Inter-alpha-trypsin inhibitor attenuates complement activation and complement-induced lung injury.
Complement activation is a central component of inflammation and sepsis and can lead to significant tissue injury. Complement factors are serum proteins that work through a cascade of proteolytic reactions to amplify proinflammatory signals. Inter-alpha-trypsin inhibitor (IaI) is an abundant serum protease inhibitor that contains potential complement-binding domains, and has been shown to improve survival in animal sepsis models. We hypothesized that IaI can bind complement and inhibit complement activation, thus ameliorating complement-dependent inflammation. We evaluated this hypothesis with in vitro complement activation assays and in vivo in a murine model of complement-dependent lung injury. We found that IaI inhibited complement activation through the classical and alternative pathways, inhibited complement-dependent phagocytosis in vitro, and reduced complement-dependent lung injury in vivo. This novel function of IaI provides a mechanistic explanation for its observed salutary effects in sepsis and opens new possibilities for its use as a treatment agent in inflammatory diseases.
Garantziotis
Stavros
S
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. garan001@mc.duke.edu
Hollingsworth
John W
JW
Ghanayem
Rami B
RB
Timberlake
Sarah
S
Zhuo
Lisheng
L
Kimata
Koji
K
Schwartz
David A
DA
D000510:Alpha-Globulins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D003169:Complement Inactivator Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003165:Complement System Proteins / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology