Ischemic damage to the GI tract occurs when splanchnic blood flow falls to a level at which delivery of oxygen and other nutrients is insufficient to maintain oxidative metabolism and hence cell integrity. Reduced blood flow to the gastrointestinal tract may occur during generalized nonocclusive ischemia (e.g., circulatory shock and congestive heart failure, especially in those treated with cardiac glycosides) and in occlusive disorders (e.g., emboli, atherosclerosis, thrombosis) that primarily involve the mesenteric circulation. Occlusion of a major intestinal artery does not result in the expected reduction in intestinal blood flow. In adult animals, occlusion of a branch of the superior mesenteric artery results in only a 30 to 50 percent reduction in intestinal blood flow, which is attributed to the extensive network of intramural and extramural collateral channels. In neonatal animals, which have less developed collateral channels, a similar arterial occlusion reduces intestinal blood flow by 70 percent. This may explain why the neonatal intestine is more vulnerable to ischemic necrosis than adult intestine.
Increases in the capillary filtration coefficient and a reduction in the osmotic reflection coefficient have been demonstrated in the GI tract after I/R. The permeability response is derived from an increase in the number of large (200 Á radius) pores, while the small-pore (50 Á radius) population is unaffected. In the intestine, the increase in the capillary filtration coefficient observed after I/R is not solely a result of increased capillary surface area.
Ischemic injury in the intestine appears to be related, either primarily or secondarily, to the effects of tissue hypoxia. Possible mechanisms of mucosal injury induced by tissue hypoxia include depletion of high-energy phosphates necessary to produce protective substances; accumulation of histamine, leading to increased microvascular permeability; production of metabolic acidosis, leading to release of lysosomal enzymes and cellular digestion; conversion of xanthine dehydrogenase to xanthine oxidase, an enzyme that can produce cytotoxic oxygen-derived free radicals during reoxygenation; and the attraction and activation of circulating granulocytes that can injure tissue by producing proteases and oxidants. There is considerable evidence that implicates both reactive oxygen species and infiltrating granulocytes in I/R injury in the GI tract. The I/R-induced microvascular responses in the GI tract are comparable to those observed during an intense inflammatory response. With the reintroduction of molecular oxygen at reperfusion endothelial cells assume both a proinflammatory and pro-thrombogenic phenotype that is characterized by the recruitment of adherent leukocytes and platelets in postcapillary venules. The platelets act to amplify the neutrophil activation response while neutrophils per se appear to mediate the endothelial barrier dysfunction associated with I/R. Extravasated neutrophils then contribute to the mucosal dysfunction and epithelial cell necrosis after I/R by releasing a variety of proteases and reactive oxygen metabolites.
Whereas an acute elevation in portal venous pressure is likely to elicit a myogenic-mediated constriction of splanchnic arterioles, chronic portal hypertension tends to exert a vasodilatory influence on the splanchnic vasculature. Furthermore, chronic portal hypertension has a significant impact on other regional vascular beds and on systemic hemodynamics. Blood flow to the gastrointestinal tract, kidneys, and skeletal muscle is significantly elevated. This presumably results from an increase in circulating vasodilators (e.g., glucagon) and a decrease in vascular sensitivity to vasoconstrictors (e.g., norepinephrine). The widespread dilation of arterioles results in a reduction of peripheral vascular resistance and a corresponding reduction of arterial blood pressure. In addition, cardiac output is elevated as a consequence of the increased venous return associated with the splanchnic and peripheral vasodilation. The elevated portal pressure results in the opening of portosystemic shunts to divert portal blood from the liver and reduce portal pressure. The increase in portal pressure impairs venous drainage from the spleen into the portal vein. This results in the accumulation of blood within, and distension of, the spleen (splenomegaly).
Organ blood flow is determined by the arterial-venous pressure gradient and vascular resistance. It follows then that portal pressure is determined by portal venous inflow and portal venous resistance. When portal vascular resistance is normal, an increase in portal venous flow will produce a proportional increase in portal pressure. However, when portal vascular resistance is increased, the relationship between portal pressure and portal venous flow is shifted upward and to the left. At any given portal venous inflow, an increased portal vascular resistance will result in an increase in portal pressure. Portal pressure can be further increased when there is a concomitant increase in portal venous flow and portal vascular resistance. Indeed, the latter instance appears to reflect the vascular changes that account for the elevated portal pressure that is observed in some experimental models of chronic portal hypertension and is likely to account for the portal hypertension associated with some forms of liver disease. With a portal vascular resistance that is 40 percent higher in the portal hypertensive than in the control state, it is predicted that increased portal inflow and increased portal vascular resistance account for 40 percent and 60 percent of the increase in portal pressure, respectively.
The portal hypertensive state leads to the development of collaterals (mostly along the esophagus; esophageal varices) to shunt blood from the congested portal vein, around the liver, to the systemic circulation (portosystemic shunting). Since a large proportion of portal venous blood bypasses the liver via portosystemic shunting, the hepatic degradation of different compounds, including circulating vasodilators, such as glucagon, is reduced. The diminished catabolism of circulating vasodilators increases their concentration in the plasma, allowing these agents to relax arteriolar vascular smooth muscle and reduce splanchnic vascular resistance. Another important action of some of the vasodilators that accumulate in chronic portal hypertension (e.g., glucagon) is to reduce the sensitivity of splanchnic arterioles to vasoconstrictors such as norepinephrine, vasopressin, and angiotensin. The net result of the direct and indirect actions of the accumulated circulating vasodilators is an increased splanchnic blood flow, which serves to perpetuate the portal hypertensive state.
Chyme: Hydrolytic products of food within the lumen of the intestine.
Portal hypertension: An abnormal elevation of hydrostatic pressure within the portal veins that drain the GI tract and empty into the liver.
Portosystemic shunting: Diversion of blood flow from the portal vein away from the liver, through either existing or newly formed channels (shunts).
Postprandial hyperemia: Increase in gastrointestinal blood flow that results from ingestion of a meal.
Reperfusion: The restoration of tissue blood flow following a period of ischemia.
Abdel-Salam, O. M., Czimmer, J., Debreceni, A., Szolcsanyi, J., and Mozsik, G. (2001). Gastric mucosal integrity: Gastric mucosal blood flow and microcirculation. An overview. J. Physiol. Paris 95, 105-127. This article summarizes evidence implicating the gastric microcirculation in protecting the gastric mucosa against ulcer formation. Carden, D. L., and Granger, D. N. (2000). Pathophysiology of ischemia-reperfusion injury. J. Pathol. 190, 255-266. This article provides a detailed review of the mechanisms that have been implicated in the pathogenesis of ischemia-reperfusion in the gastrointestinal tract. Crissinger, K. D., and Granger, D. N. (1999). Gastrointestinal blood flow. In Textbook of Gastroenterology (T. Yamada, ed.), pp. 519-546. Baltimore: Lippincott, Williams & Wilkins. Granger, D. N., Kvietys, P. R., Korthuis, R. J., and Premen, A. J. (1989). Microcirculation of the intestine. In Handbook of Physiology. Section 6, The Gastrointestinal System, Vol. 1: Motility and Circulation, Part 2, pp. 1405-1474.
Holzer, P., Livingston, E. H., and Guth, P. H. (1994). Neural, metabolic, physical, and endothelial factors in the regulation of gastric circulation.
In: Physiology of the Gastrointestinal Tract (L. R. Johnson, ed.), pp. 1311-1330. New York: Raven Press. An excellent summary of the factors that regulate blood flow in the stomach. Tepperman, B. L., and Jacobson, E. D. (1994). Circulatory factors in gastric mucosal defense and repair. In: Physiology of the Gastrointestinal Tract (L. R. Johnson, ed.), pp. 1331-1352. New York: Raven Press
Thorsten Vowinkel earned his M.D. degree from the University of Würzburg, Germany. He is a resident at the Department of General Surgery, University of Münster, Germany, and currently works as a postdoctoral fellow at the Department of Molecular and Cellular Physiology at Louisiana State University Health Sciences Center in Shreveport. His research interests include microvascular responses to intestinal ischemia-reperfusion and inflammation.
D. Neil Granger, Ph.D., is Boyd Professor and Head of the Department of Molecular and Cellular Physiology at Louisiana State University Health Sciences Center in Shreveport. He has served as President of the Micro-circulatory Society, Editor-in-Chief of Microcirculation, and was elected to serve as President of the American Physiological Society
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