Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis

Meegan, Jamie E.; Shaver, Ciara M.; Putz, Nathan D.; Jesse, Jordan J.; Landstreet, Stuart R.; Lee, Han Noo Ri; Sidorova, Tatiana N.; McNeil, J. Brennan; Wynn, James L.; Cheung‐Flynn, Joyce; Komalavilas, Padmini; Brophy, Colleen M.; Ware, Lorraine B.; Bastarache, Julie A.

doi:10.1371/journal.pone.0228727

Cited by 41 publications

(32 citation statements)

References 44 publications

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“…Among them, excess of free heme is a potential offending agent as it has been shown to exacerbate and contribute to the pathogenesis of numerous in ammatory diseases [2]. Therefore, it may be postulated that accumulated free heme and Hb could be involved in the mechanisms mediating pulmonary permeability and in ammation in COVID-19 patients [3]. Protective mechanisms against free heme include HO-effector molecules biliverdin/bilirubin, CO and ferritin.…”

Section: Discussionmentioning

confidence: 99%

Arterial Carboxyhemoglobin Levels In Covid-19 Critically Ill Patients

Paccaud

Castanares-Zapatero

Gérard

et al. 2020

Preprint

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Background : Oxidative stress conditions may be responsible for an up-regulation of the expression of heme oxygenase, the enzyme synthesizing carbon monoxide (CO) in cells. Elevated levels of arterial carboxyhemoglogin (CO-Hb) have been found in critically ill patients, including those suffering from acute lung injury. We aimed to investigate the changes of arterial CO-Hb levels in COVID-19 critically ill patients.Methods : A retrospective cohort study was conducted on the medical charts of 63 patients admitted in the ICU for severe COVID-19 infection over the period March 1 – May 31, 2020.Results : The overall ICU mortality rate was 39%. Non-survivors had a significantly higher profile of arterial CO-Hb levels than survivors (p<0.001), but arterial CO-Hb increased significantly from admission to day 30 in both groups (p<0.001). Mortality could not be predicted by the changes in arterial CO-Hb, but there was a correlation between the maximal arterial CO-Hb value and SOFA score on admission. No correlation could be demonstrated between arterial CO-Hb and serum C-reactive protein (CRP) as a marker of the inflammatory response.Conclusions : A greater increase of arterial CO-Hb levels over time may represent another marker of severity of COVID-19 infection in ICU patients.

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Section: Discussionmentioning

confidence: 99%

Arterial Carboxyhemoglobin Levels In Covid-19 Critically Ill Patients

Paccaud

Castanares-Zapatero

Gérard

et al. 2020

Preprint

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“…SIRS caused by gram-negative bacteria is known to be a host response to lipopolysaccharide [ 18 , 19 ] and accompanied by increased production of inflammatory mediators such as NO, IL-1, IL-6, and TNF-α resulting in vascular leakage and multiple organ dysfunction syndrome (MODS) [ 20 , 21 ]. Increased endothelial permeability is central to SIRS, leading to MODS and death [ 22 , 23 , 24 , 25 ]. Indeed, in addition to the cytopathic role in host defense and innate immune functions, NO plays a major role in vasodilation in SIRS [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Rubi Fructus Water Extract Alleviates LPS-Stimulated Macrophage Activation via an ER Stress-Induced Calcium/CHOP Signaling Pathway

et al. 2020

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Despite the availability of antibiotics and vaccines, many intractable infectious diseases still threaten human health across the globe. Uncontrolled infections can lead to systemic inflammatory response syndrome and the excessive production of inflammatory cytokines, known as a cytokine storm. As cytokines also play necessary and positive roles in fighting infections, it is important to identify nontoxic and anti-inflammatory natural products that can modulate cytokine production caused by infections. Rubi Fructus, the unripe fruits of Rubus coreanus Miquel, are known to possess antioxidative properties. In this study, the effect of the water extract of Rubi Fructus (RF) on the lipopolysaccharide (LPS)-induced inflammatory response in RAW 264.7 macrophages was investigated using biochemical and cell biology techniques. Our data indicated that RF inhibits p38 phosphorylation, intracellular calcium release, and the production of nitric oxide (NO), interleukin (IL)-6, monocyte chemotactic activating factor (MCP)-1, tumor necrosis factor (TNF)-α, leukemia inhibitory factor (LIF), lipopolysaccharide-induced CXC chemokine (LIX), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein (MIP)-1α, MIP-1β, MIP-2, and regulated on activation, normal T cell expressed and secreted (RANTES) in LPS-treated macrophages. In addition, we observed decreasing mRNA expression of Chop, Camk2a, Stat1, Stat3, Jak2, Fas, c-Jun, c-Fos, Nos2, and Ptgs2 without cytotoxic effects. We concluded that RF demonstrated immunoregulatory activity on LPS-stimulated macrophages via an endoplasmic reticulum (ER) stress-induced calcium/CCAAT-enhancer-binding protein homologous protein (CHOP) pathway and the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway.

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“…Using radiolabeled liposomes, we further demonstrated that free heme causes vascular permeabilization resulting in edema [ 28 ]. Accumulated free heme and Hb may thus act as pathophysiologic mechanisms mediating pulmonary permeability and inflammation [ 31 , 32 ]. Alveolar fluid clearance is hampered in ARDS and also likely in hospitalized COVID-19 patients.…”

Section: Can Injury-derived Free Heme Contribute To Covid-19 Pathomentioning

confidence: 99%

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections

et al. 2020

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SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill and show lung injury and hemolysis. Heme is a prosthetic moiety crucial for the function of a wide variety of heme-proteins, including hemoglobin and cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement activation, thrombosis, and fibrosis. Heme can be degraded by the anti-inflammatory enzyme heme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, and carbon monoxide. We therefore postulate that free heme contributes to many of the inflammatory phenomena witnessed in critically ill COVID-19 patients, whilst induction of HO-1 or harnessing heme may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative and anti-inflammatory properties. Until a vaccine against SARS-CoV-2 becomes available, we need to explore novel strategies to attenuate the pro-inflammatory, pro-thrombotic, and pro-fibrotic consequences of SARS-CoV-2 leading to morbidity and mortality. The heme-HO system represents an interesting target for novel “proof of concept” studies in the context of COVID-19.

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Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis

Cited by 41 publications

References 44 publications

Arterial Carboxyhemoglobin Levels In Covid-19 Critically Ill Patients

Arterial Carboxyhemoglobin Levels In Covid-19 Critically Ill Patients

Rubi Fructus Water Extract Alleviates LPS-Stimulated Macrophage Activation via an ER Stress-Induced Calcium/CHOP Signaling Pathway

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections

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