My laboratory focuses on the molecular mechanisms of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The bacterial endotoxin (lipopolysaccharide, LPS) can trigger a systemic hyper-inflammatory response that subsequently leads to multiple organ dysfunction syndrome. LPS binding to toll-like receptor 4 (TLR4) induces the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) resulting in production of pro-inflammatory cytokines. When this production becomes uncontrolled and excessive, it leads to the development of septic shock. Ventilator-induced lung injury (VILI) accounts for as many as one-third of all deaths attributed to acute lung injury. In particular, the risk of VILI is increased in the patients with sepsis and pneumonia. Evidence has supported the concept that development of pulmonary inflammation in response to mechanical stress results in polymorphonuclear neutrophil (PMN) infiltration into the lung tissue and hence lung injury. We are interested in identifying signal pathways modulating sepsis- and ventilator-induced inflammation and lung injury.

    Another research interest is the molecular mechanisms regulating endothelial permeability. An important function of the endothelium is to regulate the transport of liquid and solutes across the semi-permeable vascular endothelial barrier. Two cellular pathways have been identified controlling endothelial barrier function. The normally restrictive paracellular pathway, which can become "leaky" during inflammation when gaps are induced between endothelial cells at the level of adherens and tight junctional complexes, and the transcellular pathway, which transports plasma proteins the size of albumin via transcytosis in vesicle carriers originating from cell surface caveolae. We are interested in elucidating the signaling mechanisms that regulate paracellular and transcellular endothelial permeability pathways in response to inflammatory insults.          

    Finally, this lab is studying the effects of anesthetics on neutrophil-induced tissue injuries. Our studies have demonstrated that isoflurane and sevoflurane abolish activated neutrophil-induced myocardial dysfunction, an action that occurred independent of KATP channel opening. These effects were associated with reductions in superoxide anion production and neutrophil adherence to coronary vascular endothelium.

Lab Members

Selected Publications

• Hu G, Malik AB, and Minshall RD. Toll-like Receptors mediate Mechanical ventilation-induced Lung Neutrophil Sequestration and Injury. Critical Care Medicine, 2010;38:194-201     
  
• Saad MM, Eom W, Hu G, Kim SJ, Crystal GJ. Persistency and pathway of isoflurane-induced inhibition of superoxide production by neutrophils. Canadian Journal of Anaesthesia, 2010;57:50-57.
• Sun Y, Hu G, Zhang X, Minshall RD. Phosphorylation of caveolin-1 regulates oxidant- induced pulmonary vascular permeability via paracellular and transcellular pathways. Circulation Research, 2009;105:676-685.
• Xue  J, Thippegowda PB, Hu G, Bachmaier K, Christman JW, Malik AB, and Tiruppathi C. NF-κB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-κB site in the ICAM-1 gene. Physiological Genomics, 2009;38:42-53.
• Hu G and Minshall RD. Cell Biology of Pulmonary Endothelial Permeability, in The Pulmonary Endothelium. Eds, S. Rounds and N. Voelkel, Wiley Inc., New York, 2009, pp113-127.
• Hu G, Minshall RD. Regulation of Src tyrosine kinase in transcellular pathway of endothelial permeability. Microvascular Research, 2009;77:21-25. Review.
• Hu G, Place TA, and Minshall RD. Src tyrosine kinase signaling in regulation of endothelial permeability. Chemico-Biological Interactions, 2008;171:177-189. Review.
• Hu G, Ye RD, Malik AB, Dinauer MC and Minshall RD. Caveolin-1 dependent neutrophil activation in acute lung injury.  American Journal of Physiology, 2008;294:L178-186. 
• Hu G, Vogel SM, Schwartz DE, Malik AB, and Minshall RD. Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability. Circulation Research, 2008;102:e120-131.
• Hu G, Schwartz DE, Shahajan AN, Visintine DJ, Salem MR, Crystal GJ, Albrecht RF, Vogel SM, Minshall RD. Isoflurane, but not sevoflurane, increases transendothelial albumin permeability in the isolated rat lung: role for enhanced phosphorylation of caveolin-1. Anesthesiology, 2006;104:777-785.
• Hu G, Salem, MR, and Crystal GJ. Isoflurane prevents platelet-induced enhancement of coronary endothelial dysfunction by neutrophils. Anesthesia and Analgesia, 2005;101:1261-1268.
• Hu G, Salem, MR, and Crystal GJ. Role of adenosine receptors in volatile anesthetic preconditioning against neutrophil-induced contractile dysfunction in isolated rat hearts. Anesthesiology, 2005;103: 287-295.
• Hu G, Salem, MR, and Crystal GJ. Isoflurane and sevoflurane precondition against neutrophils-induced contractile dysfunction in isolated rat hearts.  Anesthesiology, 2004;100: 489-497.
• Hu G, Vasiliauskas T, Salem, MR, Rhone DP, and Crystal GJ. Neutrophils pretreated with volatile anesthetics lose ability to cause cardiac dysfunction. Anesthesiology, 2003;98: 712-718.
• Hu G, Vinten-Johansen J, Salem MR, Zhao ZQ, and Crystal GJ.  Isoflurane inhibits neutrophil-endothelium interactions in the coronary circulation: lack of a role for adenosine triphosphate-sensitive potassium channels. Anesthesia and Analgesia, 2002;94: 849-856.
• Crystal GJ, Zhou X, Alam S, Piotrowski A, and Hu G. Lack of role for nitric oxide in cholinergic modulation of myocardial contractility in vivo. American Journal of Physiology, 2001;281:H198-H206.
• Crystal GJ, Zhou X, Gurevicius J, Czinn EA, Salem MR, Alam S, Piotrowski A, and Hu G. Direct coronary vasomotor effects of sevoflurane and desflurane in in situ canine hearts. Anesthesiology, 2000;92:1103-1113.