Microcirculatory Failure Determines Lethal Hepatocyte Injury in Ischemic/Reperfused Rat Livers

Chun, Karen; Zhang, Jain; Biewer, James; Ferguson, David; Clemens, Mark G.

doi:10.1097/00024382-199401000-00002

Cited by 91 publications

(67 citation statements)

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“…8,9 In the present study, measures of ALT (mild-through-severe injury) provided evidence of injury as early as 1.5 hours into limb reperfusion. After 3 hours of reperfusion, such injury was confirmed by direct evaluation of cell death using fluorescence intravital microscopy.…”

Section: Discussionsupporting

confidence: 51%

“…[5][6][7] In fact, studies have suggested that such perfusion deficits were an essential first step toward injury to the liver parenchyma. 8,9 However, work by our laboratory and others have been unable to provide a link between perfusion deficits and remote organ injury. For example, remote injury to the mucosa of the small intestine has been reported during sepsis, despite unaltered microvascular perfusion.…”

mentioning

confidence: 95%

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Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor-α, and microvascular perfusion

et al. 1999

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Severe trauma may initiate a systemic inflammatory response, which in turn may result in remote organ injury. After limb ischemia/reperfusion (I/R), intravital fluorescence microscopy was applied to the livers of normotensive rats to investigate the initiation of remote injury to the liver. Additionally, we determined whether Kupffer cell activation and tumor necrosis factor-␣ (TNF-␣) were involved, via perfusion deficits, in such injury. TNF-␣, measured by immunoassay, peaked at 30 minutes of reperfusion, but returned to baseline within 60 minutes. Limb I/R resulted in significant increases to global hepatocellular injury measured by alanine transaminase (ALT) and lethal hepatocyte injury as seen with intravital fluorescence microscopy. Although the number of perfused sinusoids went unchanged, a significantly augmented perfusion heterogeneity was measured. After 1.5 hours of reperfusion, both TNF-␣ and Kupffer cells were shown to contribute to global hepatocellular injury (e.g., ALT). After 3 hours, TNF-␣ was no longer essential for this injury, suggesting that some other mechanism(s) activated Kupffer cells and initiated hepatocellular injury. Using propidium iodide and fluorescence microscopy, we found that both TNF-␣ and Kupffer cell activation were necessary to drive hepatocytes toward lethal injury. No additional benefits were observed with a combination of TNF-␣ inhibition and Kupffer cell suppression. These results not only implicate both Kupffer cells and TNF-␣ in the initiation of remote hepatic injury, but suggest that sinusoidal perfusion deficits are not essential for the initiation of such injury. Other mechanism(s) are likely involved in the pathogenesis of remote hepatic parenchymal injury. (HEPATOLOGY 1999;30:137-142.)

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 95%

Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor-α, and microvascular perfusion

et al. 1999

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“…It is reported that physical prevention of microvascular shutdown by flow-constant perfusion markedly reduces hepatic postischemic microvascular disturbance, which led to the attenuation of hepatocellular necrosis. 37 In this experiment, the perfusate was free of leukocytes, and its hematocrit was adjusted to 7% to 10%, whereas in our study, a pronounced postischemic deterioration of hepatic microcirculation was evidenced, because the whole blood including leukocytes was used as the perfusate. Considering that restoration of nutritive blood flow is a critical determinant of cell viability after the cessation of flow, the inhibitory effect of hyperthermic preconditioning on postischemic sinusoidal perfusion failure and sinusoidal vasoconstriction can be mediated by a dilatory effect of HO-1/HSP32.…”

Section: Resultsmentioning

confidence: 68%

Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of the rat liver

et al. 2000

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Sublethal hyperthermia and the following recovery from this heat exposure, referred to as hyperthermic preconditioning, elicits a transient state of tolerance to oxidative insults through an intracellular protective response: stress response. The impact of hyperthermic preconditioning on hepatic microcirculatory disturbance, which is one of the determinants of ischemia/reperfusion-induced injury of the liver, was investigated by using intravital fluorescence microscopy. Thirty minutes of ischemia and a subsequent 120 minutes of reperfusion was induced in an in situ isolated perfusion model of Sprague-Dawley rats. Heat stress was given by whole-body hyperthermia, and a subsequent recovery was allowed for 18 or 48 hours, respectively. Postischemic decrease in sinusoidal perfusion rate and sinusoidal diameter, leukocyte stagnation in sinusoids, and leukocyte adhesion in postsinusoidal venules were significantly attenuated in both hyperthermia-pretreated groups. A recovery of bile production, a reduction of liver enzyme release, and an attenuation of tissue edema and histological damage were also observed. A marked expression of heat shock protein (HSP) 70 and heme oxygenase (HO-1)/HSP32 was correlatively observed in the liver tissue coincident with the induction of these protective effects. Hyperthermic preconditioning provides a continuous long-term and constant inhibitory effect (up to 48 hours after heat exposure) on postischemic injury of the liver through the attenuation of microcirculatory disturbances. These beneficial effects might be associated with a concomitant increase in HSP70 and HO-1/HSP32 expression. (HEPATOLOGY 2000;31:407-415.)Ischemia/reperfusion-induced injury is one of the major perioperative complications in liver surgery and liver transplantation. The administration of specific protective agents has been attempted to reduce postischemic hepatic injury. [1][2][3] To the contrary, preconditioning therapies based on an endogenous protection response against stressful events, referred to as heat stress response, have been studied as another therapeutic strategy. Hyperthermic preconditioning, the exposure to a transient sublethal hyperthermia, and the following appropriate recovery develops protection not only to subsequent thermal stress, but also to oxidative stress such as ischemia/reperfusion. [4][5][6][7][8] Heat stress response has been reported to be associated with the induction of specific heat shock proteins (HSPs). In particular, HSP70 is generally considered to contribute to the protective mechanism of hyperthermic preconditioning, based on the finding that overexpression of HSP70 in a transgenic mouse increases the resistance of the heart to ischemic injury. 9,10 Heme oxygenase (HO)-1/HSP32 is another HSP playing a role in the modulation of the inflammatory response. HO catabolizes intracellular heme to biliverdin, which is converted to bilirubin by bilirubin reductase. During this degradation process, carbon monoxide (CO) is released. 11 HO consists of HO-1 (inducible isoenzyme) and ...

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“…The integrity of the microcirculation after graft reperfusion is dependent on the effects of inflammatory and oxidant stresses on the vasculature. 106 Inflammatory stresses occur in response to mediators released by activated neutrophils and KC, while oxidant stresses occur from the generation of toxic-free radicals. [107][108][109] These stresses affect sinusoidal blood flow by creating imbalances between vasoactive mediators, resulting in the development of focal hypoperfusion, ischemia, and necrosis in the liver.…”

Section: Hepatic Microvascular Responses To Endotoxemia and Ethanolmentioning

confidence: 99%

The hepatic circulation in health and disease: Report of a single-topic symposium

et al. 1998

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Microcirculatory Failure Determines Lethal Hepatocyte Injury in Ischemic/Reperfused Rat Livers

Cited by 91 publications

References 0 publications

Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor-α, and microvascular perfusion

Initiation of remote hepatic injury in the rat: Interactions between Kupffer cells, tumor necrosis factor-α, and microvascular perfusion

Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of the rat liver

The hepatic circulation in health and disease: Report of a single-topic symposium

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