|Victor E. Laubach|
| Position: Associate Professor of Surgery
Office Phone: 434-924-2927, Fax: 434-924-1218
Office Address: MR4 3112
Messenger Mail: PO Box 801359
PubMed listings for Victor E. Laubach
A primary area of research is mechanisms of lung ischemia-reperfusion (IR) injury. IR injury following lung transplantation remains a significant and perplexing cause of morbidity and mortality in the early postoperative period. Despite refinements in lung preservation and improvements in surgical technique and perioperative care, IR injury remains a significant cause of early morbidity and mortality after lung transplant. Clearly, prevention of IR injury is sorely needed.
Lung IR injury involves a large component of inflammation, and most studies suggest that it is the process of reperfusion of the graft, and not the ischemia per se, that plays a more important role in causing injury. We are utilizing both in vivo and in vitro models as complementary approaches to study mechanisms of lung IR injury. We have demonstrated a vital role for alveolar macrophages, NF-kB and TNF-alpha production in lung IR injury, and have described crosstalk between macrophages and alveolar epithelial cells during IR injury. Current studies are focused on evaluating the role of CD4+ T cells and the innate immune system in lung IR injury. Recent studies indicate that NKT cells are pivotal for the initiation of IR injury and that NKT cell-produced IL-17 is a key chemokine for the activation and infiltration of neutrophils which lead to tissue damage. Dendritic cell-derived IL-23 also seems to be an upstream mediator of IL-17 production and NKT cell activation. In addition, oxidative stress mechanisms are being studied. Here, NADPH oxidase-generated reactive oxygen species is a key component of immune cell activation upon reperfusion, and we are studying the role of NADPH oxidase in various cell types in mediating IR-induced inflammatory pathways. Our laboratory uses various knockout and chimeric mice, immune cell ablation studies with diphtheria toxin in susceptible transgenic mice, adoptive transfer studies, and cultured immune cells to address mechanistic questions both in vivo and in vitro to study mechanisms of lung IR injury. In testing our hypotheses we hope to gain further knowledge of the pathways that mediate lung IR injury that will enable the development of specific small molecules that can be used in future clinical studies.
Another related project is focusing on the role of the various adenosine receptors (A1, A2A, A2B, and A3) in lung IR injury. Using various adenosine receptor knockout mice as well as selective adenosine receptor agonists and antagonists, data is indicating that A1, A2A, and A3 receptors are protective while the A2B receptor is pro-inflammatory. Ongoing studies are further evaluating these roles as well as identifying adenosine receptor-expressing cell types which mediate these roles.
A second area of interest is in mechanisms of lung regeneration. It is well established that pneumonectomy (PNX, removal of a lung) induces rapid, hyperplastic, compensatory growth of the remaining lung in experimental animals. This compensatory lung growth (CLG) provides an ideal model for identifying intrinsic regenerative programs of the lung that may be employed for therapeutic purposes. Little is known about the regenerative potential of human lungs. Although CLG has been reported in children after major lung resection, lung regeneration in adults rarely occurs and remains a significant challenge. A long-term goal of our laboratory is to generate knowledge that allows induction of alveolar regeneration or that rescues failed alveologenesis in humans. Such understanding will facilitate the development of therapies for the management of end-stage lung disease, lung volume reduction surgery, and transplantation.
We have shown that angiogenesis is required for CLG and believe that angiogenesis is a major driving force required for CLG. We have shown that: 1) epidermal growth factor (EGF), a potent angiogenic factor, and its receptor (EGFR) are induced after PNX, 2) exogenous EGF augments CLG, and 3) inhibition of EGFR prevents CLG. Thus EGFR signaling is a key mediator of CLG. We have also shown that several transcription factors important in EGFR signaling and angiogenesis (AP-1 cMyc, and NF-kB) are induced after PNX. Endothelial nitric oxide synthase (eNOS) is another angiogenic factor, and we have demonstrated a failure of CLG in eNOS knockout mice which we believe is due to impaired angiogenesis. Both shear stress and EGFR activation induce eNOS activity via PI3K/Akt activation. Thus EGF and eNOS may play critical, interdependent angiogenic roles in CLG. Finally, since many angiogenic growth factors are secreted by pulmonary epithelium, we also are exploring possible cross-talk between the epithelium and endothelium important in CLG. Our research currently focuses on angiogenic mechanisms of CLG and the potential to induce lung growth via angiogenic therapy. Our overall hypothesis is that angiogenesis drives CLG via EGF and eNOS signaling mechanisms.
Yang Z, Sharma AK, Linden J, Kron IL, and Laubach VE. CD4+ T lymphocytes mediate acute pulmonary ischemia-reperfusion injury. J Thorac Cardiovasc Surg 137(3):695-702, 2009.
Yang Z, Sharma AK, Marshall M, Kron IL, and Laubach VE. NADPH oxidase in bone marrow-derived cells mediates pulmonary ischemia-reperfusion injury. Am J Resp Cell Mol Biol 40(3):375-381, 2009.
Laubach VE, French BA and Okusa MD. [Invited Review] Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opin Ther Targets 15(1):103-18, Jan 2011.
Sharma AK, LaPar DJ, Zhao Y, Li L, Lau CL, Kron IL, Iwakura Y, Okusa MD, Laubach VE. Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury. Am J Respir Crit Care Med 183(11):1539-49, Jun 2011.
LaPar DJ, Sharma AK, Hajzus VA, Zhao Y, Lau CL, French BA, Kron IL, Laubach VE. Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by RAGE signaling. Am J Resp Cell Mol Biol (In Press, Published ahead of print on October 6, 2011).
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