Shu Fang Liu, PhD

Associate Investigator
Center for Immunology and Inflammation
The Feinstein Institute for Medical Research
Director, Laboratory of Pulmonary and Critical Care Medicine
270-5 76th Avenue, Research Building, RM B371
New Hyde Park, NY 11040
Telephone: 718 470 7o78
Fax: 718 470 0827.
E-mail: sliu@lij.edu

Academic Degree:
Ph.D. in Molecular Pharmacology, 1993, Imperial College, University of London, England.

Academic Affiliations: Associate Professor of Medicine Albert Einstein College of Medicine

Research Overview:

Our laboratory focuses on molecular mechanisms of septic shock, and septic multiple organ injury (MOI), conditions that claim thousands of life each year. Using modern molecular biology techniques, we are identifying the molecular events that take place when bacterial infections initiate the inflammatory process and lead to the development of septic shock and septic MOI. The purpose of our research is to discover new targets for novel therapies for treating this life-threatening condition. We have recently discovered that in addition to triggering uncontrolled systemic inflammation, bacterial infection also suppresses the expression of multiple “housekeeping genes”, whose products are critical for the maintenance of normal organ functions, and impairs our body’s anti-inflammatory and protective mechanisms. 

We are investigating how bacterial infection represses housekeeping gene expression and impairs the anti-inflammatory and protective mechanisms, and are trying to find the ways of boost these anti-inflammatory and protective mechanisms. Our recent studies have also demonstrated that endothelial-targeted blockade of inflammatory pathways can effectively prevent septic MOI, while avoiding the impairment of our body’s host defense capability, a serious side-effect commonly seen in systemic inhibition of inflammatory pathways. This may lead to the development of novel anti-sepsis therapies.

Research Description:

There are 3 on-going research projects in the laboratory. In the first project, we are studying endothelial selective blockade of NF-κB signaling pathway as therapeutic potential in the treatment of septic shock and septic multiple organ injury (MOI) using a murine models of septic shock.  The transcription factor, nuclear factor kappa B (NF-κB) is a major driving force of systemic inflammation. NF-κB activation mediates the expression of hundreds of pro-inflammatory genes, many of their products play an important roles in pathogenesis of septic shock and septic MOI. Studies by our laboratory and others have shown that inhibition of NF-κB activation corrected virtually all major aspects of septic abnormalities. Thus, NF-κB is an ideal target for therapeutic intervention. However, systemic inhibition of NF-κB pathway impairs our host defense mechanisms to fight bacterial infection and causes immune suppression, which are harmful. To develop effective anti-NF-κB therapies, we need to develop alanced approach that attenuates NF-κB-mediated inflammatory and injurious response and also preserves NF-κB-mediated host immune defense response. To this end, we have generated transgenic mice that conditionally over-express mutant I-κBα (I-κBαmt), an inhibitor of NF-κB, selectively on endothelial cells using tetracycline-regulated gene expression system. Utilizing this mouse strain, we have recently demonstrated that endothelial-restricted blockade of NF-κB-driven inflammatory pathways effectively prevented septic MOI, while avoiding the impairment of our body’s host defense capability, a serious side-effect commonly seen in systemic inhibition of inflammatory pathways. This suggests that selective blockade of endothelial NF-κB pathway balances the beneficial and detrimental effects of NF-κB inhibition. We are currently investigating the mechanisms underlying the different effects of endothelial NF-κB inhibition on the two immune responses.

Our second on-going research project investigates how bacterial toxin suppresses or impairs the anti-inflammatory mechanisms and housekeeping gene expression. This project was developed based on our discovery that challenge of mice or rats with LPS in vivo down-regulates the GC box-binding transcription factor, Sp1, activity and diminishes cellular Sp1 protein, which is accompanied by reduced expression of Sp1-dependent housekeeping genes and increased lung microvascular permeability. Because Sp1 regulates the transcriptional expression of hundreds of housekeeping genes, tissue repairing genes as well as multiple anti-inflammatory genes, our finding leads us to propose a novel mechanism that bacterial toxin causes septic shock and septic MOD/I by suppressing the Sp1-mediated housekeeping, anti-inflammatory and tissue repairing mechanisms. We have elucidated the molecular mechanisms underlying the LPS-induced down-regulation f Sp1 activity. We have demonstrated that that LPS down-regulates Sp1 activity by promoting Sp1 dephophorylation and Sp1 protein degradation, and that Sp1 protein degradation is the major mechanism underlying the LPS down-regulation of Sp1 activity. We have further demonstrated that LPS challenge induces a protease activity, which degrades Sp1 protein and down-regulates Sp1 activity. We have identified, characterized and purified the protease that is responsible for LPS-induced Sp1 protein degradation and named it as LPS inducible Sp1 degrading enzyme (LISPDE). We are currently determining the amino acid sequence of LISPDE protein.

Our third research project investigates the molecular mechanisms through which obstructive sleep apnea (OSA) promotes the development of cardiovascular diseases. OSA is a very common health problem affecting a large portion of the population, and has been recognized as an important risk factor for increased cardiovascular morbidity and mortality. The mechanisms linking OSA with cardiovascular diseases remain largely to be explored. This project was developed based on our initial observation that OSA patients have a markedly elevated neutrophil and monocyte NF-κB activity, and significantly elevated plasma levels of NF-κB-dependent gene products. Our initial observation has stimulated a great interest in this field. Our report has stimulated an editorial and resulted in more than 10 follow up studies worldwide showing that OSA patients have increased plasma levels of markers of systemic inflammation. Because chronic intermittent hypoxia (CIH) is a prominent feature of OSA pathophysiology, we are studying the cardiovascular consequences of exposure to CIH, and studying the mechanisms mediating the CIH effects. We have established a mouse model of CIH. We found that CIH activates NF-κB and that vascular tissue is particularly sensitive to CIH as indicated by increased NF-κB activity and increased expression of NF-κB-dependent gene product. We have also demonstrated that exposure of mice to CIH causes persistent systemic hypertension, increases vascular sensitivity to vasoconstrictor and impairs endothelium-dependent vasodilatation. We are currently investigating the mechanisms mediating CIH induced other cardiovascular dysfunction and pathology. 

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Lab Members:

Name:   Dongmei Song
Position:   Postdoctoral Research Fellow
Research:   Studies the mechanistic role of endothelial intrinsic NF-k B in the perturbations of vascular homeostasis.
E-mail:   mmsong70@yahoo.com

Name:   Gang Liu
Position:   Postdoctoral Research Fellow
Research:   Studies the role of N-kB in inflammation resolution.
E-mail:   lg19790418@163.com

Name:   Xiaobing Ye
Position:   Senior Research Assistant
Research:   Studies how bacterial endotoxin suppresses housekeeping gene expression.
E-mail:   Bing_ye@hotmail.com

Name:   Honglei Xu
Position:   Visiting Scientist
Research:   Studies the role of NF-k B in organ injury recovery.
E-mail:   Hxu@hotmail.com

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Selected Publications:

Ye, X., Ding, D., Zhou, Z., Chen, G. &  Liu, S.F. Divergent Roles of Endothelial NF-κB In Multiple Organ Injury and Bacterial Clearance In Murine Models of Sepsis. J. Exp. Med. 205:1303-1315, 2008.  

Ye, X., Liu, S.F.  Lipopolysaccharide causes Sp1 protein degradation by inducing a unique trypsin-like serine protease in rat lungs. Biochim Biophys Acta. 1773:243-53, 2007.

Liu SF and Malik AB. NF-κB activation as a pathologic mechanism of septic shock and inflammation. . Liu SF, Malik AB. NF-κB activation as a pathologic mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell Mol. Physiol. 290: L622-L645, 2006.

Greenberg, H., Ye, X., Wilson, D., Htoo, A.K., Henderson, T., & Liu, S.F. Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem Biophys Res Commun. 5;343:591-6, 2006.

Htoo, A.K., Greenberg, H., Tongia, S., Chen, G., Henderson, T., Wilson, D. & Liu, S.F. Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation. Sleep Breath. 10:43-50, 2006.

Cohen, R.I., Wilson, D., Ye, X. & Liu, S.F. Nitric oxide modifies the sarcoplasmic reticular calcium release channel in endotoxemia by both guanosine-3',5' (cyclic) phosphate-dependent and independent pathways. Crit. Care Med. 34: 173-181, 2006.

Cohen, R.I., Hassell, A.M., Ye, X., Marzouk, K., Liu, S.F. Lipopolysaccharide down-regulates inducible nitric oxide synthase expression in swine heart in vivo. Biochem Biophys Res Commun. 307:451-458, 2003.

Ye, X., Liu, S.F. Lipopolysaccharide down-regulates promoter selective transcription factor 1 binding activity by promoting Sp1 protein dephosphorylation and degradation. J. Biol. Chem. 277: 31863-31870, 2002.

Lu, Y-T, Chen, P-G & Liu, S.F.Time course of lung ischemia reperfusion induced ICAM-1 expression and its role in ischemia-reperfusion lung injury. J. Appl. Physiol. 93: 620-628, 2002.

Iqbal, M., Cohen, R.I., Marzouk, K. & Liu, S.F. Time course of nitric oxide, peroxynitrite and antioxidants in the endotoxemic heart. Crit. Care Med. 30: 1291-1296, 2002.

Cohen, R.I., Hassell, A.M., Marzouk, K., Marini, C., Liu, S.F. & Scharf, S.M. Renal Effects of Nitric Oxide in Endotoxemia. Am. J. Respir. Crit. Care Med. 164:1890-1895, 2001.
Ye, X. & Liu, S.F. Lipopolysaccharide regulates constitutive and inducible transcription factor activities differentially in vivo in the rat. Biochem. Biophys. Res. Commun. 288:927-32, 2001.

Liu, S.F. and Evans, T.W. Role of nitric oxide in the regulation of pulmonary vascular tone. In: Mitchell, J. and Belvisi, M. eds. Nitric Oxide in Pulmonary Processes: Role in Physiology and Pathophysiology of Lung disease. Birkhäuser Verlag Publishing Ltd., Basel, 89-110, 2000.

Liu, S.F., Ye X.B. & Malik,A.B. Inhibition of NF-κB activation by pyrrolidine dithiocarbamate prevents in vivo expression proinflammatory genes. Circulation 100: 1330-1337, 1999.

Liu, S.F., Ye, X.B. & Malik, A.B. Pyrrolidine Dithiocarbamate Prevents I-κB Degradation and Reduces Microvascular Injury Induced by Lipopolysaccharide in Multiple Organs. Mol. Pharmacol. 55: 658-667, 1999.

Lu, Y-T, Liu, S.F., Mitchell, J.M., Malik, A.B., Hellewell, P.G. & Evans, T.W. The role of endogenous nitric oxide in modulating ischemia-reperfusion injury in the isolated, blood perfused rat lung. Am. J. Respir. Crit. Care Med. 157: 273-279, 1998.

Liu, S.F., Ye, X.B. & Malik, A.B. In vivo inhibition of NF-κB activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J. Immunol. 159: 3976-3983, 1997.

Liu, S.F., Haddad E-M., Adcock, I., Salmon M., Koto, H., Gibey, T., Barnes P.J. & Chung K.F. Inducible nitric oxide synthase after sensitization and allergen challenge of Brown Norway rat lung Br. J. Pharmacol. 121: 1241-1246, 1997.

Liu, S.F., Barnes, P.J. & Evans T.W. Time course and cellular localization of lipopolysaccharide induced inducible nitric oxide synthase mRNA expression in the rat in vivo. Crit. Care Med. 25: 512-518, 1997.

Newton, R., Seybold J., Liu, S.F., & Barnes, P.J. Alternate COX-2 transcripts are differentially regulated: implication for post-transcriptional control. Biochem. Biophys. Res. Commun. 243: 85-89, 1997.

Liu, S.F. and Barnes, P.J. Neural control of pulmonary vascular tone. In: Crystal, R.G., West, J.B., Weibel, E.R. & Barnes, P.J. eds. THE LUNG: Scientific Foundations, 2nd ed. Lippincott.Raven Publisher, Philadelphia, 1457-1472, 1996.

Liu, S.F., Adcocck, I.M., Old, R.W., Barnes, P.J. & Evans, T.W. Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysacchride treatment in vivo in the rat. Crit. Care Med. 24: 1219-1225, 1996. 

Liu, S.F., Newton, R., Evans, T.W. & Barnes, P.J. Differential regulation of cyclooxygenase-1 and cyclooxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin. Sci. 90: 301-306, 1996.

Barnes, P.J. and Liu, S.F. Regulation of pulmonary vascular tone. Pharmacol. Rev. 47: 87-131, 1995.

Griffiths M.J.D., Liu, S.F., Curzen, N.P., Messent M. & Evans T.W. In vivo treatment with endotoxin induces nitric oxide synthase in rat main pulmonary arteries. Am. J. Physiol. 268: L509-L518, 1995.

Haddad, E-B., Liu, S.F., Salmon, M., Robichaud, A., Barnes, P.J. & Chung, K.F. Expression of inducible nitric oxide synthase mRNA in Brown Norway rats exposed to ozone: effect of dexamethasone. Eur. J. Pharmacol. (Evironmental Toxicol. Pharmacol.) 293: 287-290, 1995.

Haddad E-M., Salmon M., Sun J., Liu, S.F., Das A., Adcock I., Barnes P.J. & Chung K.F. Dexamethasone inhibits ozone-induced gene expression of macrophage inflammatory protein-2 in rat lung. FEBS Lett. 363: 285-288, 1995.

Liu, S.F. and Barnes, P.J. Role of endothelium in the control of pulmonary vascular tone. Endothelium 2: 11-33, 1994.

Liu, S.F., Kuo, H-P, Barnes, P.J. & Evans T.W. Vagal stimulation-induced changes in pulmonary vascular permeability in guinea pig. Am. J. Respir. Crit. Care Med. 149: 744-750, 1994.

Liu, S.F., Adcocck, I.M., Old, R.W., Barnes, P.J. & Evans, T.W. Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem. Biophys. Res. Commun. 196: 1208-1213, 1993.

Liu, S.F., Crawley, D.E., Evans, T.W. & Barnes, P.J. Endothelium-dependent nonadrenergic, noncholinergic neural relaxation in guinea pig pulmonary artery. J. Pharmacol. Exp. Ther. 260: 541-548, 1992.

Liu, S.F., Rohde J.L.A., Crawley, D.E., Evans, T.W. & Barnes P.J. Role of nitric oxide and guanosine 3',5'-cyclic monophosphate in mediating nonadrenergic, noncholinergic neural relaxation in guinea pig pulmonary arteries. Br. J. Pharmacol. 107: 861-866, 1992.

Liu,S.F., Hislop A.A., Haworth S.G. & Barnes P.J. Developmental changes in endothelium-dependent pulmonary vasodilatation in pigs. Br. J. Pharmacol. 106: 324-330, 1992.

Liu, S.F., Dewar, A., Crawley, D.E., Barnes, P.J. & Evans, T.W. Effect of tumor necrosis factor on hypoxic pulmonary vasoconstriction. J. Appl. Physiol. 72: 1044-1049, 1992.
Crawley, D.E., Liu, S.F., Barnes, P.J. & Evans, T.W. Endothelin-3 is a potent pulmonary vasodilator in the rat. J. Appl. Physiol. 72: 1425-1431, 1992.

Kuo, H-P, Liu, S.F. & Barnes, P.J. The effect of endogenous nitric oxide on neurogenic plasma exudation in guinea pig airways. Eur. J. Pharmacol. 221: 385-388, 1992.

Crawley D.E., Zhao L., Giembycz M.A., Liu, S.F., Barnes, P.J., Winter R.J.D. & Evans T.W. Chronic hypoxia selectively impairs soluble guanylyl cyclase-mediated pulmonary arterial relaxation in the rat. Am. J. Physiol. 263: L325-L332, 1992.

Liu, S.F., Crawley, D.E., Barnes, P.J. & Evans, T.W. Endothelium-derived relaxing factor inhibits hypoxic pulmonary vasoconstriction in rat. Am. Rev. Respir. Dis. 143: 32-37, 1991.

Liu, S.F., Crawley, D.G., Evans, T.W. & Barnes, P.J. Endogenous nitric oxide modulates adrenergic neural vasoconstriction in guinea-pig pulmonary artery. Br. J. Pharmacol. 104: 565-569, 1991.

Liu, S.F., Yacoub, M. & Barnes, P.J. Effect of histamine on human bronchial arteries in vitro. Naunyn-Schiedeberg's Arch. Pharmacol. 342: 90-93, 1990.

Liu, S.F., Cai, Y.N., Evans, T.W., McCormark, D.G. Barer, G.R. & Barnes, P.J. Ligustrazine is a vasodilator of human pulmonary and bronchial arteries. Eur. J. Pharmacol. 191: 345-350, 1990.

Crawley, D.E., Liu, S.F., Evans, T.W. & Barnes, P.J. Inhibitory role of endothelium-derived relaxing factor in rat and human pulmonary arteries. Br. J. Pharmacol. 101: 166-170, 1990.

Liu, S.F., McCormark, D.G., Evans, T.W. & Barnes, P.J. Characterization and distribution of P2-purinoceptors on rat pulmonary vessels. J. Pharmacol. Exp. Ther. 251: 1204-1210, 1989.

Liu, S.F., McCormark, D.G., Evans, T.W. & Barnes, P.J. Evidence for two types P2-purinoceptors in human small pulmonary arteries. Br. J. Pharmacol. 98: 1014-1020, 1989.