Previously, we observed in a rat model that intravenous administration of intramuscular immunoglobulin preparations induced a long-lasting hypotension, which appeared to be associated with the presence of IgG polymers and dimers in the preparations, but unrelated to complement activation. We found evidence that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different manufacturers, in anesthetized rats. Eight of the IVIG preparations showed no hypotensive effects (less than 15% decrease), whereas the other 8 had relatively strong effects (15%-50% decrease). The hypotensive effects correlated with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypotensive reaction on IVIG infusion, and administration after the onset of hypotension resulted in normalization of the blood pressure. We also observed PAF production on in vitro incubation of human neutrophils with IVIG, which could be blocked by anti-Fcγ receptor antibodies. This indicates that induction of PAF generation may also occur in a human system. Our findings support the hypothesis that the clinical side effects of IVIG in patients may be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fcγ receptors. Because phagocyte activation may also lead to the release of other inflammatory mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for the treatment of those adverse reactions.
In the present study we investigated the therapeutic action of antithrombin III (AT III) in taurocholate-induced experimental pancreatitis with high lethality in rats. High-dose AT III treatment greatly improved the survival rate not only when given as pretreatment but also when given 2 hr after induction. No favorable effect on survival rate was observed on administration after 5 hr. Both intravascular and intraperitoneal AT III administration locally restored decreased AT III levels in the peritoneal cavity and increased plasma AT III to supranormal levels. The primary pancreatic insult seemed to be unaffected by the treatment, because neither the rise in plasma lipase nor the development of ascites or the extension of the pancreatic necrosis were diminished. Because heparin pretreatment of the rats was also effective, the mechanism of the beneficial action was probably mediated by inhibition of the proteases of the coagulation cascade, thereby preventing intravascular coagulation in the pancreas and distant organs and subsequent systemic complications. The high efficacy of AT III treatment in this experimental model may stimulate clinical studies evaluating the efficacy of AT III treatment in an early stage of acute pancreatitis.
C1-inhibitor is the only known inhibitor of the classical pathway of complement and the major inhibitor of the contact pathway of coagulation. Like other serine proteinase inhibitors, C1-inhibitor can exist in three conformations, ie, the native, the proteinase-complexed, and the proteolytically inactivated form. Here we studied the plasma elimination kinetics of these three forms of human C1-inhibitor in rats. The clearance of the complexed form of C1-inhibitor appeared to be the most rapid and depended in part on the proteinase involved (observed plasma t1/2 was 20 minutes for C1s-C1-inhibitor, 32 minutes for kallikrein-C1-inhibitor, and 47 minutes for beta XIIa-C1- inhibitor), whereas that of native C1-inhibitor was the slowest (observed plasma t1/2 4.5 hours). Inactivated C1-inhibitor was cleared with an apparent plasma t1/2 of 1.6 hours. Thus, the short plasma t1/2 of complexed relative to native C1-inhibitor explains why in patients only low concentrations of C1-inhibitor complexes may be observed despite activation of the contact and/or complement systems.
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