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Background and Research Focus

My laboratory investigates mechanisms of lung injury and cytoprotection during oxidant stress. Specifically, we have focused on the lung endothelium as a central mediator of lung injury and repair responses. We identified the importance of the stress-response protein heme oxygenase-1 (HO-1) and its gaseous reaction product, carbon monoxide (CO), in resisting oxidant-induced endothelial cell death via mitochondrial pathways. We found that a family of signaling molecules, mitogen-activated protein kinases (MAPKs), mediates HO-1's and CO’s protective effects as well as optimal IL-13-induced lung inflammation / remodeling and, more recently, critical innate immune responses. The innate immune system consists of pattern-recognition receptors called toll-like receptors (TLRs), of which TLR4 is the LPS-responsive receptor. We discovered that TLR4 is required for lung structural cell survival in aging and oxidant challenges. These studies represent important paradigm shifts in our understanding of TLRs and lung biology and are now the basis of translational studies in people with acute lung injury and age-related chronic lung disease, such as chronic obstructive pulmonary disease (COPD). In the process of our investigations, we were the first to demonstrate the utility of intranasal, lung-targeted and endothelial-targeted silencing RNA (siRNA) constructs in vivo. In parallel, we have also generated endothelial-targeted transgenic and knockout mouse models to specifically interrogate the role of the endothelium in lung disease. Our coordinated use of siRNA technology and genetic approaches in both cell and mouse models offer immense insight into disease pathogenesis and may identify novel therapeutic targets for a range of lung diseases.

Current Topics:

  1. Role of the innate immune system in oxidant lung and vascular injury
  2. Role of the innate immune system in COPD
  3. Role of heme oxygenase-1 in acute lung and vascular injury
  4. Role of aging in lung injury and repair
  5. MAPKs in oxidant lung injury