Inhibition of C5 or absence of C6 protects from sepsis mortality.
Inhibiting complement anaphlytoxin C5a during sepsis may prevent sepsis mortality. Although human anti-C5 antibodies exist, their therapeutic use in microbial sepsis has been avoided because of the hypothesis that inhibiting C5b will prevent formation of the bactericidal membrane attack complex (MAC) and worsen clinical outcome. We wished to test the hypothesis that inhibition of C5 would improve outcomes in sepsis. Sepsis was induced in rats by laparotomy and cecal ligation and puncture (CLP) by an IACUC-approved protocol. Sham animals underwent laparotomy without CLP. Following CLP rats were randomized to receive a single IV dose of purified IgG ant-C5 antibody (Ab) or control IgG Ab. Anti-C5 Ab treated rats (n = 20) had significantly lower mortality vs. controls (n = 21), 20% vs. 52% (P = 0.019, log-rank). Analysis of bacterial load by culture of spleen and liver homogenates showed a reduction in colony forming units in anti-C5 Ab treated rats vs. control IgG (P = 0.003 and 0.009, respectively). Anti-C5 treatment reduced lung injury as measured by total MPO content of lung tissue (P = 0.024). Finally, rats genetically deficient in C6 production, unable to form MAC but capable of producing C5a and C5b, were protected from CLP-induced sepsis mortality. Our results show that in anti-C5 antibody therapy prevents CLP sepsis-induced mortality and improves lung injury. Inhibition of the complement MAC does not increase bacterial load or mortality, therefore, the use of anti-C5 therapy may be beneficial rather than detrimental in sepsis.
Buras
Jon A
JA
Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. jburas@bidmc.harvard.edu
Rice
Lauren
L
Orlow
Daniel
D
Pavlides
Stavros
S
Reenstra
Wende R
WR
Ceonzo
Kathleen
K
Stahl
Gregory L
GL
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000276:immunology; D003183:Complement C6 / Q000172:deficiency / Q000235:genetics*; D015938:Complement Membrane Attack Complex / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology; D015536:Down-Regulation; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality*; D013154:Spleen / Q000382:microbiology; D015996:Survival Rate
D000906:Antibodies; D003182:Complement C5; D003183:Complement C6; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D015850:Interleukin-6