Nigel Mackman

Nigel Mackman

Nigel Mackman

John Parker Professor of Medicine
Department of Medicine

Ph.D., Genetics
University of Leicester, UK

Biosketch [.pdf]

Department of Medicine
Division of Hematology/Oncology

Contact Information ->>

Research Interests

  • Role of Tissue Factor in hemostasis, thrombosis and ischemia-reperfusion (I/R) injury

Research Synopsis

My lab studies the gene expression in human monocytes, focusing on tissue factor (TF), which is the primary cellular initiator of blood coagulation, and the proinflammatory cytokine TNFα.

We have elucidated the role of different intracellular signaling pathways in the induction of the TF and TNFα genes in monocytes.  These pathways include the mitogen activated protein kinases (MAPK) ERK1/2, p38 and JNK1/2.  In addition, my lab has studied the I kappa kinase that phosphorylates the IκB inhibitor proteins leading to their degradation and release of NFκB proteins into the nucleus.  More recently, we have investigated the inhibition of the MAPK pathways by the PI3K-Akt pathway and also by antioxidant compounds. 

In parallel to the in vitro studies, my lab has established several animal models of various diseases to analyze prothrombotic and proinflammatory responses in vivo.  These include the endotoxemia model and a renal ischemia/reperfusion (I/R) injury model.  We are interested determining the mechanism of crosstalk between coagulation and inflammation in these models.  We have focused on the protease activated receptor (PAR) family because these proteins are activated by coagulation proteases.

Gram-negative bacterial infections release LPS that activates monocytes of the innate immune system. These cells express various inflammatory mediations, including cytokines and procoagulant molecules, to combat the infection. However, over-reaction to LPS can lead to septic shock. We are studying the signaling pathways and other mechanisms by which anti-inflammatory mediators and anticoagulants reduce the inflammatory response to LPS during sepsis.

I/R injury is a significant clinical problem that contributes to morbidity and mortality.  We showed that inhibition of either TF or the downstream coagulation protease, thrombin, reduces infarct size in a rabbit model of myocardial I/R injury. Furthermore, we determined that the TF-thrombin pathway contributed to the inflammatory response during myocardial I/R injury by increasing chemokine expression and recruitment of neutrophils. More recently, we found that activation of the major thrombin receptor, called PAR-1, contributed to cardiac remodeling after I/R injury.  We have written a patent proposing that inhibition of PAR-1 represents a novel therapeutic approach to treat cardiac hypertrophy and heart failure. 

The lab also studies the role of TF in tumor growth and tumor angiogenesis.  In collaborative studies with Janusz Rak in Toronto, we have demonstrated that TF expression in human colorectal cancer cells was regulated by activation of the K-ras oncogene and inactivation of the p53 tumor suppressor.  In addition, a selective reduction in TF expression in cancer cells was associated with reduced growth and reduced angiogenesis when the cells were injected into mice.  We have also demonstrated that cancer patients have elevated levels of circulating TF, which may contribute to the increased incidence of thrombosis in these patients.

Finally, my lab has generated a number of mouse models expressing different levels of TF.  These mice have been used to provide new insights into the role of TF in both hemostasis and thrombosis.  We have proposed a model of tissue-specific hemostasis.  In the future, the lab will continue to study the role of the clotting cascade and platelets in hemostasis, thrombosis and inflammation.  I hope to discover new treatment for hemostatic and thrombotic diseases.

Publications

pubmed

Click above for PubMed publications.

  • Pawlinski, R., Tencati, M., Holscher, T., Pedersen, B., Voet, T., Tilley, R.E., Marynen, P., Mackman, N. (2007) Role of cardiac myocyte tissue factor in heart hemostasis.  J Thromb Haemost, in press.
  • Redecha, R., Tilley, R., Tencati, M., Salmon, J., Kirchhofer, D., Mackman, N., Girardi, G. (2007) Tissue factor: a link between C5a and Neutrophil activation in antiphospholipid antibody-induced fetal injury.  Blood, in press.
  • Luyendyk, J.P., Piper, J.D., Tencati, M., Reddy, K.V., Holscher, T., Zhang, R., Luchoomun, J., Chen, X., Min, W., Kunsch, C., Mackman, N.  (2007) A novel class of antioxidants inhibits LPS induction of tissue factor by selective inhibition of the activation of ASK1 and MAP kinases. Arterioscler Thromb Vasc Biol, in press.
  • Ganey, P., Luyendyk, J. Newport, S., Eagle, T. Maddow, J. Mackman, N., Roth, R. (2007) Role of coagulation system activation in acetaminophen-induced hepatotoxicity in mice.  Hepatology, in press.
  • Shigeoka, A., Hoscher, T.D., King, A.J., Hall, F.W., Kiosses, W.B., Tobias, P.S., Mackman, N., McKay, D.B.  (2007) TLR2 is Constitutively Expressed within the Kidney and Participates in Ischemic Renal Injury through both MyD88-dependent and independent pathways. J Immunol, in press.
  • Davis, D., Wilson, K., Sam, M., Kennedy, S., Mackman, N., Charlesworth, J., Erlich, J. (2007) The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential expression of urokinase plasminogen activator. J Mol and Cell Cardiol 42: 559-71. Abstract
  • Sevastos, J., Kennedy, S.E., Davis, D.R., Sam, M., Peake, P.W., Charlesworth, J.A., Mackman, N., Erlich, J.H.  (2007)Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury.  Blood 109: 577-583. Abstract
  • Frank, R.D., Holscher, T., Schabbauer, G. Tencati, M., Pawlinski, R., Weitz, J.I., Mackman, N.  (2006) The anti-inflammatory activity of a synthetic pentasaccharide is not dependent on its anticoagulant activity.  Throm Haemost 96: 802-806. Abstract
  • Schwertz, H., Tolley, N.D., Foulks, J.M.,Denis, M.M., Risenmay, B.W., Buerke, M., Mackman, N., Harris, E.M., Kraiss, L.W., Zimmerman, G.A.,Weyrich, A.S.  (2006) Signal-dependent pre-mRNA splicing modulates the pro-coagulant activity of human platelets.  J Exp Med 20: 2433-2440. Abstract
  • Mullarky, I.K., Szaba, F.M., Winchel, C.G., Parent, M.A., Kummer, L.W., Mackman, N., Johnson, L.L., Smiley, S.T. (2006) In situ hemostasis assays demonstrate that interferon-gamma suppresses infection-stimulated hepatic fibrin deposition by promoting fibrinolysis.  J Thromb Haemost 4: 1580-1587. Abstract

 

Contact Information


Office Location:
917 Mary Ellen Jones Bldg.

Mailing Address:
CB # 7037
Chapel Hill, NC 27599-7037

Office Phone: 919-843-3961
Lab Phone:
Fax: 919-966-7639
nmackman[at]med.unc.edu

 

 

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