enzyme, catalase, to the pulmonary endothelium alleviates oxidative stress in an in vivo model of lung transplantation. Intravenously injected enzymes, conjugated with an antibody to platelet-endothelial cell adhesion molecule-1, accumulate in the pulmonary vasculature and retain their activity during prolonged cold storage and transplantation. Immunotargeting of catalase to donor rats augments the antioxidant capacity of the pulmonary endothelium, reduces oxidative stress, ameliorates ischemia-reperfusion injury, prolongs the acceptable cold ischemia period of lung grafts, and improves the function of transplanted lung grafts. These findings validate the therapeutic potential of vascular immunotargeting as a drug delivery strategy to reduce endothelial injury. Potential applications of this strategy include improving the outcome of clinical lung transplantation and treating a wide variety of endothelial disorders.

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Figure 1: Immunotargeting of anti-PECAM/β-Gal to the pulmonary endothelium in rats.
Figure 2: Anti-PECAM/catalase immunotargeting, internalization, lysosomal trafficking, and protection against H2O2 in endothelial cell culture.
Figure 3: Anti-PECAM/catalase targeting protects perfused lungs from oxidative stress.
Figure 4: Anti-PECAM/catalase ameliorates lung transplant ischemia-reperfusion injury.
Figure 5: Anti-PECAM/catalase alleviates oxidative stress in transplanted lungs.
Figure 6: Safety of anti-PECAM/catalase immunotargeting.

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Acknowledgements

The authors thank M. Nakada (Centocor, Malvern, Pennsylvania) for a generous gift of anti-PECAM mAb 62, R. Wiewrodt and V. Shuvaev (University of Pennsylvania) for their advice and valuable help in characterization of the conjugates size by Dynamic Light Scattering, A.P. Thomas for help in conjugate preparation and experiments with cell cultures, and D.W. Harshaw for help in experiments with perfused rat lungs. The authors also acknowledge the help of T. Tagawa and S. Kanaan (Washington University) for their support with the transplantation experiments and R. Schuessler and B.W. McKane for their statistical and laboratory assistance. S.M. is supported by a fellowship from the Fundacion Ramon Areces (Spain). The work was supported by US National Institutes of Health SCOR in Acute Lung Injury (NHLBI HL 60290, Project 4 to V.R.M. and S.M.A.), ALA Research Grant (no. RG-087-N to M.C.S.) and National Institutes of Health grant 1 R01 HL41281 (to G.A.P.).

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Author notes

  1. Benjamin D. Kozower and Melpo Christofidou-Solomidou: The first two authors contributed equally to this study.

Authors and Affiliations

  1. Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, 63110, MO

    Benjamin D. Kozower & G. Alexander Patterson

  2. Department of Medicine, University of Pennsylvania Medical School, Philadelphia, 19104, PA

    Melpo Christofidou-Solomidou & Steven M. Albelda

  3. Institute for Environmental Medicine, University of Pennsylvania Medical School, Philadelphia, 19104, PA

    Thomas D. Sweitzer, Silvia Muro, Donald G. Buerk & Vladimir R. Muzykantov

  4. Department of Pathology, Temple University Hospital, Philadelphia, 19140, PA

    Charalambos C. Solomides

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Correspondence to Vladimir R. Muzykantov.

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Kozower, B., Christofidou-Solomidou, M., Sweitzer, T. et al. Immunotargeting of catalase to the pulmonary endothelium alleviates oxidative stress and reduces acute lung transplantation injury. Nat Biotechnol 21, 392–398 (2003). https://doi.org/10.1038/nbt806

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