The Inter-α-Trypsin Inhibitor Family: Versatile Molecules in Biology and Pathology

Abstract

<jats:p> Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a complex containing the proteoglycan bikunin to which heavy chain proteins are covalently attached to the chondroitin sulfate chain. Besides its matrix protective activity through protease inhibitory action, IαI family members interact with extracellular matrix molecules and most notably hyaluronan, inhibit complement, and provide cell regulatory functions. Recent evidence for the diverse roles of the IαI family in both biology and pathology is reviewed and gives insight into their pivotal roles in tissue homeostasis. In addition, the clinical uses of these molecules are explored, such as in the treatment of inflammatory conditions including sepsis and Kawasaki disease, which has recently been associated with severe acute respiratory syndrome coronavirus 2 infection in children: </jats:p>

Understanding of COVID-19 Pathology: Much More Attention to Plasma Proteins

“…The major forms of these proteins in human plasma consist of two heavy chains and a single light chain called bikunin, covalently linked through esterification of chondroitin sulfate chain on bikunin. The minor forms contain different kinds of a single heavy chain coupled to bikunin in the same manner ( 26 ). IAIPs play a role in the regulation of a variety of responses including inflammation, wound healing, ovulation and cancer invasion/metastasis ( 26 ).…”

“…The minor forms contain different kinds of a single heavy chain coupled to bikunin in the same manner ( 26 ). IAIPs play a role in the regulation of a variety of responses including inflammation, wound healing, ovulation and cancer invasion/metastasis ( 26 ). In a neonatal animal model of sepsis, IAIPs decreased significantly after the induction of sepsis and supplementary therapy improved the lethality ( 27 , 28 ).…”

Exciting New Developments and Emerging Themes in Glycosaminoglycan Research

“…Inter-α-trypsin inhibitor (IαI) is a fascinating molecule with a bit of something for everyone, having myriad roles in cell regulation and matrix integrity in health and disease. 10 Structurally, IαI is composed of the chondroitin sulfate proteoglycan (CSPG) bikunin complexed with two heavy chain (HC) proteins, HC1 and HC2, covalently attached to the chondroitin sulfate (CS) chain. Lord et al provide a much-needed update of IαI function, explaining how contrasting activities likely reflect the temporal tissue context and specific composition of IαI family members.…”

Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia

“…Therefore, other anti-inflammatory approaches may offer clinically valid alternatives or adjunctive therapeutic effects to hypothermia for the treatment of HIE [ 17 , 18 , 19 ]. Inter-alpha Inhibitor Proteins (IAIPs) are a family of plasma proteins found abundantly in mammals including rats, sheep, and humans and are thought to play a significant role in regulating inflammation [ 20 , 21 , 22 , 23 , 24 , 25 ]. Administration of IAIPs and their metabolites has been investigated in multiple inflammatory disorders, including sepsis and the destructive inflammatory responses to SARS-CoV-2 [ 25 ], and has shown systematic protective effects in rodents via reduction in complement activation and other pro-inflammatory mechanisms [ 26 , 27 , 28 ].…”

“…Inter-alpha Inhibitor Proteins (IAIPs) are a family of plasma proteins found abundantly in mammals including rats, sheep, and humans and are thought to play a significant role in regulating inflammation [ 20 , 21 , 22 , 23 , 24 , 25 ]. Administration of IAIPs and their metabolites has been investigated in multiple inflammatory disorders, including sepsis and the destructive inflammatory responses to SARS-CoV-2 [ 25 ], and has shown systematic protective effects in rodents via reduction in complement activation and other pro-inflammatory mechanisms [ 26 , 27 , 28 ]. Experimental HI-related brain injury can be induced in rodents via carotid ligation and exposure to a hypoxic environment [ 29 ].…”