Liposome-induced pulmonary hypertension: properties and mechanism of a complement-mediated pseudoallergic reaction

Intravenous injection of liposomes can cause significant pulmonary hyperten sion in pigs, a vasoconstrictive response that provides a sensitive model f or the cardiopulmonary distress in humans caused by some liposomal drugs. T he reaction was recently shown to be a manifestation of "complement activat ion-related pseudoallergy" (CARPA; Szebeni J, Fontana JL, Wassef NM, Mongan PD, Morse DS, Dobbins DE, Stahl GL, Bunger R, and Alving CR. Circulation 9 9: 2302-2309, 1999). In the present study we demonstrate that the compositi on, size, and administration method of liposomes have significant influence on pulmonary vasoactivity, which varied between instantaneously lethal (fo llowing bolus injection of 5 mg lipid) to nondetectable (despite infusion o f a 2,000-fold higher dose). Experimental conditions augmenting the pulmona ry hypertensive response included the presence of dimyristoyl phosphatidylg lycerol, 71 mol% cholesterol, distearoyl phosphatidylcholine, and hemoglobi n in liposomes, increased vesicle size and polydispersity, and bolus inject ion vs. slow infusion. The vasoactivity of large multilamellar liposomes wa s reproduced with human C3a, C5a, and xenoreactive immunoglobulins, and it correlated with the complement activating and natural antibody binding pote ntial of vesicles. Unilamellar, monodisperse liposomes with 0.19 +/- 0.10 m m mean diameter had no significant vasoactivity. These data indicate that l iposome-induced pulmonary hypertension in pigs is multifactorial, it is due to natural antibody-triggered classic pathway complement activation and it can be prevented by appropriate tailoring of the structure and administrat ion method of vesicles.