Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

Zhang, Yanlin; Zhao, Jian; Guan, Li; Mao, Lijun; Li, Shuqiang; Jin-yuan, Zhao

doi:10.1186/s12995-020-00282-z

Cited by 9 publications

(3 citation statements)

References 67 publications

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“…animal models and patients of ARDS, extracellular histones have been proven to be associated with damages [35,36]. Study showed that heparin/low molecular weight heparin exerted a positive effect on mortality in COVID-19 patients by neutralizing the extracellular histones [37].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway

Xiong¹,

Ai²,

Bao³

et al. 2023

Front. Biosci. (Landmark Ed)

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Background: Neonatal acute respiratory distress syndrome (ARDS) is a clinical disorder characterized by excessive acute inflammatory response in lung parenchyma and has high morbidity and mortality. However, the therapeutic treatments are still lacking. The aim of this study is to evaluate the role of unfractionated heparin in neonatal ARDS and explore the underlying mechanism of its effects. Methods: To conduct the ARDS model, the mouse pups were treated by intraperitoneal injection of lipopolysaccharide (LPS) (10 mg/kg). For unfractionated heparin intervention group, C57BL/6 mouse pups received a single subcutaneous injection of unfractionated heparin (400 IU/kg) 30 minutes prior to LPS. The survival rate was recorded for each group. Histological analysis was used to evaluate lung injury. MPO (myeloperoxidase) concentration level in lung tissues and extracellular histones in serum were detected by enzyme linked immunosorbent assay (ELISA). A commercially available kit was used to detect inflammatory cytokine levels in serum. Real time quantitative polymerase chain reaction (qPCR) and western blot were used to detect the mRNA and protein in the JAK2/STAT3 signaling pathway, respectively. Results: Intervention of unfractionated heparin significantly increased the survival rate of mouse pups with ARDS, restored lung architecture, inhibited neutrophil infiltration as evidenced by reduced MPO concentration, and attenuated the LPS-induced inflammatory responses, characterized by the down-regulation of proinflammatoy factors and up-regulation of anti-inflammatory factor when compared with the ARDS group. In addition, the concentration of extracellular histones, which have been proven to be mediated in the pathogenesis of ARDS, was diminished by unfractionated heparin. Moreover, the protein expressions of p-JAK2 (Y1007/1008) and p-STAT3 (Y705) in the ARDS group were remarkably up-regulated, which were reversed by unfractionated heparin. Conclusions: Unfractionated heparin protects LPS-induced ARDS via inhibiting JAK2/STAT3 pathway in neonatal mice, which might present a novel therapeutic target for ARDS of neonates.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway

Xiong¹,

Ai²,

Bao³

et al. 2023

Front. Biosci. (Landmark Ed)

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“…LPS stimulation leads to systemic inflammatory and toxic responses by activating Toll-like receptors ( 21), the complement system (22), and inflammasome pathways, which provoke apoptosis, necrosis, and NET formation (7), and histone release into the circulation. These extracellular histones play a pathogenic role in the development of ARDS through promoting alveolar macrophage proptosis (23), direct cytotoxic endothelial damage (24) and pro-inflammatory effects with cytokine production (25) (26), resulting in overwhelming cell damage and death (22). Furthermore, these extracellular histones can induce platelet aggregation (28) and coagulation activation (29), immuno-thrombosis formation (30) and innate immunity by activating Toll-like receptors and the NLRP3 inflammasome (27).…”

Section: Discussionmentioning

confidence: 99%

Histone neutralization in a rat model of acute lung injury induced by double-hit lipopolysaccharide

Wang

Zhen³

et al. 2021

Preprint

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Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit. Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N=8, received saline only) or LPS (N=60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 hours by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only (N=12); LPS + 5, 25, or 100 mg/kg intravenous STC3141 every 8 hours (LPS+L, LPS+M, LPS+H, respectively, each N=12); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 hours for 56 hours (LPS+D, N=12) The animals were observed for 72 hours. Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS+H and +D animals had significantly lower circulating histone levels; only the LPS+D group had significantly lower bronchoalveolar lavage fluid (BALF) histone concentrations. The LPS+L, +M, +H and +D groups had improved oxygenation compared to the LPS group and the LPS+H and +D groups had a lower lung wet-to-dry ratio. All animals survived. Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved oxygenation, and decreased lung edema formation. Keywords: ALI, ARDS, histone, histone neutralization, STC3141, rat LPS model

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“…Histone H4 is one of the five core histone proteins that are involved in the formation of nucleosomes in chromatin [ 81 ]. The unexpected cytotoxic role of extracellular H4 is reported in sepsis via the interaction with toll-like receptor (TLR) 2 and 4, which are upregulated in inflammatory injuries [ 82 ]. Regarding Hsp90ab1 (aka Hsp90b), it is shown in osteosarcoma cells that secreted Hsp90ab1 proteins inhibit the activation of latent TGFβ [ 83 ].…”

Section: Double-edged Role Of Tumor-suppressing Proteinsmentioning

confidence: 99%

The Double-Edged Proteins in Cancer Proteomes and the Generation of Induced Tumor-Suppressing Cells (iTSCs)

Huo

et al. 2023

Proteomes

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Unlike a prevalent expectation that tumor cells secrete tumor-promoting proteins and stimulate the progression of neighboring tumor cells, accumulating evidence indicates that the role of tumor-secreted proteins is double-edged and context-dependent. Some of the oncogenic proteins in the cytoplasm and cell membranes, which are considered to promote the proliferation and migration of tumor cells, may inversely act as tumor-suppressing proteins in the extracellular domain. Furthermore, the action of tumor-secreted proteins by aggressive “super-fit” tumor cells can be different from those derived from “less-fit” tumor cells. Tumor cells that are exposed to chemotherapeutic agents could alter their secretory proteomes. Super-fit tumor cells tend to secrete tumor-suppressing proteins, while less-fit or chemotherapeutic agent-treated tumor cells may secrete tumor-promotive proteomes. Interestingly, proteomes derived from nontumor cells such as mesenchymal stem cells and peripheral blood mononuclear cells mostly share common features with tumor cell-derived proteomes in response to certain signals. This review introduces the double-sided functions of tumor-secreted proteins and describes the proposed underlying mechanism, which would possibly be based on cell competition.

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Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

Cited by 9 publications

References 67 publications

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway

Histone neutralization in a rat model of acute lung injury induced by double-hit lipopolysaccharide

The Double-Edged Proteins in Cancer Proteomes and the Generation of Induced Tumor-Suppressing Cells (iTSCs)

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