A Central Role for Free Heme in the Pathogenesis of Severe Sepsis

Larsen, Rasmus; Gozzelino, Raffaella; Jeney, Viktória; Tokaji, László; Bozza, Fernando A.; Japiassú, André Miguel; Bonaparte, Dolores; Cavalcante, Moisés Marinho; Chora, Ângelo Ferreira; Ferreira, Ana; Marguti, Ivo; Cardoso, Sílvia; Sepúlveda, Nuno; Smith, Ann; Soares, Miguel P.

doi:10.1126/scitranslmed.3001118

Cited by 428 publications

(531 citation statements)

References 51 publications

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“…Upon oxidation, extracellular hemoglobin releases its prosthetic heme groups, which act as catalysts in the production of reactive oxygen species (ROS) and nitrogen species (RNS). This can lead to oxidative stress and cellular damage in host parenchyma tissues 12,13,16,31 , driving the pathogenesis of severe forms of malaria 30 .…”

Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

“…Moreover, current antimicrobial approaches also often fail to treat infectious diseases. In these cases, a rational pharmacological targeting of stress and damage responses controlling tissue damage control may act therapeutically through the establishment of disease tolerance to infection, as illustrated for pharmacological targeting of adenosine receptors 109 or labile heme 16 , which establish disease tolerance to sepsis 16,109 or malaria 20,21,30 in mice.…”

Section: Pharmacological Modulation Of Disease Tolerancementioning

confidence: 99%

“…In some instances, administration of hemopexin, a plasma protein that binds avidly to labile heme and neutralizes its deleterious effects, confers tissue damage control and disease tolerance to sepsis in mice 16 . The pathological effects of labile heme can also be neutralized by gasotransmitters such as CO 21 or NO 29 , which bind avidly to ferrous heme-iron (Fe 2+ ) in hemoproteins.…”

Section: Pharmacological Modulation Of Disease Tolerancementioning

confidence: 99%

“…This notion has been challenged over the past years by the (re)discovery of disease tolerance 5,6 . This evolutionarily conserved host defense strategy, which was first described in plants 7,8 , is fully operational in flies 9,10 and mammals, including rodents 11,12 and humans 13 , where it preserves host homeostasis in response to viral 14,15 , bacterial [15][16][17][18] , fungal 19 and protozoan 11,13,20,21 infections. In contrast to resistance to infection, disease tolerance does not exert a direct negative effect on these pathogens 6 .…”

Section: Introductionmentioning

confidence: 99%

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Disease tolerance and immunity in host protection against infection

2017

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The immune system has most likely evolved to limit the negative impact exerted by pathogens on host homeostasis. This defense strategy relies on the concerted action of innate and adaptive components of the immune system, which sense and target pathogens for containment, destruction or expulsion. Resistance to infection refers to these immune functions, which reduce the pathogen load of an infected host as the means to preserve homeostasis. Immune-driven resistance to infection is coupled to an additional, and arguably as important, defense strategy that limits the extent of dysfunction imposed to host parenchyma tissues during infection, without exerting a direct negative impact on pathogens.This defense strategy, called disease tolerance, relies on tissue damage control mechanisms that prevent the deleterious effects of pathogens, while uncoupling immunedriven resistance mechanisms from immunopathology and disease. Here we provide a unifying view of resistance and disease tolerance within the framework of immunity to infection.

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Section: Stress Responses In Tissue Damage Controlmentioning

confidence: 99%

Section: Pharmacological Modulation Of Disease Tolerancementioning

confidence: 99%

Section: Pharmacological Modulation Of Disease Tolerancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disease tolerance and immunity in host protection against infection

2017

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“…The same stress-responsive program is involved in conferring tissue damage control and disease tolerance to severe sepsis driven by polymicrobial infection 98 .…”

Section: Boxmentioning

confidence: 99%

Tissue damage control in disease tolerance

Soares

Gozzelino

Weis

2014

Trends in Immunology

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The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

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Reconstructing sickle cell disease: A data‐based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence‐based medicine

2011

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The ''hyperhemolytic paradigm'' (HHP) posits that hemolysis in sickle disease sequentially and causally establishes increased cell-free plasma Hb, consumption of NO, a state of NO biodeficiency, endothelial dysfunction, and a high prevalence of pulmonary hypertension. The basic science underpinning this concept has added an important facet to the complexity of vascular pathobiology in sickle disease, and clinical research has identified worrisome clinical issues. However, this critique identifies and explains a number of significant concerns about the various HHP component tenets. In addressing these issues, this report presents: a very brief history of the HHP, an integrated synthesis of mechanisms underlying sickle hemolysis, a review of the evidentiary value of hemolysis biomarkers, an examination of evidence bearing on existence of a hyperhemolytic subgroup, and a series of questions that should naturally be applied to the HHP if it is examined using critical thinking skills, the fundamental basis of evidence-based medicine. The veracity of different HHP tenets is found to vary from true, to weakly supported, to demonstrably false. The thesis is developed that the HHP has misidentified the mechanism and clinical significance of its findings. The extant research questions identified by these analyses are delineated, and a conservative, evidence-based approach is suggested for application in clinical medicine. Am. J. Hematol. 86:123-154, 2011. V

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A Central Role for Free Heme in the Pathogenesis of Severe Sepsis

Cited by 428 publications

References 51 publications

Disease tolerance and immunity in host protection against infection

Disease tolerance and immunity in host protection against infection

Tissue damage control in disease tolerance

Reconstructing sickle cell disease: A data‐based analysis of the “hyperhemolysis paradigm” for pulmonary hypertension from the perspective of evidence‐based medicine

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