Victor E. Laubach
Primary AppointmentProfessor, Surgery
- BA,BS, Biology, Pennsylvania State University, University Park, PA
- PhD, Genetics, George Washington University School of Medicine
Bldg MR4, Room 3112
Charlottesville, VA 22908
Translational research on mechanisms and prevention of lung ischemia-reperfusion (IR) injury following transplantation
Current Research Projects:
T cell-mediated IR injury. We have recently described a paradigm shift in our understanding of the role of T cells in lung IR injury by showing that the activation of invariant natural killer T (iNKT) cells is a key initiator of IR injury by producing IL-17, a key chemokine for the infiltration of neutrophils that contribute to tissue damage. We are continuing to explore the role of iNKT cells and their interaction with alveolar epithelial cells, macrophages and endothelial cells.
NADPH oxidase. We have shown that NADPH oxidase (NOX2)-generated reactive oxygen species is a key component of immune cell activation during IR, and current studies are aimed at testing the hypothesis that NOX2 is a key mechanism for the activation of iNKT cells and macrophages after IR.
Macrophage-mediated IR injury. We have demonstrated an important role for alveolar macrophages and macrophage-derived TNF-alpha in lung IR injury. We are continuing to explore the role of alveolar macrophages as well as their cross-talk with alveolar epithelial cells and iNKT cells.
RAGE/HMGB1 axis. We have shown that macrophage-derived HMGB1 mediates lung IR injury by binding RAGE on iNKT cells and inducing IL-17 production, and we are continuing to study these signaling mechanisms. One potential mechanism being explored is whether RAGE-mediated IL-17 production requires NOX2 activation. In addition, we are exploring how alveolar macrophages release HMGB1 and whether this involves Toll-like Receptor (TLR) signaling in an autocrine fashion.
Adenosine 2A receptor (A2AR) activation. We have shown that A2AR agonists potently attenuate lung IR injury. Data suggest that A2ARs on iNKT cells are largely responsible for the protective effects of A2AR agonists. These effects may entail the inactivation of NOX2 to block IL-17 production by iNKT cells. Ongoing studies are aimed at further defining mechanisms responsible for the anti-inflammatory effects of A2AR agonists.
Ex vivo lung perfusion (EVLP). An exciting new project in our laboratory involves the implementation of a novel technique called ex vivo lung perfusion (EVLP). EVLP is a method of ex vivo perfusion of an questionable (marginal) donor lung with Steen Solution in order to assess its function and to potentially rehabilitate the donor lung for successful transplantation. 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 and save more lives of those patients on the transplant waiting list. We are utilizing EVLP in several experimental models including murine, porcine and even marginal human donor lungs. EVLP provides an ideal platform to apply various therapeutic strategies to the isolated organ to enhance rehabilitation of donor lungs. Our laboratory is currently applying the use of an A2AR agonist during EVLP to rehabilitate non-heart beating donor (NHBD) lungs and prevent IR injury.
Models used in the lab:
We heavily utilize a mouse model of IR injury involving various knockout, transgenic and chimeric mice, immune cell ablation studies and adoptive transfer studies. We also utilize an in vitro model of IR using various pulmonary and immune cells, in isolated or co-culture conditions, to answer specific questions about cellular signaling after IR. Finally, our laboratory utilizes a large animal (porcine) model of IR injury, EVLP and lung transplantation as a pre-clinical model.
Techniques used in the lab:
Routine techniques we use in the laboratory include cell culture, purification of primary cells, quantitative RT-PCR, flow cytometry, FACS, ELISA, multiplex (bead-array) cytokine assay, Western blot, ELISPOT assay, gene array, immunohistochemistry, biochemical assays, confocal microscopy and oxidative stress evaluation. Some murine methods we use include thoracic surgery, bone marrow transplantation, immune cell ablation, adoptive transfer of immune cells, pulmonary function measurements using an isolated mouse lung system, bronchoalveolar lavage, and measurement of pulmonary microvascular permeability.