Attenuation of endothelium-dependent dilation of pig pulmonary arterioles after cardiopulmonary bypass is prevented by monoclonal antibody to complement C5a.
We examined whether pulmonary endothelial dysfunction associated with cardiopulmonary bypass (CPB) may be mediated by complement C5a in pigs. Pigs were placed on normothermic CPB for 1 h with or without a previous administration of 1.6 mg/kg anti-C5a monoclonal antibody (MAb), then reperfused for 2 h. Pulmonary tissue myeloperoxidase activity was measured. Expression of nitric oxide synthase (NOS) was measured by reverse transcriptase polymerase chain reaction and Western blotting. Pulmonary arterioles approximately 100 microm in diameter were preconstricted with the thromboxane analog U46619 1 microM, and relaxation responses to adenosine diphosphate 10(-9)-10(-4) M, substance P 10(-12)-10(-6) M, and sodium nitroprusside 10(-9)-10(-4) M were examined in vitro by videomicroscopy. Relaxation to the endothelium-dependent dilators adenosine diphosphate and substance P was attenuated after CPB; this attenuation was prevented by the previous administration of MAb. Relaxation to sodium nitroprusside was not affected by CPB. Neutrophil sequestration, as measured by MPO activity, increased after CPB, either with or without MAb. Transcription of NOS was unchanged by CPB, but translation of constitutive NOS was decreased after CPB, and this decrease was prevented by a previous administration of MAb. We conclude that pig pulmonary endothelial dysfunction associated with CPB may be mediated by C5a. The mechanism may involve changes in NOS translation.


CONCLUSIONS
In pigs, pulmonary endothelial dysfunction may occur after cardiopulmonary bypass due to product(s) of complement activation.
Park
K W
KW
Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center and Center for Experimental Therapeutics and Reperfusion Injury, Harvard Medical School, Boston, Massachusetts 02215, USA. kpark@caregroup.harvard.edu
Tofukuji
M
M
Metais
C
C
Comunale
M E
ME
Dai
H B
HB
Simons
M
M
Stahl
G L
GL
Agah
A
A
Sellke
F W
FW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001160:Arterioles / Q000503:physiopathology; D002315:Cardiopulmonary Bypass; D015936:Complement C5a / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D008168:Lung / Q000098:blood supply*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D013552:Swine; D014664:Vasodilation
D000911:Antibodies, Monoclonal; D015936:Complement C5a; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III