Welcome to the Mackman Laboratory

Nigel Mackman, Ph.D. Associate Professor with tenure Departments of Immunology & Cell Biology The Scripps Research Institute 10550 North Torrey Pines Road, CVN-18 La Jolla, CA 92037 Tel: (858) 784-8594 Fax: (858) 784-7545 E-mail: nmackman@scripps.edu

The Mackman laboratory is interested in the mechanisms of LPS induction of gene expression in human monocytes. 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 role of various transcription factors, such as AP-1, NF-kB and Egr-1, in the induction of these inflammatory response genes. In addition, we are characterizing the signaling pathways and other mechanisms by which anti-inflammatory mediators and anticoagulants reduce the inflammatory response to LPS during sepsis.

Myocardial ischemia-reperfusion (I/R) injury is a significant clinical problem that contributes to loss of myocardial tissue after restoration of blood flow after angioplasty, administration of thrombolytes and coronary artery bypass surgery. Recently, we have shown that the inhibition of either tissue factor, the primary cellular initiator of the coagulation cascade, or the downstream coagulation protease, thrombin, reduces infarct size in a rabbit model of myocardial I/R injury. Furthermore, we determined that the tissue factor-thrombin pathway contributed to the inflammatory response during myocardial I/R injury by increasing chemokine expression and recruitment of neutrophils. Future studies will determine the role of thrombin and its cellular receptor, PAR-1, in this inflammatory response in the heart. In addition, we will determine if thrombin stimulation of cardiomyocytes promotes cell death.

A common theme of the Mackman Lab's main research projects is the crosstalk between the coagulation cascade and inflammation. The laboratory has generated novel mouse models that are used to elucidate the mechanisms of crosstalk in sepsis and in myocardial and kidney I/R injury. Future studies will use pharmacologic inhibitors and genetically modified mice to analyze the role of tissue factor, coagulation proteases and PARs in ischemia-reperfusion injury, intimal hyperplasia, atherosclerosis, lung injury and tumor angiogenesis.

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