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Sepsis and ARDS: The Dark Side of Histones.

Xu Z, Huang Y, Mao P, Zhang J, Li Y - Mediators Inflamm. (2015)

Bottom Line: However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS).Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS.In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

ABSTRACT
Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanisms of extracellular histones in the development of sepsis and ALI/ARDS. In response to various physical challenges (e.g., trauma, infection), polymorphonuclear neutrophils (PMN) and macrophages are recruited and activated through complement interaction (C5a and C5a receptors), which is often needed for extracellular histones presented in ALI/ARDS models. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released. Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. They can also act on TLR2, TLR4, and TLR9 and activate the NLRP3 inflammasome to amplify inflammatory responses by the growing release of cytokines and other mediators. Moreover, circulating histones may also enhance coagulation disorders by acting on TLR2 and TLR4. On the other hand, extracellular histones perpetuate detrimental cell/tissue injury and could in turn induce the formation of NETs by activating the NLRP3 inflammasome, which together lead to more histones being released and greater severity of sepsis and ALI/ARDS.
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fig1: Proposed mechanisms of extracellular histones in the development of sepsis and ALI/ARDS. In response to various physical challenges (e.g., trauma, infection), polymorphonuclear neutrophils (PMN) and macrophages are recruited and activated through complement interaction (C5a and C5a receptors), which is often needed for extracellular histones presented in ALI/ARDS models. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released. Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. They can also act on TLR2, TLR4, and TLR9 and activate the NLRP3 inflammasome to amplify inflammatory responses by the growing release of cytokines and other mediators. Moreover, circulating histones may also enhance coagulation disorders by acting on TLR2 and TLR4. On the other hand, extracellular histones perpetuate detrimental cell/tissue injury and could in turn induce the formation of NETs by activating the NLRP3 inflammasome, which together lead to more histones being released and greater severity of sepsis and ALI/ARDS.

Mentions: The pathology of ARDS is characterized by an acute inflammatory response linked to the overwhelming recruitment and accumulation of neutrophils, fibrin deposits, alveolar hemorrhage, and pulmonary edema fluid [13, 84, 85]. Recent studies have shown that extracellular histones are responsible for pulmonary edema, which is characterized by increased endothelial and epithelial permeability [18, 42, 86]. In vivo, airway administration of calf thymus histones led to a dose-dependent disruption of the alveolar permeability barrier during ALI, with observations of alveolar albumin leakage and a histological examination revealing obvious lung edema [18, 42]. In vitro, compared with controls, transwells plated with endothelial cells by pretreatment with histones showed that FITC-labeled albumin was significantly elevated in the lower wells, which indicates a histone-induced endothelial permeability increase [18, 86]. Furthermore, recombinant parasite histones also induced endothelial permeability via a charge-dependent mechanism that led to downregulation of the junction protein [86]. Taken together, these data suggest that extracellular histones play a crucial role in barrier dysfunction during ALI. However, in addition to the charge-dependent mechanism, TLR2, TLR4, and TLR9, as the receptors of histones [30, 37, 38], may also give rise to permeability changes, which should be investigated further (Figure 1).


Sepsis and ARDS: The Dark Side of Histones.

Xu Z, Huang Y, Mao P, Zhang J, Li Y - Mediators Inflamm. (2015)

Proposed mechanisms of extracellular histones in the development of sepsis and ALI/ARDS. In response to various physical challenges (e.g., trauma, infection), polymorphonuclear neutrophils (PMN) and macrophages are recruited and activated through complement interaction (C5a and C5a receptors), which is often needed for extracellular histones presented in ALI/ARDS models. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released. Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. They can also act on TLR2, TLR4, and TLR9 and activate the NLRP3 inflammasome to amplify inflammatory responses by the growing release of cytokines and other mediators. Moreover, circulating histones may also enhance coagulation disorders by acting on TLR2 and TLR4. On the other hand, extracellular histones perpetuate detrimental cell/tissue injury and could in turn induce the formation of NETs by activating the NLRP3 inflammasome, which together lead to more histones being released and greater severity of sepsis and ALI/ARDS.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644547&req=5

fig1: Proposed mechanisms of extracellular histones in the development of sepsis and ALI/ARDS. In response to various physical challenges (e.g., trauma, infection), polymorphonuclear neutrophils (PMN) and macrophages are recruited and activated through complement interaction (C5a and C5a receptors), which is often needed for extracellular histones presented in ALI/ARDS models. However, the accumulation of PMNs sometimes occurs with infection without complement activation. Under these conditions, histones derived from NETosis and dying nonleukocytic cells could be released. Once the histones are present in the extracellular space, they can directly bind to and damage phospholipids in cell membranes in a charged-dependent mechanism, leading to increased membrane permeability and death. They can also act on TLR2, TLR4, and TLR9 and activate the NLRP3 inflammasome to amplify inflammatory responses by the growing release of cytokines and other mediators. Moreover, circulating histones may also enhance coagulation disorders by acting on TLR2 and TLR4. On the other hand, extracellular histones perpetuate detrimental cell/tissue injury and could in turn induce the formation of NETs by activating the NLRP3 inflammasome, which together lead to more histones being released and greater severity of sepsis and ALI/ARDS.
Mentions: The pathology of ARDS is characterized by an acute inflammatory response linked to the overwhelming recruitment and accumulation of neutrophils, fibrin deposits, alveolar hemorrhage, and pulmonary edema fluid [13, 84, 85]. Recent studies have shown that extracellular histones are responsible for pulmonary edema, which is characterized by increased endothelial and epithelial permeability [18, 42, 86]. In vivo, airway administration of calf thymus histones led to a dose-dependent disruption of the alveolar permeability barrier during ALI, with observations of alveolar albumin leakage and a histological examination revealing obvious lung edema [18, 42]. In vitro, compared with controls, transwells plated with endothelial cells by pretreatment with histones showed that FITC-labeled albumin was significantly elevated in the lower wells, which indicates a histone-induced endothelial permeability increase [18, 86]. Furthermore, recombinant parasite histones also induced endothelial permeability via a charge-dependent mechanism that led to downregulation of the junction protein [86]. Taken together, these data suggest that extracellular histones play a crucial role in barrier dysfunction during ALI. However, in addition to the charge-dependent mechanism, TLR2, TLR4, and TLR9, as the receptors of histones [30, 37, 38], may also give rise to permeability changes, which should be investigated further (Figure 1).

Bottom Line: However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS).Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS.In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

ABSTRACT
Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases.

No MeSH data available.


Related in: MedlinePlus