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

ABSTRACT: Background:Chlorine gas (Cl2) exposure remains a public health concern in household, occupational, and transportation accidents around the world. The death rate associated with acute respiratory distress syndrome (ARDS) caused by high concentrations of Cl2 is very high, mainly because the pathogenesis of ARDS remains unclear. Histone H4 has been identified as an important endogenous pro-inflammatory molecule. The present study aimed to examine the pathogenic role of histone H4 in Cl2-induced ARDS. Methods:ARDS was induced by Cl2 exposure in male C57BL/6 mice. Circulating histone H4, blood gas, pulmonary edema, endothelial activation, and neutrophil infiltration were measured during acute lung injury (ALI). Histone H4 or anti-H4 antibody was administered through the tail vein 1?h prior to Cl2 exposure to study the pathogenic role of histone H4. Toll-like receptor 2 knock-out (Tlr2-KO) and Tlr4-KO mice were used in conjunction with blocking antibody against TLR1, TLR2, TLR4, or TLR6 to explore the mechanism involved in histone H4-mediated injury. Results:Cl2 exposure induced a concentration-dependent ALI. The levels of circulating histone H4 were positively correlated with Cl2 concentrations. Pretreatment with intravenous histone H4 further aggravated lethality rate, blood gas, endothelial activation, and neutrophil infiltration, while anti-H4 antibody showed protective effects. Tlr4 deficiency improved lethality rate, blood gas, and pulmonary edema, and prevented endothelial and neutrophil activation caused by Cl2 exposure. More importantly, Tlr4 gene deletion greatly diminished the effect of histone H4 or anti-H4 antibody observed in wild-type (WT) mice. The impact of Tlr2 on inflammatory injury was not significant. The role of TLRs was also validated by endothelial activation mediated by histone H4 in vitro. Conclusions:Circulating histone H4 played a pro-inflammatory role in ARDS caused by Cl2. TLR4 was closely involved in histone H4-mediated inflammatory injury. Therefore, intervention targeting histone H4 is potentially protective.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7545935 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Zhang Yanlin Y Zhao Jian J Guan Li L Mao Lijun L Li Shuqiang S Zhao Jinyuan J

Journal of occupational medicine and toxicology (London, England) 20201008

<h4>Background</h4>Chlorine gas (Cl<sub>2</sub>) exposure remains a public health concern in household, occupational, and transportation accidents around the world. The death rate associated with acute respiratory distress syndrome (ARDS) caused by high concentrations of Cl<sub>2</sub> is very high, mainly because the pathogenesis of ARDS remains unclear. Histone H4 has been identified as an important endogenous pro-inflammatory molecule. The present study aimed to examine the pathogenic role of ...[more]

PMID: 33062035

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Project description:Cl(2) gas toxicity is complex and occurs during and after exposure, leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl(2) exposure can occur in diverse situations encompassing mass casualty scenarios, highlighting the need for postexposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we assessed the efficacy of a single dose of nitrite (1 mg/kg) to decrease ALI when administered to rats via intraperitoneal (ip) or intramuscular (im) injection 30 min after Cl(2) exposure. Exposure of rats to Cl(2) gas (400 ppm, 30 min) significantly increased ALI and caused RAS 6-24h postexposure as indexed by BAL sampling of lung surface protein and polymorphonucleocytes (PMNs) and increased airway resistance and elastance before and after methacholine challenge. Intraperitoneal nitrite decreased Cl(2)-dependent increases in BAL protein but not PMNs. In contrast im nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase-dependent manner. Histological evaluation of airways 6h postexposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl(2)-exposed rats. Both ip and im nitrite improved airway histology compared to Cl(2) gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with im compared to ip nitrite. Airways were rendered more sensitive to methacholine-induced resistance and elastance after Cl(2) gas exposure. Interestingly, im nitrite, but not ip nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of im and ip therapy showed a twofold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl(2) exposure-dependent increases in circulating leukocytes. Halving the im nitrite dose resulted in no effect in PMN accumulation but significant reduction of BAL protein levels, indicating a distinct nitrite dose dependence for inhibition of Cl(2)-dependent lung permeability and inflammation. These data highlight the potential for nitrite as a postexposure therapeutic for Cl(2) gas-induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics.

Project description:BackgroundOne of the major postoperative complications of esophageal cancer is acute respiratory distress syndrome (ARDS), which poses a great threat to patients' lives. In this research, the cause of ARDS after esophageal cancer surgery was explained from the aspect of the single-nucleotide polymorphism at rs7873784, rs10759930 and rs10983755 of the Toll-like receptor 4 (TLR4) gene.MethodsA total of 75 patients complicated with ARDS after esophageal cancer surgery in our hospital were collected as the ARDS group and 150 patients without ARDS after surgery as the control group. Deoxyribonucleic acids (DNAs) in the peripheral blood of patients were extracted, and the polymorphism loci (rs7873784, rs10759930 and rs10983755) of the TLR4 gene were amplified through polymerase chain reaction (PCR) and sent to a company for sequencing. The concentration of serum TLR4 was detected by kits.ResultsThe frequencies of the G allele at rs7873784 (P=0.011) and C allele at rs10759930 (P=0.000) in the ARDS group were remarkably lower than those in the control group. Besides, the frequencies of GG genotype at rs7873784 (P=0.000) and CC and CT genotypes at rs10759930 (P=0.000) in the control group were notably higher than those in the ARDS group, while the frequency of AA genotype at rs10983755 (P=0.001) in the ARDS group was clearly lower than that in control group. The survival status of patients with complications of ARDS was notably correlated with CT genotype at rs10759930 of the TLR4 gene since patients with genotype CT were more likely to die (P=0.001). The GG genotype at rs10983755 of the TLR4 gene was remarkably related to the mean mechanical ventilation time (P=0.003) and the average length of intensive care unit (ICU) stay (P=0.018). The ARDS group had a lower frequency of GCG haplotype (P=0.009) and a higher frequency of GTA haplotype (P=0.001) than the control group. The linkage disequilibrium D' was 0.781 between rs7873784 and rs10759930 of the TLR4 gene, and two loci were linked to each other. In addition, the concentration of serum TRL4 in patients with genotype CC at rs7873784 (P=0.034), genotype CT at rs7873784 (P=0.000) and genotype GG at rs10983755 (P=0.000) of the TLR4 gene in the ARDS group was higher than that in the control group.ConclusionThe single-nucleotide polymorphisms at rs7873784, rs10759930 and rs10983755 of the TLR4 gene are significantly related to ARDS after esophageal cancer surgery.

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

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

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