title: Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury.
abstract: Extracellular histones are mediators of tissue injury and organ dysfunction; therefore they constitute potential therapeutic targets in sepsis, inflammation, and thrombosis. Histone cytotoxicity in vitro decreases in the presence of plasma. Here, we demonstrate that plasma inter-α inhibitor protein (IAIP) neutralizes the cytotoxic effects of histones and decreases histone-induced platelet aggregation. These effects are mediated through the negatively charged glycosaminoglycans (GAGs) chondroitin sulfate and high-molecular-weight hyaluronan (HMW-HA) associated with IAIP. Cell surface anionic glycosaminoglycans heparan sulfate and HA protect the cells against histone-mediated damage in vitro. Surface plasmon resonance showed that both IAIP and HMW-HA directly bind to recombinant histone H4. In vivo neutralization of histones with IAIP and HMW-HA prevented histone-induced thrombocytopenia, bleeding, and lung microvascular thrombosis, decreased neutrophil activation, and averted histone-induced production of inflammatory cytokines and chemokines. IAIP and HMW-HA colocalized with histones in necrotic tissues and areas that displayed neutrophil extracellular traps. Increasing amounts of IAIP-histone complexes detected in the plasma of septic baboons correlated with increase in histones and/or nucleosomes and consumption of plasma IAIP. Our data suggest that IAIP, chondroitin sulfate, and HMW-HA are potential therapeutic agents to protect against histone-induced cytotoxicity, coagulopathy, systemic inflammation, and organ damage during inflammatory conditions such as sepsis and trauma.
authors: Department of Pediatrics, Neonatal and Perinatal Medicine Division, University of Oklahoma Health Sciences Center, Oklahoma City, OK;
authors: Hala
authors: http://orcid.org/0000-0002-7112-564X
authors: H
authors: Chaaban
authors: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and.
authors: Ravi S
authors: http://orcid.org/0000-0002-4177-9095
authors: RS
authors: Keshari
authors: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and.
authors: Robert
authors: http://orcid.org/0000-0001-9590-6160
authors: R
authors: Silasi-Mansat
authors: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and.
authors: Narcis I
authors: http://orcid.org/0000-0002-4809-9885
authors: NI
authors: Popescu
authors: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and.
authors: Padmaja
authors: P
authors: Mehta-D'Souza
authors: ProThera Biologics, Inc., East Providence, RI.
authors: Yow-Pin
authors: http://orcid.org/0000-0003-2697-7963
authors: YP
authors: Lim
authors: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; and.
authors: Florea
authors: http://orcid.org/0000-0003-1249-9278
authors: F
authors: Lupu
mesh_terms: D000510:Alpha-Globulins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001777:Blood Coagulation; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D019276:Glycocalyx / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism*; D018922:HL-60 Cells; D006470:Hemorrhage / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006657:Histones / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009707:Nucleosomes / Q000378:metabolism; D010215:Papio; D010974:Platelet Aggregation; D018805:Sepsis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013921:Thrombocytopenia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000510:Alpha-Globulins; D016207:Cytokines; D006025:Glycosaminoglycans; D006657:Histones; D009707:Nucleosomes; C011877:inter-alpha-inhibitor
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