Role of the complement system in antigen-induced bronchoconstriction and changes in blood pressure in the guinea pig.
Systemic anaphylaxis involves life-threatening bronchoconstriction and a serious hypotensive response often complicated by cardiac arrhythmias. The purpose of the present study was to determine whether complement system activation is essential to the bronchoconstriction and the changes in blood pressure seen in guinea pig models of anaphylaxis. The soluble complement receptor 1 (sCR1; BRL 55730) was used to inhibit activation of the classical and alternative pathways of complement in the guinea pig, and to determine whether this inhibition prevents bronchoconstriction and changes in blood pressure induced by i.v. antigen injection in guinea pigs that are either passively or actively sensitized to the antigen ovalbumin. sCR1 at 15 mg/kg did not affect significantly either the antigen-induced bronchoconstriction or the changes in blood pressure in a guinea pig passively sensitized with immunoglobulin G antibody to ovalbumin. However, it shortened the duration of the antigen-induced increase in blood pressure and inhibited the antigen-induced decrease in circulating platelets in an actively sensitized guinea pig. Continued studies using a cumulative dose of sCR1 of 105 mg/kg administered over a 24-hr period demonstrated that sCR1 attenuated the bronchoconstrictor response and the decrease in circulating platelets and prevented the hypotension induced by antigen in an actively sensitized guinea pig. At a cumulative dose of 105 mg/kg, sCR1 did not inhibit the bronchoconstrictor or blood pressure response to either histamine or bradykinin, indicating that its attenuation of cardiovascular and respiratory reactivity is specific for complement-related processes. The anaphylactic response was accompanied by complement activation as evidenced by cleavage of the C3 molecule. In the presence of sCR1, no C3 cleavage products were detectable in the plasma. Our studies demonstrate that complement activation is an essential step in the antigen-induced bronchoconstriction and the changes in blood pressure in an actively sensitized guinea pig model of anaphylaxis. Continued studies of the differing mechanisms and mediators of anaphylaxis are of importance, and the complement system clearly warrants consideration as a source of those mediators.
Regal
J F
JF
Department of Pharmacology, University of Minnesota, Duluth.
Fraser
D G
DG
Toth
C A
CA
D000818:Animals; D000906:Antibodies / Q000032:analysis; D000941:Antigens / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D016084:Bronchoconstriction / Q000502:physiology*; D003167:Complement Activation / Q000187:drug effects; D003176:Complement C3 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D003165:Complement System Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007114:Immunization; D007275:Injections, Intravenous; D008297:Male; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology*; D011951:Receptors, Complement / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D012995:Solubility
D000906:Antibodies; D000941:Antigens; D003176:Complement C3; D003169:Complement Inactivator Proteins; D011951:Receptors, Complement; D011994:Recombinant Proteins; C082885:soluble complement inhibitor 1; D012710:Serum Albumin, Bovine; D006632:Histamine; D010047:Ovalbumin; D003165:Complement System Proteins; D001920:Bradykinin