[Preclinical investigation of alpha 1-acid glycoprotein (orosomucoid)].
The molecular properties of alpha 1-acid glycoprotein are briefly discussed. This molecule has been shown in in vitro experiments to have both a stabilizing effect on vascular permeability and antiinflammatory properties. We were able to demonstrate these two effects in vivo in guinea pigs (skin, Evan's Blue extravasation) and in rats (paw, carrageenan induced inflammation). Further experiments were performed in rats relating to possible therapeutic indications for alpha 1-acid glycoprotein: (1) inhibitory effect on brain edema formation after experimental stroke, (2) therapeutic effect in the puromycin aminonucleoside-induced minimal change nephrosis, (3) improvement of vital parameters in hemorrhagic-hypovolemic shock, (4) increase in survival rate in septic peritonitis, and (5) promising effects in burn-induced remote lung injury. The high content of sialic acid and the high negative charge of alpha 1-acid glycoprotein are believed to be major contributors to its stabilizing effect on vascular permeability. The protein is bound to the glycocalyx of the endothelial cells (and presumably to structures of the glomerular basement membrane), thereby hindering the passage of other polyanionic molecules through the vascular wall. The antiinflammatory/immunomodulatory effect of alpha 1-acid glycoprotein appears mainly due to suppression of polymorphonuclear neutrophils. This action is dependent on the glycan part of the molecule, which is highly variable (microheterogeneity). It is obvious that there are differences between the different glycan forms as far as the antiinflammatory property of the protein is concerned. Together with data in the literature, the results presented here suggest a variety of potential indications for therapeutic use of alpha 1-acid glycoprotein in humans.
Pichler
L
L
Hauptabteilung Pharmakologie/Toxikologie/Präklinik, Baxter Hyland Immuno, Wien, Osterreich.
Muchitsch
E M
EM
Schwarz
H P
HP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000150:complications; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D006168:Guinea Pigs; D009504:Neutrophils / Q000187:drug effects; D009961:Orosomucoid / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
D000893:Anti-Inflammatory Agents; D009961:Orosomucoid