Debra L. Laskin, Ph.D.

Professor II and Chair, Dept. of Pharmacology and Toxicology, Rutgers University School of Pharmacy
Ph.D., Medical College of Virginia, 1980

The overall focus of the research in my laboratory is immunology. We are particularly interested in nonspecific immunity mediated by macrophages, which are critical cellular components of the host response to tissue injury. Although the involvement of macrophages in protecting against invading pathogens and tumor cells is well documented, recent studies from our laboratory have demonstrated that macrophages also have a dark side. Thus they can be activated to release excessive quantities of proinflammatory and cytotoxic mediators that actually promote tissue injury. An analysis of this process represents the main focus of our research. Two mouse models are being utilized to investigate the role of macrophages and inflammatory mediators in toxicity: the lung and the liver. In each of these tissues, we found that exposure of mice to xenobiotics is associated with localized accumulation of macrophages. Moreover, macrophages isolated from the lung or liver of animals treated with tissue specific toxicants are "activated" to release increased quantities of inflammatory mediators such as tumor necrosis factor alpha, nitric oxide and superoxide anion.

To analyze the role of these cytotoxic mediators in toxicity, both pharmacologic inhibitors and knockout mice are being utilized. Whereas in some model systems, both approaches result in similar results in others such as hepatic necrosis induced by acetaminophen administration, opposing results are obtained. Thus, in this model, anti-TNFα antibody prevents toxicity, while TNFα knockout mice were more sensitive to acetaminophen. These data suggest that there are limitations to the use of transgenic animals which may be related to compensatory alterations in cytotoxic mediators production and this is being investigated. Another aspect of our studies is to elucidate biochemical mechanisms mediating macrophage activation in the liver and the lung. This has involved investigations on signaling molecules such as MAP kinases, and transcription factors such as NFkB, C/EBP and AP-1. Much of our research has taken advantage of new technological developments in biochemistry, molecular biology and flow cytometry/image analysis.

  • Fakhrzadeh, L., Laskin, J.D., Gardner, C.R., Laskin, D.L. (2004). Resistance of SOD +/+ mice to ozone toxicity and increases in nitric oxide and TNF-a production. American Journal of Respiratory Cell and Molecular Biology, 30:280-287.
  • Fakhrzadeh, L., Laskin, J.D., Laskin, D.L. (2004). Ozone-induced production of nitric oxide and TNFa and tissue injury are dependent on NF-kB. American Journal of Physiology. Lung Cell Physiology, 287(2):L279-285.
  • Hanna, N., Vasquez, P., Pham, P., Heck, D.E., Laskin, J.D., Laskin, D.L. and Weinberger, B. (2005). Mechanisms underlying reduced apoptosis in neonatal neutrophils. Pediatric Research, 57: 56-62.
  • Weinberger, B., Hanna, N., Laskin, J.D., Heck, D.E., Gardner, C.R., Gerecke, D.R., and Laskin, D.L. (2005). Mechanisms mediating the biologic activity of synthetic proline, glycine and hydroxyproline polypeptides in human neutrophils. Mediators of Inflammation, 1: 31-38.
  • Vetrano, A.M., Heck, D.E., Mariano, T.M., Mishin, V.M., Laskin, D.L., and Laskin, J.D. (2005). Characterization of the oxidase activity in mammalian catalase, Journal of Biological Chemistry, 280: 35372-35381.
  • Dambach, D., Durham, S., Laskin, J.D., and Laskin, DL. (2006). Distinct roles of NF-kB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicology and Applied Pharmacology, 211: 157-165.
  • Weinberger, B., Vetrano, A., Murthy, S., Syed, K., Hanna, N., Laskin, J.D., and Laskin, D.L. (2007). Influence of labor on neonatal neutrophil apoptosis and inflammatory activity. Pediatric Research, in press.
  • Gray JP, Heck DE, Mishin V, Smith PJ, Hong JY, Thiruchelvam M, Cory-Slechta DA, Laskin DL, and Laskin JD. (2007). Paraquat increases cyanide-insensitive respiration in murine lung epithelial cells by activating an NAD(P)H: Paraquat Oxidoreductase: Identification of the enzyme as thioredoxin reductase. Journal of Biological Chemistry, in press.
  • Sunil, V.R., Patel, K.J., Nielson-Hamilton, M., Laskin, J.D., and Laskin, D.L. Induction of lipocalin 24p3 in lung and liver during acute endotoxemia. Experimental and Molecular Pathology, in press.
  • Sunil, V.R., Patel, K.J., Mainelis, G., Turpin, B.J., Ridgely, S., Laumbach, R.J., Kipen, H.M., Nazarenko, Y., Veleeparambil, M., Gow, A.J., Laskin, J.D., Laskin DL. (2009). Pulmonary effects of inhaled diesel exhaust in aged mice. Toxicology and Applied Pharmacology, 241: 283-293.
  • Laskin, D.L. (2009). Macrophages and inflammatory mediators in chemical toxicity: A battle of forces? Chemical Research in Toxicology, 22: 1376-1385.
  • Gardner, C.R., Gray, J.P., Joseph, L.B., Cervelli, J., Bremer, N., Kim, Y., Mishin, V., Laskin, J.D., Laskin, D.L. (2010). Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity. Toxicology and Applied Pharmacology, 245: 36-46.
  • Vetrano, A.M., Laskin, D.L., Archer, F., Syed K., Gray, J.P., Laskin, J.D., Nwebube, N., Weinberger, B. (2010). Inflammatory effects of phthalates in neonatal neutrophils. Pediatric Research, 68: 134-139.
  • Laskin, D.L., Chen, L., Hankey, P.A., Laskin, J.D. (2010). Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia. Journal of Leukocyte Biology. 88: 373-382.
  • Malaviya, R., Sunil, V.R., Cervelli, J., Anderson, D.R., Holmes, W.W., Conti, M.L., Gordon, R.E., Laskin, J.D., Laskin, D.L. (2010). Inflammatory effects of inhaled sulfur mustard in rat lung. Toxicology and Applied Pharmacology, 248: 89-99.
  • Laskin, D.L. and Laskin, J.D. (2010). Inflammation and Cancer. In: Cancer Medicine, 8th edition. W.K. Hong, R.C. Bast, W.N. Hait, D.W. Kufe, R.E. Pollock, R.R. Weichselbaum, J.F. Holland, E. Frei, eds., New York: PMPH Publishing House, pp. 270-278.
  • Laskin, D.L., Gardner C.R., Laskin JD, (2010). Phagocytes. In Comprehensive Toxicology, 2nd edition, Volume 5 Immune System Toxicology. D. Lawrence, ed., UK: Elsevier, pp. 133-153.
  • Sunil, V.R., Patel, K., Shen, J., Reimer, D., Gow, A., Laskin, J.D., Laskin, D.L. (2010) Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard. Toxicology and Applied Pharmacology, 2010 Sep 29. [Epub ahead of print].
  • Laskin, D.L., Sunil, V.R., and Laskin, J.D. (2011). Macrophages in tissue injury: agents of defense or destruction? Annual Review of Pharmacology and Toxicology, 51, 267-288.