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

Abstract

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.)

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

“…As previously described, renal peritubular capillary perfusion was analysed using a stereological point-counting grid, such that the density of points counted was proportional to the density of peritubular capillaries within the viewing fi eld [ 27 ] . Capillaries were selected by drawing three parallel lines on the video monitor perpendicular to the capillary axis and counting all capillaries that crossed.…”

Effect of the Portacaval Shunt on Reperfusion Injury after 65% Hepatectomy in Pigs

“…TNF-␣ is known to play a major role in neutrophil and Kupffer cell activation and cytokine production during I/R injury [24] . TNF-␣ seems to be essential in initiating this injury and its levels fall substantially after 3 h of reperfusion [25] . The levels of the hepatoprotective IL-6 that acts by downregulating TNF-␣ [26] peaked at 3 h of reperfusion in group A and at 12 h in group B, with group B values outnumbering those of group A at 6 and 12 h ( fig.…”

Low-dose inhaled carbon monoxide attenuates the remote intestinal inflammatory response elicited by hindlimb ischemia-reperfusion

“…However, despite extensive investigation, few clinical therapeutic options currently exist to prevent and/or alleviate the detrimental consequences of this response. Experimental evidence suggests that blocking key components of the inflammatory cascade, such as proinflammatory cytokine expression, leukocyte recruitment, and/or lipid peroxidation, may represent effective strategies to preserve the integrity of such organs during SIRS (3,5,6,10,12,13,23,24,31). Therefore, the discovery of novel therapeutics that mimic this protective phenotype may represent essential tools in the prevention of MODS.…”