ArticleBlood2015
Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury.
Article in Blood, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
57 citing papers in PubMed, 84 citations in OpenAlex.
- Rapid Detection of Inter-alpha Inhibitor Proteins in Neonatal Sepsis and Necrotizing Enterocolitis.medRxiv : the preprint server for health sciences · 2026Article
- Beyond hemostasis, the immunomodulatory nature of platelets.Research and practice in thrombosis and haemostasis · 2025Review
- S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum.The Journal of experimental medicine · 2025Article
- A dose-adjusted, open-label, pilot study of the safety, tolerability, and pharmacokinetics of STC3141 in critically ill patients with sepsis.Pharmacology research & perspectives · 2024Article
- Glycosaminoglycans: Participants in Microvascular Coagulation of Sepsis.Thrombosis and haemostasis · 2024Review
- M6229 Protects against Extracellular-Histone-Induced Liver Injury, Kidney Dysfunction, and Mortality in a Rat Model of Acute Hyperinflammation.International journal of molecular sciences · 2024Article
- Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review.Frontiers in immunology · 2024Review
- Impact of neonatal nutrition on necrotizing enterocolitis.Seminars in pediatric surgery · 2023Review
- The role of neutrophil extracellular traps in necrotizing enterocolitis.Frontiers in pediatrics · 2023Review
- The Endothelial Glycocalyx and Neonatal Sepsis.International journal of molecular sciences · 2022Review
- Serum level of total histone 3, H3K4me3, and H3K27ac after non-emergent cardiac surgery suggests the persistence of smoldering inflammation at 3 months in an adult population.Clinical epigenetics · 2022Article
- Novel aspects of sepsis pathophysiology: NETs, plasma glycoproteins, endotheliopathy and COVID-19.Journal of pharmacological sciences · 2022Review
- Review
- Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma.International journal of molecular sciences · 2022Article
- Modulation of hyaluronan signaling as a therapeutic target in human disease.Pharmacology & therapeutics · 2022Review
- Article
- Emerging prediction methods for early diagnosis of necrotizing enterocolitis.Frontiers in medicine · 2022Review
- Neutrophil extracellular trap inhibition increases inflammation, bacteraemia and mortality in murine necrotizing enterocolitis.Journal of cellular and molecular medicine · 2021Observational
- Changes in Cellular Localization of Inter-Alpha Inhibitor Proteins after Cerebral Ischemia in the Near-Term Ovine Fetus.International journal of molecular sciences · 2021Article
- Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice.The Journal of clinical investigation · 2021Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.