Protective effects of soluble CR1 in complement- and neutrophil-mediated tissue injury.
Complement activation is an important step for triggering of acute inflammatory reactions. Soluble human recombinant complement receptor type 1 (sCR1) blocks complement activation by both classical and alternative pathways. In addition to glycogen-induced peritonitis, three models of complement-dependent acute inflammatory injury have been used to assess the protective effects of sCR1: lung and dermal injury after intraalveolar or intradermal deposition of IgG immune complexes; acute lung injury resulting from intravascular activation of complement after the i.v. injection of cobra venom factor; and acute skin and lung injury (at 4 h) after thermal trauma involving 25 to 30% total body surface area. Vascular injury was quantified by increases in vascular permeability, hemorrhage, neutrophil infiltration, and, as indicated, tissue water content. Intravenous infusion of sCR1 reduced lung and dermal vascular injury in all models studied. In glycogen-induced peritoneal exudates sCR1-reduced neutrophil accumulation by 79%. In animals undergoing IgG immune complex-induced alveolitis, sCR1 treatment reduced vascular permeability and hemorrhage by 72 and 71%, respectively, and tissue accumulation of neutrophils was reduced by 68%. After cobra venom factor injection, sCR1 reduced increases in lung vascular permeability by 67%, hemorrhage by 73%, and lung myeloperoxidase content by 55%. Four hours after thermal injury of skin, sCR1-treated animals demonstrated significant protection against lung injury; increases in vascular permeability and hemorrhage were reduced by 45 and 46%, respectively, and myeloperoxidase content was lowered by 39%. In thermal injury of the skin, sCR1 injection reduced dermal vascular permeability by 25% at 1 h (p = NS) and 44% at 4 h. Water content in skin biopsies was also decreased. There was a dose-response relationship between the amount of sCR1 infused and the extent of protection in each of the injury models. These data demonstrate that sCR1 offers significant protection against complement-dependent tissue injury in the animal models studied and that the protective effects are related to reduced neutrophil content.
Mulligan
M S
MS
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
Yeh
C G
CG
Rudolph
A R
AR
Ward
P A
PA
D000818:Animals; D000936:Antigen-Antibody Complex / Q000502:physiology; D002056:Burns / Q000503:physiopathology; D003165:Complement System Proteins / Q000502:physiology*; D004546:Elapid Venoms / Q000633:toxicity; D006003:Glycogen / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011951:Receptors, Complement / Q000032:analysis; D017463:Receptors, Complement 3b; D011994:Recombinant Proteins / Q000494:pharmacology
D000936:Antigen-Antibody Complex; D004546:Elapid Venoms; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D011994:Recombinant Proteins; C016310:cobra venom factor; D006003:Glycogen; D003165:Complement System Proteins; D009195:Peroxidase