Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat.

Abstract

Cytokines are recognized as critical early mediators of organ injury. We attempted to determine whether or not severe hepatic ischemia/reperfusion injury results in tumor necrosis factor-a (TNF-a) release with subsequent local and systemic tissue injury. After 90 min of lobar hepatic ischemia, TNF was measurable during the reperfusion period in the plasma of all 14 experimental animals, with levels peaking between 9 and 352 pg/ml. Endotoxin was undetectable in the plasma of these animals. Pulmonary injury, as evidenced by a neutrophilic infiltrate, edema and intra-alveolar hemorrhage developed after hepatic reperfusion. The neutrophilic infiltrate was quantitated using a myeloperoxidase (MPO) assay; this demonstrated a significant increase in MPO after only 1 h of reperfusion. Anti-TNF antiserum pretreatment significantly reduced the pulmonary MPO after hepatic reperfusion. After a 12-h reperfusion period, there was histologic evidence of intra-alveolar hemorrhage and pulmonary edema. Morphometric assessment showed that pretreatment with anti-TNF antiserum was able to completely inhibit the development of pulmonary edema. Liver injury was quantitated by measuring serum glutamic pyruvic transaminase which showed peaks at 3 and 24 h.Anti-TNF antiserum pretreatment was able to significantly reduce both of these peak elevations. These data show that hepatic ischemia/reperfusion results in TNF production, and that this TNF is intimately associated with pulmonary and hepatic injury. (J. Clin. Invest. 1990Invest. . 85:1936Invest. -1943.) hepatic injury -ischemia * lung injury -reperfusion * tumor necrosis factor

Protective effect of prednisolone on ischemia-induced liver injury in rats

“…Various factors such as the reactive oxygen species [19] , platelet-activating factor [20] , thromboxane A 2 [21] , leukotriene B 4 [22] and endothelin-1 [23] have been identified. In addition, inflammatory cytokines like interleukin-1β and tumor necrosis factor-α also play an important role in hepatic ischemia-reperfusion injury [17] . All these substances induce a rise in [Ca 2+ ] i .…”

“…Although the molecular mechanisms of bleb formation are unknown at present, Ca 2+ -dependent disruption of the cytoskeleton is considered to play an important role in the blebbing of plasma membrane [8,9] . Calpain μ, a Ca 2+ -sensitive for m of Ca 2+ -activated neutral protease (EC 3,4,22,17), has been shown to degrade various cytoskeletal proteins such as talin, α-actinin and filamin [10][11][12][13][14] .…”

“…This inhibition is mediated by the induction of IκBα inhibitory protein, which traps activated NF-κB in inactive cytoplasmic complexes. On the other hand, inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, are involved in the pathophysiolog y of hepatic ischemia-reperfusion injury [17] . The liver also plays a central role in the metabolism of these acute reactant cytokines.…”

“…The liver also plays a central role in the metabolism of these acute reactant cytokines. In the liver, these mediators are produced in large amounts by Kupffer cells or endothelial cells [18] , and are released rapidly under various insults like hypoxia [17] .…”

FK 506 pre-treatment is associated with reduced levels of tumor necrosis factor and interleukin 6 following hepatic ischemia/reperfusion

“…Previous studies have reported that TNF not only has a deleterious effect on hepatocytes but also has damaging pulmonary effects resulting in pulmonary neutrophil sequestration and hemorrhagic edema (42,43). This observation may be of clinical importance especially in the field of transplantation as primary non-function of the graft is associated frequently with the rapid development of pulmonary insufficiency (46).…”