Pathophysiology of the Hepatic Microcirculation

Significant interactive roles for endotoxin, cytokines, chemokines, reactive free radicals, nitric oxide (NO), endothelin (ET-1), carbon monoxide (CO), sinusoidal lining cells, leukocytes, and platelets have been demonstrated in the pathophysiology of hepatic microvascular disturbances and parenchymal injury resulting from infection, toxicants, and ischemia/reperfusion following hemorrhage or liver transplantation. The responses of the hepatic microvascula-ture are of two basic types: (a) an inflammatory response involving paracrine activation of the sinusoidal endothelial cells (SEC) by mediators released from adjacent Kupffer cells and/or hepatic parenchymal cells following stimulation by toxicants, leading to the upregulation of adhesion molecules and the subsequent adhesion of leukocytes to the SEC, as well as swelling of the SEC, both of which restrict sinusoidal blood flow; and (b) direct injury of the SEC, resulting in loss of fenestrae, formation of gaps, penetration of the sinusoidal lining by blood cells, destruction of SEC, and obstruction of the sinusoid by SEC debris. The inflammatory response results from endotoxemia, sepsis, ischemia-reperfusion injury, and acute alcohol ingestion while direct injury is elicited by acetaminophen (APAP) or during hepatic venoocclusive disease by pyrrolizidine alkaloids. Both types of injury may occur together or sequentially, as is seen when ethanol sensitizes sinusoidal lining cells to other toxicants such as APAP or endotoxin, which exacerbates the extent of injury. It should be noted that because of the highly anastomotic nature of the hepatic sinusoid bed, plugging of single or scattered segments of sinusoids results in redirection of blood flow into adjacent unplugged vessels. However, unless the injury is highly localized, these latter vessels eventually become plugged, resulting in microcirculatory failure.

Glossary

Hepatic lobule: A polygonal structure having as its central axis a central venule, with portal tracts distributed along its peripheral boundary; major functional unit in the liver.

Hepatic microvascular system: Comprises all blood and lymphatic vessels immediately involved in the delivery and removal of fluids to and from the hepatic lobule and its parenchymal cells, namely, portal venules, hepatic arterioles, sinusoids, central venules, and lymphatics.

Hepatic sinusoids: Unique exchange vessels in the liver composed of specialized nonparenchymal cells (sinusoidal endothelial cells, Kupffer cells, and stellate cells) that exhibit structural and functional heterogeneity.

Further Reading

Bloch, E. (1955). The in vivo microscopic vascular anatomy and physiology of the liver as determined with the quartz-rod method of transillumination. Angiology 6, 340-349. Bloch was involved in the earliest hepatic microcirculatory studies, the results of which are contained in this paper.

Clemens, M., and Zhang, J. (1999). Regulation of sinusoidal perfusion: In vivo methodology and control by endothelins. Semin. Liver Dis. 19, 383-396. A review of some of the current concepts concerning regulation of sinusoidal blood flow.

Ekataksin, W., Zou, Z., Wake, K., Chunhabundit, P., Somana, R., Nishida, J., and McCuskey, R. (1997). The hepatic microcirculatory subunits: An over-three-century-long search for the missing link between the exocrine unit and an endocrine unit in mammalian liver lobules. In Recent Advances in Microscopy ofCells, Tissues and Organs (P. Motta, ed.), pp. 407-412. Rome: University of Rome "La Sapienza." A review of the various functional unit concepts and the evidence for hepatic microvascular subunits.

Matsumoto, T., and Kawakami, M. (1982). The unit-concept of hepatic parenchyma—a reexamination based on angio architectural studies. Acta Pathol. Japon. 32, 285-314. Matsumoto first described subdividing the lobule into primary lobules.

McCuskey, R. (1994). The hepatic microvascular system. In The Liver: Biology and Pathobiology (I. Arias, J. Boyer, N. Fausto, W. Jakoby, D. Schachter, and D. Shafritz, eds), 3rd ed., pp. 1089-1106. New York: Raven Press. Comprehensive review of the structure and function of hepatic microvascular system in health and disease.

McCuskey, R. (2000). Morphologic mechanisms for regulating blood flow through hepatic sinusoids. Liver 20, 3-7. Review of morphologic sites for regulating sinusoidal blood flow and controversies.

McCuskey, R., and Reilly F. (1993). Hepatic microvasculature: Dynamic structure and its regulation. Semin. Liver Dis. 13, 1-12. Review of the effects of various substances and nerve stimulation of the hepatic microcirculation.

Rappaport, A. (1973). The microcirculatory hepatic unit. Microvasc. Res. 6, 212-228. Rappaport originated the concept of the acinus as the functional unit in the liver.

Wisse, E., Braet, F., Luo, D., DeZanger, R., Jans, D., Crabbe, E., and Vermoesen, A. (1996). Structure and function of sinusoidal lining cells in the liver. Toxicol. Pathol. 24, 100-111. Review of the structure and function of the cells that comprise the sinusoidal lining.

Wisse, E., DeZanger, R., Jacobs, R., Charels, K., Van der Smissen, P., and McCuskey, R. (1985). The liver sieve: Consideration concerning the structure and function of endothelial fenestrae, the sinusoid wall and the space of Disse. Hepatology 5, 683-692. Review of the structure and function of hepatic sinusoidal endothelium.

Capsule Biography

Robert S. McCuskey is Professor and Head of Cell Biology and Anatomy, as well as Professor of Physiology and Professor of Pediatrics, at the University of Arizona College of Medicine. During 2003-2005, he also is President of the American Association of Anatomists. Dr. McCuskey has been studying the hepatic microvasculature in health and disease for more than 40 years.

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