The capacity of modest inflammation to potentiate hepatotoxic responses to drugs (e.g., ranitidine) and other xenobiotic agents has been characterized in several animal models. A common finding is that both neutrophils (PMNs) and hemostasis with consequent tissue hypoxia are critical players in inflammation- potentiated hepatotoxicity. Activated PMNs kill hepatic parenchymal cells (HPCs) through the release of toxic proteases such as elastase and cathepsin G. Recently, we found that the killing of HPCs by PMN elastase is accelerated and potentiated by hypoxia. The goals of the proposal are to test the hypothesis that hypoxia and PMN proteases interact to cause HPC injury during drug-inflammation interaction and to begin to understand the molecular basis for this interaction. The influence of hypoxia on the development and dose-responsiveness of HPC killing by PMN proteases in vitro and the importance of this interaction in a drug-inflammation model in vivo will be determined. Since hypoxia-inducible factor-1 alpha (HIF-1 alpha) can initiate cell death signaling and is expressed before the onset of hepatotoxicity during drug-inflammation interaction in vivo, we will delineate its role in HPC killing during hypoxia/PMN protease interaction in vitro and during drug-inflammation interaction in vivo. Finally, since PMN proteases destroy protein disulfide isomerase (PDI), a cytoprotective hypoxic stress protein in HPC membranes, the role of PDI inactivation in elastase/hypoxia-mediated HPC death will be explored. Pharmacological, antisense oligonucleotide, conditional null and gene overexpression approaches will be employed in these studies to provide knowledge of mechanisms by which a hypoxic environment likely to occur during inflammatory conditions enhances the capacity of cytotoxic PMN proteases to damage HPCs. The results will contribute to understanding inflammatory tissue injury generally and how inflammation acts as a susceptibility factor for toxicity due to drugs and other xenobiotic agents. Public Health Relevance: Drug toxicity and many liver diseases involve white blood cells such as neutrophils operating in an oxygen-deficient tissue environment to cause liver injury. Understanding how neutrophils interact with oxygen deficiency to promote liver injury could lead to better ways to prevent or treat adverse drug reactions and other types of inflammatory liver injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Shreffler, Carol K
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Michigan State University
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East Lansing
United States
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Sparkenbaugh, Erica M; Ganey, Patricia E; Roth, Robert A (2012) Hypoxia sensitization of hepatocytes to neutrophil elastase-mediated cell death depends on MAPKs and HIF-1?. Am J Physiol Gastrointest Liver Physiol 302:G748-57
Sparkenbaugh, Erica M; Saini, Yogesh; Greenwood, Krista K et al. (2011) The role of hypoxia-inducible factor-1? in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 338:492-502
Roth, Robert A; Ganey, Patricia E (2011) Animal models of idiosyncratic drug-induced liver injury--current status. Crit Rev Toxicol 41:723-39
Aibo, Daher Ibrahim; Birmingham, Neil P; Lewandowski, Ryan et al. (2010) Acute exposure to ozone exacerbates acetaminophen-induced liver injury in mice. Toxicol Sci 115:267-85
Shaw, Patrick J; Ganey, Patricia E; Roth, Robert A (2010) Idiosyncratic drug-induced liver injury and the role of inflammatory stress with an emphasis on an animal model of trovafloxacin hepatotoxicity. Toxicol Sci 118:7-18
Deng, Xiaomin; Luyendyk, James P; Ganey, Patricia E et al. (2009) Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol Rev 61:262-82
Deng, Xiaomin; Liguori, Michael J; Sparkenbaugh, Erica M et al. (2008) Gene expression profiles in livers from diclofenac-treated rats reveal intestinal bacteria-dependent and -independent pathways associated with liver injury. J Pharmacol Exp Ther 327:634-44
Copple, Bryan L; Roth, Robert A; Ganey, Patricia E (2006) Anticoagulation and inhibition of nitric oxide synthase influence hepatic hypoxia after monocrotaline exposure. Toxicology 225:128-37
Copple, Bryan L; Rondelli, Catherine M; Maddox, Jane F et al. (2004) Modes of cell death in rat liver after monocrotaline exposure. Toxicol Sci 77:172-82
Kinser, Shawn; Sneed, Rosie; Roth, Robert et al. (2004) Neutrophils contribute to endotoxin enhancement of allyl alcohol hepatotoxicity. J Toxicol Environ Health A 67:911-28

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