TOXICOLOGY AND APPLIED PHARMACOLOGY 139, 213–226 (1996) ARTICLE NO. 0160 CONTEMPORARY ISSUES IN TOXICOLOGY Mechanisms of Inflammatory Liver Injury: Adhesion Molecules and Cytotoxicity of Neutrophils 1 HARTMUT JAESCHKE,* ,2 C. WAYNE SMITH,² M ARK G. CLEMENS,‡ PATRICIA E. GANEY,§ AND ROBERT A. ROTH§ *Cardiovascular Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001; ² Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; ‡Division of Pediatric Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland 21287; and §Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824 Received December 14, 1995; accepted April 16, 1996 much of the research in hepatotoxicology turned to these Mechanisms of Inflammatory Liver Injury:Adhesion Molecules cells for answers to questions about mechanisms of liver and Cytotoxicity of Neutrophils. JAESCHKE, H., SMITH, C. W., injury. Much has been learned and continues to be learned CLEMENS, M. G., GANEY, P. E., AND ROTH, R. A. (1996). Toxicol. from isolated hepatocyte preparations. However, the liver is Appl. Pharmacol. 139, 213–226. not merely one large parenchymal cell; it contains numerous During recent years, increasing experimental evidence has sug- other cell types, such as Kupffer cells, endothelial cells, and gested that hepatic nonparenchymal cells, in particular Kupffer fat-storing cells (i.e., stellate or Ito cells). Moreover, these cells and neutrophils, can contribute significantly to the pathogen- resident cells of the liver are in close association with cells esis of liver injury in various chemical toxicities. Neutrophils are of the blood that flows through liver sinusoids. It has only central to the mechanism of injury afterhepatic ischemia reperfu- been in the past several years that investigators have discov- sion and endotoxemia. In this symposium summary, an overview ered the importance of these nonparenchymal cells, includ- of critical aspects of neutrophil-dependent liverinjury is presented. ing circulating blood cells, in the genesis of hepatocellular A general introduction to the involvement of adhesion molecules injury. The vignettes below, presented originally as a sympo- in neutrophil rolling and transendothelial migration is provided. sium at the 1995 Annual Meeting of the Society of Toxicol- Mediators and mechanisms of neutrophil sequestration in the liver vasculature, extravasation, and adherence-dependent cytotoxicity ogy, each focus on different aspects of the roles of blood are discussed using the examples of endotoxin-induced hepatic neutrophils as contributors to hepatocellular injury during failure and ischemia-reperfusion injury. These processes involve a inflammation. complex network of inflammatory mediators including cytokines, Neutrophils are well known for their role in inflammatory chemokines, and lipid-derived compounds. The role of neutrophil- responses and specifically in phagocytosing and killing of derived cytotoxic mediators, e.g., reactive oxygen and proteases, in pathogenic organisms. To carry out these functions, they the molecular mechanisms of parenchymal cell injury is discussed. employ a number of mediators that promote inflammation Furthermore, interactions between neutrophils and contractile, and effect bacterial killing (Fig. 1). In recent years, it has perisinusoidal, stellate cells that influence microvascular blood become clear that the neutrophil, probably through some flow in the liver are discussed. Results of these and other investiga- of these same mediators, can injure host tissue, including tions are leading to increased understanding of the complex inter- actions between neutrophils and tissues that result in injury. parenchymal cells of the liver.  1996 Academic Press, Inc. There are now a number of situations for which liver injury is thought to have a component that depends upon neutrophils including hepatic ischemia reperfusion (Jaeschke In the area of hepatotoxicology as in other areas of biol- et al., 1990, 1993b), endotoxin shock (Jaeschke et al., 1991b; ogy, directions for investigation have been to some degree Hewett et al., 1992), and a-naphthylisothiocyanate toxicity driven by advances in technology. For example, in the last (Dahm et al., 1991). Endotoxemia provides one illustration. quarter century we have learned to isolate and maintain he- Systemic exposure of rats to gram-negative bacterial endo- patic parenchymal cells in culture. With this occurrence, toxin leads to liver injury. The hepatic lesions include ne- crotic parenchymal cells, and within the lesions there are many neutrophils. These cells accumulate in the liver prior 1 Summary of the Symposium presented at the 34th Annual Meeting of to the onset of liver injury, they appear within lesions as the Society of Toxicology, Baltimore, Maryland, March 1995. 2 To whom correspondence and reprint requests should be addressed. well as in surrounding areas where lesions may be devel- 213 0041-008X/96 $18.00 Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved.