ArticlePharmacology research & perspectives2018
Revisiting the putative role of heme as a trigger of inflammation.
Article in Pharmacology research & perspectives, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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.
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Who cites it
32 citing papers in PubMed, 64 citations in OpenAlex.
- The Effects of Free Heme on Functional and Molecular Changes DuringFrontiers in immunology · 2022Trial
- Sickle cell disease-associated pulmonary hypertension: an integrated framework linking pathologies, mechanisms, and clinical phenotypes.EBioMedicine · 2026Review
- Regulatory interplay between nitric oxide and heme in redox signaling and inflammation.Redox biology · 2026Review
- Haptoglobin and Hemopexin Redirect Heme-Driven Oxidative Stress and Neurotoxicity in Organotypic Brain Slices.ACS chemical neuroscience · 2026Article
- GPR35 mediates monocyte recruitment to the sites of Listeria monocytogenes infection.Cellular and molecular life sciences : CMLS · 2025Article
- Biosynthetic blood surrogates: Current status and future opportunities.Bioengineering & translational medicine · 2025Review
- Targeting lung heme iron by aerosol hemopexin adminstration in sickle cell disease pulmonary hypertension.Free radical biology & medicine · 2025Article
- Circulating free heme induces cytokine storm and pulmonary hypertension through the MKK3/p38 axis.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function.Advances in experimental medicine and biology · 2024Review
- Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.The Journal of clinical investigation · 2023Article
- Nitrite decreases sickle hemoglobin polymerization in vitro independently of methemoglobin formation.Toxicology and applied pharmacology · 2023Article
- Haptoglobin Treatment for Aneurysmal Subarachnoid Hemorrhage: Review and Expert Consensus on Clinical Translation.Stroke · 2023Review
- Sterile inflammation in liver transplantation.Frontiers in medicine · 2023Review
- MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and secondary brain edema in a mouse model of intracerebral hemorrhage.Journal of neuroinflammation · 2022Article
- Scalable manufacturing platform for the production of PEGylated heme albumin.Biotechnology and bioengineering · 2022Article
- Article
- Spatial transcriptome data from coronal mouse brain sections after striatal injection of heme and heme-hemopexin.Data in brief · 2022Article
- Modeling oxidative injury response in human kidney organoids.Stem cell research & therapy · 2022Article
- Toxic effects of cell-free hemoglobin on the microvascular endothelium: implications for pulmonary and nonpulmonary organ dysfunction.American journal of physiology. Lung cellular and molecular physiology · 2021Article
- Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study.Antioxidants (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell-free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb-based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein-binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein-free heme under in vivo equilibrium conditions. We demonstrate that the capacity of heme to activate human neutrophil granulocytes strictly depends on the availability of non protein-associated heme. In human endothelial cells as well as in mouse macrophage cell cultures and in mouse models of local and systemic heme exposure, protein-associated heme or Hb do not induce inflammatory gene expression over a broad range of exposure conditions. Only experiments in protein-free culture medium demonstrated a weak capacity of heme-solutions to induce toll-like receptor-(TLR4) dependent TNF-alpha expression in macrophages. Our data suggests that the equilibrium-state of free and protein-associated heme critically determines the proinflammatory capacity of the metallo-porphyrin. Based on these data it appears unlikely that inflammation-promoting equilibrium conditions could ever occur in vivo.
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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.