Patty J Lee MD

Associate Professor of Medicine (Pulmonary); Interim Section Chief (1/1/10 - 6/30/12)

Research Interests

Oxidant-induced acute and chronic lung injury; Toll-like receptors in lung and endothelium; Lung-targeted RNA interference; Heme oxygenase-1 in lung and vascular injury

Current Projects

  1. Role of the innate immune system in oxidant lung injury
  2. Role of the innate immune system in chronic obstructive lung disease
  3. Heme oxygenase-1 in oxidant lung and vascular injury
  4. Role of aging in lung injury and repair
  5. MAPKs in oxidant lung injury

Research Summary

Dr. Lee's laboratory studies the mechanisms whereby the lung responds to and protects against oxidant injury. Oxidant injury is caused by excessive reactive oxygen species and is an important component of processes such as acute respiratory failure, inhaled oxygen therapy, lung transplantation and chronic obstructive lung disease. We have identified important molecules, such as heat shock proteins, and more recently, innate immunity receptors that function to protect the lungs against oxidant challenges. We have also developed techniques to silence specific genes in the lung and endothelial cells in vivo, which allows us to ascertain gene function in a highly specific manner.

Extensive Research Description

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 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-challenged conditions. These studies represent important paradigm shifts in our understanding of TLR 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 lung disease. 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.


Selected Publications

  • Vaz Fragoso C, Lee PJ The Aging Lung, J Gerontol Biol Sci 2011, 2012 Mar 5:67A(3):233-235.
  • Volkova M, Zhang Y, Shaw AC, Lee PJ. The role of toll-like receptors in age-associated lung diseases, J Gerontol A Biol Sci Med Sci 2012 Mar; 67A(3):247-253.
  • Siner J, Jiang G, Cohen ZI, Zhang X, Shan P, Zhang X, Lee CG, Elias JA, and Lee PJ. VEGF-induced heme oxygenase-1 confers cytoprotection from lethal hyperoxia in vivo, FASEB J, 21: 1422-1432, 2007.
  • Zhang X, Shan P, Jiang G, Cohn L, and Lee PJ. Toll-like receptor 4 deficiency causes pulmonary emphysema. J Clin Invest, 116: 3050-3059, 2006. PMCID: PMC1616193
  • Qureshi ST*, Zhang X*, Aberg E, Bousette N, Giaid A, Shan P, Medzhitov RM, and Lee PJ. Inducible activation of TLR4 confers resistance to hyperoxia-induced pulmonary apoptosis. J Immunol, 176: 4950-4958, 2006 (*authors contributed equally)
  • Zhang X, Shan P, Jiang G, Zhang S-M, Otterbein LE, Fu X-Y, and Lee PJ. Endothelial STAT3 is essential for the protective effects of HO-1 in oxidant-induced lung injury. FASEB J, 20: E1528-1538, 2006.
  • Lee PJ, Zhang X, Shan P, Ma B, Lee CG, Homer RJ, Zhu Z, Rincon M, Mossman BT, and Elias JA. ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo. J Clin Invest, 116: 163-173, 2006.
  • Zhang X, Shan P, Qureshi S, Homer R, Medzithov R, Noble PW, and Lee PJ. Cutting edge: Toll-like receptor 4 deficiency confers susceptibility to lethal oxidant lung injury. J Immunol, 175: 4834-4838, 2005.
  • Zhang X, Shan P, Jiang D, Noble PW, Abraham NG, Kappas A, and Lee PJ. Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion-induced lung apoptosis. J Biol Chem. 279: 10677-10684, 2004. PMID 14688267 PMC Journal – In Process
  • Zhang X, Shan P, Otterbein LE, Alam J, Flavell RA, Davis RJ, Choi AMK, and Lee PJ. Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen activated protein kinase pathway and involves caspase 3. J Biol Chem. 278:1248-1258, 2003

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