Hemodynamic changes induced by liposomes and liposome-encapsulated hemoglobin in pigs - A model for pseudoallergic cardiopulmonary reactions to liposomes: Role of complement and inhibition by soluble CR1 and anti-C5a antibody

Background-Intravenous administration of some liposomal drugs can trigger i mmediate hypersensitivity reactions that include symptoms of cardiopulmonar y distress. The mechanism underlying the cardiovascular changes has not bee n clarified. Methods nod Results-Anesthetized pigs (n=18) were injected intravenously wi th 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynam ic, hematologic, and laboratory changes were recorded. The significant (P<0 .01) alterations included 79+/-9% (mean+/-SEM) rise in pulmonary arterial p ressure, 30+/-7% decline in cardiac output, 11+/-2% increase in heart rate, 236+/-54% increase in pulmonary vascular resistance, 71+/-27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma throm boxane B-2. These changes peaked between and 5 minutes after injection, sub sided within 10 to 20 minutes, were lipid dose-dependent (ED50=4.5+/-1.4 mg ), and were quantitatively reproducible in the same animal several times ov er 7 hours. The liposome-induced rises of pulmonary arterial pressure showe d close quantitative and temporal correlation with elevations of plasma thr omboxane B-2 and were inhibited by an anti-C5a monoclonal antibudy (GS1), b y sCR1 or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound Ige and IgM natural anti bodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes ca used essentially identical pulmonary changes. Conclusions-The intense, nontachyphylactic, highly reproducible, complement -mediated pulmonary hypertensive effect of minute amounts of intravenous li posomes in pigs represents a unique, unexplored phenomenon in circulation p hysiology. The model provides highly sensitive detection and study of cardi opulmonary side effects of liposomal drugs and many other pharmaceutical pr oducts due to "complement activation-related pseudoallergy" (CARPA).