ATTENUATION OF SHOCK-INDUCED INFLAMMATION IN THE RAT-LIVER DEPENDS ONTHE TIME OF TNF-ALPHA INHIBITION

The relevance of tumor necrosis factor-a (TNF-alpha) inducing early in flammatory reactions in the liver after hemorrhagic shock, for example , leukocyte adhesion, has been well described. This study evaluated th e anti-inflammatory effects of a monoclonal antibody against TNF-alpha (TN3.19.12) in terms of the time of application, namely, prior to sho ck induction, at the time of resuscitation, and after resuscitation. T he hepatic microcirculation was investigated by intravital fluorescenc e microscopy in female Sprague-Dawley rats undergoing severe hemorrhag ic shock for 60 min and subsequent resuscitation. TN3.19.12 or placebo was given in a randomized and blinded manner either 60 min prior to s hock induction, 1 min prior to resuscitation, or 15 min after the onse t of resuscitation. The number of firmly adherent leukocytes in the li vers of treated animals depended on the time of application of TN3.19. 12. Leukocyte adhesion was significantly reduced when TN3.19.12 was gi ven prior to shock induction or at the time of resuscitation and was l ess effective when administered after the onset of resuscitation. The results further confirm that TNF-a initiates very early pathological l eukocyte adhesion in the liver 5 h following shock. Inhibition of leuk ocyte adhesion after shock, however, depends strongly on the time of T NF-alpha blocking. While TN3.19.12 prior to shock induction resulted i n most effective attenuation, only very early treatment allowed limita tion of posttraumatically increased leukocyte adhesion.