ReviewMolecular medicine (Cambridge, Mass.)2020
Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?
Review in Molecular medicine (Cambridge, Mass.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 148 papers, 1 of them a synthesis that pooled it.
What it found
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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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
148 citing papers in PubMed, 1 synthesis or guideline pooled it, 230 citations in OpenAlex.
- Elevated HMGB1 Levels in Neonates With Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis.Canadian respiratory journal · 2026Pooled it
- Vagus nerve control of HMGB1 accessibility: a bioelectronic strategy for inflammation and pain.Bioelectronic medicine · 2026Review
- Extracellular Vesicles as Drivers of Lung Endothelial Dysfunction in ARDS: Mechanisms and Therapeutic Opportunities.Comprehensive Physiology · 2026Review
- Review
- HMGB1 and metabolic pathways in Acinetobacter baumannii pneumonia: an associative study.BMC infectious diseases · 2025Article
- Identification of hub genes associated with severe COPD via WGCNA and immune infiltration analysis.Scientific reports · 2025Article
- Damage-associated molecular patterns (DAMPs) in diseases: implications for therapy.Molecular biomedicine · 2025Review
- Direct interaction of HMGB1 with SARS-CoV-2 facilitates its infection via RAGE-dependent endocytosis.iScience · 2025Article
- Metabolic Reprogramming in Respiratory Viral Infections: A Focus on SARS-CoV-2, Influenza, and Respiratory Syncytial Virus.Biomolecules · 2025Review
- Enterovirus D68 infection in cotton rats results in systemic inflammation with detectable viremia associated with extracellular vesicle and neurologic disease.Scientific reports · 2025Article
- Article
- Dengue Virus Infection: Immune Response and Therapeutic Targets.The American journal of tropical medicine and hygiene · 2025Review
- Protective Effects of Qingre Sanjie Jiaonang on Pulmonary Fibrosis: A Pilot Study.Journal of inflammation research · 2025Article
- RNA-binding proteins regulate osteoarthritis via RNA metabolism regulation.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2024Review
- Tim-3 pathway dysregulation and targeting in sepsis-induced immunosuppression.European journal of medical research · 2024Review
- Generation of Anti-Mastitis Gene-Edited Dairy Goats with Enhancing Lysozyme Expression by Inflammatory Regulatory Sequence using ISDra2-TnpB System.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Immune responses in COVID-19 patients: Insights into cytokine storms and adaptive immunity kinetics.Heliyon · 2024Review
- Structure and Functions of HMGB3 Protein.International journal of molecular sciences · 2024Review
- Article
- NFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins.Nature communications · 2024Article
88 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males.
conclusionBased on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.
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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.