In conclusion, the liver is unique in its histoarchitecture compared to other organs. Additional differences exist within the liver itself, and these become more obvious during an inflammatory response. Herein we have touched on the concept that the disruption of the normal liver occurs through a multitude of cells and proinflammatory mediators. The challenge in the future is to define various models that best describe the mechanisms that are critical to induction and/or maintenance of liver damage. Understanding the precise mechanisms of hepatic injury or inflammation may permit the development of specific anti-inflammatory strategies. Only then can we aim at preventing effector cell recruitment while leaving general homeostatic liver functions intact.
Adhesion molecules: Molecular determinants that regulate homeostatic recirculation and tissue-specific trafficking of cells.
Inflammation: A localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or sequester both the injurious agent and the injured tissue. Histologically, it involves a complex series of events, including dilation of arterioles, capillaries, and venules, with increased permeability and blood flow, exudation of fluids, including plasma proteins, and leukocyte migration into the inflammatory focus.
Liver: A solid organ located in the right upper quadrant of the abdomen that plays a major role in metabolism, digestion, detoxification, and elimination of substances from the body.
Mediators: Substances released from cells as a result of the interaction between antigen and antibody or by the action of antigen with a sensitized lymphocyte.
Recruitment: The collection or increased abundance of cells into a defined area, such as antigen-experienced lymphocytes into inflammatory effector sites via specific vascular addressins and chemokines.
*Papers of interest have been marked for their special relevance to this topic and as outstanding reviews.
1. Ekataksin, W., and Kaneda, K. (1999). Liver microvascular architecture: An insight into the pathophysiology of portal hypertension. Semin. Liver Dis. 19, 359-382.
2. Knolle, P. A., and Gerken, G. (2000). Local control of the immune response in the liver. Immunol. Rev. 174, 21-34.
3. Sheth, K., and Bankey, P. (2001). The liver as an immune organ. Curr. Opin. Crit. Care 7, 99-104.
4. Bone-Larson, C. L., Simpson, K. J., Colletti, L. M., Lukacs, N. W., Chen, S. C., Lira, S., Kunkel, S. L., and Hogaboam C. M. (2000). The role of chemokines in the immunopathology of the liver. Immunol. Rev. 177, 8-20.* This particular review addresses the current understanding of the manner in which chemokines contribute to both acute and chronic liver injury by examining a variety of clinical and experimental studies.
5. Jaeschke, H. (2000). Reactive oxygen and mechanisms of inflammatory liver injury. J. Gastroenterol. Hepatol. 15, 718-724.
6. Jaeschke, H. (2003). Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am. J. Physiol Gastrointest. Liver Physiol 284, G15-G26.* This review is an excellent source for understanding the mechanisms that are key in the development of hepatic inflammation after an ischemic event. It discusses the role of cytokines, reactive oxidant species, complement, adhesion molecules, and neutrophil trafficking in the inflamed liver.
7. Ramadori, G., and Armbrust, T. (2001). Cytokines in the liver. Eur. J. Gastroenterol. Hepatol. 13, 777-784.
8. Jaeschke, H. (1997). Cellular adhesion molecules: Regulation and functional significance in the pathogenesis of liver diseases. Am. J. Physiol 273, G602-G611.* Hartmut Jaeschke is world renowned for his work in studying liver inflammation. This review focuses on CAMs that have been shown to be relevant to inflammatory liver disease processes and discusses their regulation and functional significance.
9. Lalor, P. F., Shields, P., Grant, A., and Adams, D. H. (2002). Recruitment of lymphocytes to the human liver. Immunol. Cell Biol. 80, 52-64.* Many studies have identified lymphocytes to be key mediators of liver inflammation. This review is an excellent source for understanding and comparing the molecular mechanisms that regulate the entry of lymphocytes into the normal and inflamed liver.
10. Wong, J., Johnston, B., Lee, S. S., Bullard, D. C., Smith, C. W., Beaudet, A. L., and Kubes, P. (1997). A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J. Clin. Invest 99, 2782-2790.
Dr. Bonder is a Canadian Association of Gastroenterology postdoctoral fellow with Dr. Kubes at the University of Calgary. Her work focuses on the recruitment of leukocytes to splanchnic organs during inflammation.
Dr. Kubes is chair of the Immunology Research Group in the Department of Physiology and Biophysics. His laboratory is supported by grants from the Canadian Institutes for Health Research (CIHR) and a CIHR group grant.
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