Victor E. Laubach
- BA,BS, Pennsylvania State University, University Park, PA
- PhD, George Washington University School of Medicine
- Associate Professor, Molecular Physiology and Biological Physics
- Phone: 924-2927
- Email: firstname.lastname@example.org
- Website: http://www.medicine.virginia.edu/clinical/departments/surgery/research/tcv-lab
Mechanisms of Lung Ischemia-Reperfusion Injury following Transplantation.
My laboratory studies mechanisms of lung ischemia-reperfusion (IR) injury following transplantation. IR injury remains a significant and perplexing cause of morbidity and mortality after transplant and also leads to an increased risk for chronic graft dysfunction and rejection. We are using both in vivo and in vitro models as complementary approaches to study mechanisms of lung IR injury and therapeutic strategies.
Our laboratory has published numerous studies that have revealed cellular mechanisms of lung IR injury. For example, we have demonstrated a vital role for alveolar macrophages, neutrophils and invariant natural killer T cells (iNKT cells) in lung IR injury. We have also described important crosstalk between macrophages and alveolar epithelial cells as well as macrophages and T cells during IR injury. We are currently looking further into the role of iNKT cells and potential interaction of the innate immune system with alveolar epithelial cells and endothelial cells.
In terms of proinflammatory cytokine responses, we have recently described a paradigm shift in our understanding of the role of iNKT cells in lung IR injury by showing that NKT cells are pivotal for the initiation of IR injury by producing IL-17, a key chemokine for the infiltration of neutrophils that lead to tissue damage. In addition, macrophage-derived TNF-alpha is very important in mediating neutrophil infiltration as well as activation of epithelial cells and iNKT cells. Dendritic cell-derived IL-23 and IL-12 also appears to be an upstream mediator of IL-17 production and NKT cell activation, and current studies are exploring this further.
In terms of molecular and chemical mediators of lung IR injury, we have shown that NADPH oxidase-generated reactive oxygen species (superoxide) is a key component of immune cell activation during IR, and we are studying the role of NADPH oxidase in mediating IR-induced inflammatory pathways. We believe that activation of NADPH oxidase is a key mechanism for the activation of iNKT cells and macrophages. In addition, we have recently shown that macrophage derived high mobility group box 1 (HMGB1) mediates lung IR injury by activating iNKT cells through binding of the receptor for advanced glycation end-products (RAGE).
Our laboratory is also interested in defining the roles for various adenosine receptors (A1, A2A, A2B, and A3 receptors) in lung IR injury. Using various adenosine receptor knockout mice as well as selective adenosine receptor agonists and antagonists, we have shown that A1, A2A, and A3 receptors are protective while the A2B receptor is pro-inflammatory. Ongoing studies are further evaluating more in-depth mechanisms of how activation of A2A receptor is anti-inflammatory and significantly protects against lung IR injury.
We heavily utilize a mouse model of IR injury involving various knockout and chimeric mice, immune cell ablation studies, and adoptive transfer studies. We also utilize an in vitro model of IR injury using various pulmonary and immune cells, in isolated or co-culture conditions, to answer more detailed questions about molecular mediators of IR injury. Finally, our laboratory also utilizes a large animal (pig) model of lung transplantation and IR injury as a pre-clinical model that closely mimics the human transplant scenario. Another exciting new project in our laboratory involves the implementation of a novel technique called ex vivo lung perfusion (EVLP) in a “lung box”. EVLP is a method of ex vivo perfusion of a questionable (marginal) donor lung with Steen Solution in order to monitor its function and to potentially rehabilitate marginal donor lungs (which are typically rejected for transplantation) in order to be successfully transplanted. Most donor lungs (>80%) are rejected for transplantation for various reasons, and the successful application of EVLP to rehabilitate these lungs could drastically increase the donor lung pool size in order to save more lives of those patients on the transplant waiting list. We are utilizing EVLP in our pig lung transplant model as well as with marginal human donor lungs. EVLP in the lung box provides a perfect opportunity to apply various therapeutic strategies in order to rehabilitate lungs, and our lab is currently applying the use of an A2A receptor agonist during EVLP to rehabilitate marginal donor lungs and prevent IR injury.
Some routine laboratory methods we use include flow cytometry, ELISA, bead-array method for mulitiplex cytokine assay, cell culture, purification of primary cells, Western blot, ELISPOT assay, gene array, immunohistochemistry, biochemical assays, confocal microscopy and oxidative stress evaluation. Some mouse methods we use include thoracic surgery, bone marrow transplantation, immune cell ablation, adoptive transfer of immune cells, pulmonary function measurements on an isolated mouse lung system, bronchoalveolar lavage, and measurement of pulmonary microvascular permeability.
- Ross S. D., Kron I. L., Gangemi J. J., Shockey K. S., Stoler M., Kern J. A., Tribble C. G., Laubach V. E.. Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-kappaB Am J Physiol Lung Cell Mol Physiol. 279(3): L528-36.
- Leuwerke S. M., Kaza A. K., Tribble C. G., Kron I. L., Laubach V. E.. Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice Am J Physiol Lung Cell Mol Physiol. 282(6): L1272-8.
- Zhao M., Fernandez L. G., Doctor A., Sharma A. K., Zarbock A., Tribble C. G., Kron I. L., Laubach V. E.. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury Am J Physiol Lung Cell Mol Physiol. 291(5): L1018-26.
- Sharma A. K., Fernandez L. G., Awad A. S., Kron I. L., Laubach V. E.. Proinflammatory response of alveolar epithelial cells is enhanced by alveolar macrophage-produced TNF-alpha during pulmonary ischemia-reperfusion injury Am J Physiol Lung Cell Mol Physiol. 293(1): L105-13.
- Yang Z., Sharma A. K., Linden J., Kron I. L., Laubach V. E.. CD4+ T lymphocytes mediate acute pulmonary ischemia-reperfusion injury J Thorac Cardiovasc Surg. 137(3): 695-702; discussion 702.
- Yang Z., Sharma A. K., Marshall M., Kron I. L., Laubach V. E.. NADPH oxidase in bone marrow-derived cells mediates pulmonary ischemia-reperfusion injury Am J Respir Cell Mol Biol. 40(3): 375-81.
- Sharma A. K., Linden J., Kron I. L., Laubach V. E.. Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation Respir Res. 10(1): 58.
- Anvari F., Sharma A. K., Fernandez L. G., Hranjec T., Ravid K., Kron I. L., Laubach V. E.. Tissue-derived proinflammatory effect of adenosine A2B receptor in lung ischemia-reperfusion injury J Thorac Cardiovasc Surg. 140(4): 871-7.
- Laubach V. E., French B. A., Okusa M. D.. Targeting of adenosine receptors in ischemia-reperfusion injury Expert Opin Ther Targets. 15(1): 103-18.
- Sharma A. K., LaPar D. J., Zhao Y., Li L., Lau C. L., Kron I. L., Iwakura Y., Okusa M. D., Laubach V. E.. Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury Am J Respir Crit Care Med. 183(11): 1539-49.
- Lapar D. J., Hajzus V. A., Zhao Y., Lau C. L., French B. A., Kron I. L., Sharma A. K., Laubach V. E.. Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by receptor for advanced glycation end-products signaling Am J Respir Cell Mol Biol. 46(3): 299-305.
- Mulloy D. P., Stone M. L., Crosby I. K., Lapar D. J., Sharma A. K., Webb D. V., Lau C. L., Laubach V. E., Kron I. L.. Ex vivo rehabilitation of non-heart-beating donor lungs in preclinical porcine model: delayed perfusion results in superior lung function J Thorac Cardiovasc Surg. 144(5): 1208-15.
- Mulloy D. P., Sharma A. K., Fernandez L. G., Zhao Y., Lau C. L., Kron I. L., Laubach V. E.. Adenosine a3 receptor activation attenuates lung ischemia-reperfusion injury Ann Thorac Surg. 95(5): 1762-7.
- Fernandez L. G., Sharma A. K., Lapar D. J., Kron I. L., Laubach V. E.. Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury J Thorac Cardiovasc Surg. 145(6): 1654-9.
- Sharma A. K., LaPar D. J., Stone M. L., Zhao Y., Lau C. L., Kron I. L., Laubach V. E.. Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury Am J Transplant. .