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Immunology. macrophages. nitric oxide. inflammationThe 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 such as ethanol. acetaminophen. or ozone 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. Selected PublicationsShakarjian MP, Heck DE, Gray JP, Sinko PJ, Gordon MK, Casillas RP, Heindel ND, Gerecke DR, Laskin DL, Laskin JD. (2009) Mechanisms Mediating the Vesicant Actions of Sulfur Mustard after Cutaneous Exposure. Toxicol Sci. Oct 15. [Epub ahead of print] PMID: 19833738 Sunil VR, Patel KJ, Mainelis G, Turpin BJ, Ridgely S, Laumbach RJ, Kipen HM, Nazarenko Y, Veleeparambil M, Gow AJ, Laskin JD, Laskin DL. (2009) Pulmonary effects of inhaled diesel exhaust in aged mice. Toxicol Appl Pharmacol. 241(3):283-93. Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EM, Doorn JA, Slikker W. (2009) Nitrative and oxidative stress in toxicology and disease. Toxicol Sci. 112(1):4-16. Laskin DL. (2009) Macrophages and Inflammatory Mediators in Chemical Toxicity: A Battle of Forces. Chem Res Toxicol. Jul 31. [Epub ahead of print] Black AT, Gray JP, Shakarjian MP, Laskin DL, Heck DE, Laskin JD. (2008) Increased oxidative stress and antioxidant expression in mouse keratinocytes following exposure to paraquat. Black AT, Gray JP, Shakarjian MP, Mishin V, Laskin DL, Heck DE, Laskin JD. (2008) UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes. Weinberger B, Quizon C, Vetrano AM, Archer F, Laskin JD, Laskin DL. (2008) Mechanisms mediating reduced responsiveness of neonatal neutrophils to Lipoxin A4. Pediatr Res. Jun 4. [Epub ahead of print] Chen LC, Laskin JD, Gordon MK, Laskin DL. (2008) Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia. Exp Mol Pathol. 84(2):145-55. Fakhrzadeh L, Laskin JD, Laskin DL. (2008) Regulation of caveolin-1 expression, nitric oxide production and tissue injury by tumor necrosis factor-alpha following ozone inhalation. Wang Y, Gray JP, Mishin V, Heck DE, Laskin DL, Laskin JD. (2008) Role of cytochrome P450 reductase in nitrofurantoin-induced redox cycling and cytotoxicity. Free Radic Biol Med. x 44(6):1169-79. Black AT, Gray JP, Shakarjian MP, Laskin DL, Heck DE, Laskin JD. (2008) Distinct effects of ultraviolet B light on antioxidant expression in undifferentiated and differentiated mouse keratinocytes. Carcinogenesis. 29(1):219-25. Sunil VR, Laumbach RJ, Patel KJ, Turpin BJ, Lim HJ, Kipen HM, Laskin JD, Laskin DL. (2007) Chen LC, Gordon RE, Laskin JD, Laskin DL. (2007) Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia. Exp Mol Pathol. 83(3):311-26. Sunil VR, Patel KJ, Nilsen-Hamilton M, Heck DE, Laskin JD, Laskin DL. (2007) Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Exp Mol Pathol. 83(2):177-87. Weinberger B, Vetrano AM, Syed K, Murthy S, Hanna N, Laskin JD, Laskin DL. (2007) Influence of labor on neonatal neutrophil apoptosis, and iInflammatory activity. Pediatr Res. 61(5 Pt 1):572-7. Gray JP, Heck DE, Mishin V, Smith PJ, Hong JY, Thiruchelvam M, Cory-Slechta DA, Laskin DL, 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. J Biol Chem. 282(11):7939-49. Laumbach RJ. Fiedler N. Gardner CR. Laskin DL. Fan ZH. Zhang J. Weschler CJ. Lioy PJ. Devlin RB. Ohman-Strickland P. Kelly-McNeil K. Kipen HM. (2005) Nasal effects of a mixture of volatile organic compounds and their ozone oxidation products. J Occup Environ Med. 47(11):1182-9. Martey CA. Vetrano AM. Whittemore MS. Mariano TM. Heck DE. Laskin DL. Heindel ND. Laskin JD. (2005) Inhibition of interferon-gamma signaling by a mercurio-substituted dihydropsoralen in murine keratinocytes. Biochem Pharmacol. 70(12):1726-34. Kipen HM. Laskin DL. (2005) Smaller is not always better: nanotechnology yields nanotoxicology. Am J Physiol Lung Cell Mol Physiol. 289(5):L696-7. Dambach DM. Durham SK. Laskin JD. Laskin DL. (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol. 211(2):157-65. Vetrano AM. Heck DE. Mariano TM. Mishin V. Laskin DL. Laskin JD. (2005) Characterization of the oxidase activity in mammalian catalase. J Biol Chem. 280(42):35372-81. 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. 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-alpha production. American Journal of Respiratory Cell and Molecular Biology 30:280-287. Hanna. N.. Bonifacio. L.. Reddy. P.. Hanna. I.. Weinberger. B.. Murphy. S.. Laskin. D.. Sharma. S. (2004). IFN-g-mediated inhibition of COX-2 expression in the placenta from term and preterm labor pregnancies. American Journal Reproductive Immunology 51: 311-318. 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.. Graboski. S.. Laskin. D.L.. Weinberger. B. (2004). Effects of
ibuprofen and hypoxia on neutrophil apoptosis in neonates. Biology of the
Neonate. 86(4): 235-239. Gardner. C.R.. Laskin. J.D.. Dambach. D.. Chiu. H.. Durham. S.K.. Zhou. P.. Bruno. M.K.. Gerecke. D.R.. Gordon. M.K... and Laskin. D.L. (2003). Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor-1 receptor. Potential role of inflammatory mediators. Toxicology and Applied Pharmacology 192:119-130. Chiu. H.. Gardner. C.R.. Dambach. D.M.. Brittingham. J.A.. Durham. S.K.. Laskin. J.D. and Laskin. D.L. (2003). Role of p55 tumor necrosis factor receptor 1 in acetaminophen induced antioxidant defense. American Journal of Physiology. Gastrointestinal and Liver 285: G959-G966. Chiu. H.. Gardner. C.R.. Dambach. D.M.. Durham. S.K.. Brittingham. J.A.. Laskin. J.D.. and Laskin. D.L. (2003). Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice. Toxicology and Applied Pharmacology 193: 218-227. Sunil. V.. Connor. A.. Laskin. J.D. and Laskin. D.L. (2002). Activation of type II alveolar epithelial cells during acute endotoxemia. American Journal of Physiology: Lung Cellular and Molecular Physiology 282: L872-L880. Fakhrzadeh. L.. Laskin. J.D. . Laskin. D.L. (2002). Deficiency in inducible nitric oxide synthase (NOSII) protects mice from ozone induced lung injury. American Journal of Respiratory and Cell Biology 26: 413-419. Dambach. D.M.. Watson. L.M. . Gray. K.R. . Durham. S.K. and Laskin. D.L. (2002). Role of CCR2 in macrophage recruitment and cytokine expression in the liver during acetaminophen induced hepatotoxicity. Hepatology 35:1093-1103. Ahmad. N.. Laskin. J.D. and Laskin. D.L. (2002). Regulation of cyclooxygenase-2 expression in hepatic macrophages by nitric oxide during acute endotoxemia. Journal of Leukocyte Biology 71: 1005-1011. Chiu. H.. Brittingham. J. and Laskin. D.L. (2002). Induction of heme oxygenase (HO-1) in the liver following acetaminophen administration to rats: protection by hemin and biliverdin. Toxicology and Applied Pharmacology 181: 106-115. Billack. B.. Heck. D.E. . Mariano. T.M.. Gardner. C.R.. Sur. R.. Laskin. D.L.. and Laskin. J.D. (2002). Induction of cyclooxygenase-2 by heat shock protein 60 in macrophages and endothelial cells. American Journal Physiology Cell Physiology 283:C1267-1277. |
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