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 immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified.


RESULTS
Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (P<0.01) alterations included 79+/-9% (mean+/-SEM) rise in pulmonary arterial pressure, 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 thromboxane B2. These changes peaked between 1 and 5 minutes after injection, subsided 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 over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B2 and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes.


CONCLUSIONS
The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation-related pseudoallergy" (CARPA).
Szebeni
J
J
Department of Membrane Biochemistry, Walter Reed Army Institute of Research, Washington, DC, USA.
Fontana
J L
JL
Wassef
N M
NM
Mongan
P D
PD
Morse
D S
DS
Dobbins
D E
DE
Stahl
G L
GL
Bünger
R
R
Alving
C R
CR
D000818:Animals; D003167:Complement Activation / Q000187:drug effects; D015936:Complement C5a / Q000502:physiology*; D003165:Complement System Proteins / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000008:administration & dosage*; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology*; D007213:Indomethacin / Q000494:pharmacology; D007231:Infant, Newborn; D008081:Liposomes / Q000633:toxicity*; D011652:Pulmonary Circulation / Q000187:drug effects; D017464:Receptors, Complement 3d / Q000502:physiology*; D012127:Respiratory Distress Syndrome, Newborn / Q000209:etiology*; D013552:Swine; D013928:Thromboxane A2 / Q000096:biosynthesis
D006454:Hemoglobins; D008081:Liposomes; D017464:Receptors, Complement 3d; D013928:Thromboxane A2; D015936:Complement C5a; D003165:Complement System Proteins; D007213:Indomethacin