Inter-alpha-trypsin inhibitor attenuates complement activation and complement-induced lung injury.

Abstract

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.

• Authors: Stavros Garantziotis, John W Hollingsworth, Rami B Ghanayem, Sarah Timberlake, Lisheng Zhuo, Koji Kimata, David A Schwartz
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 6 Pg. 4187-92 (Sep 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17785858 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Alpha-Globulins
• Complement Inactivator Proteins
• Protein Subunits
• inter-alpha-inhibitor
• Complement System Proteins

Topics

• Alpha-Globulins (deficiency, genetics, metabolism, physiology)
• Animals
• Complement Activation (genetics, immunology)
• Complement Inactivator Proteins (deficiency, genetics, metabolism, physiology)
• Complement System Proteins (metabolism, toxicity)
• Female
• Immune Complex Diseases (immunology, metabolism, pathology, prevention & control)
• Lung (immunology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phagocytosis (immunology)
• Protein Binding (immunology)
• Protein Subunits (deficiency, genetics, metabolism, physiology)