Myeloid-specific Hdac10 deletion protects against LPS-induced acute lung injury via P62 acetylation at lysine 165.

BACKGROUND: Aberrant activation of macrophages is associated with pathogenesis of acute lung injury (ALI). However, the potential pathogenesis has not been explored. OBJECTIVES: We aimed to identify whether histone deacetylase (HDAC) 10 is involved in lipopolysaccharide (LPS)-exposed ALI and reveal the underlying pathogenesis by which it promotes lung inflammation in LPS-exposed ALI via modifying P62 with deacetylation. METHODS: We constructed an ALI mice model stimulated with LPS to determine the positive effect of Hdac10 deficiency. Moreover, we cultured murine alveolar macrophage cell line (MH-S cells) and primary bone marrow-derived macrophages (BMDMs) to explore the pro-inflammatory activity and mechanism of HDAC10 after LPS challenge. RESULTS: HDAC10 expression was increased both in mice lung tissues and macrophage cell lines and promoted inflammatory cytokines production exposed to LPS. Hdac10 deficiency inhibited autophagy and inflammatory response after LPS stimulation. In vivo, Hdac10fl/fl-LysMCre mice considerably attenuated lung inflammation and inflammatory cytokines release exposed to LPS. Mechanistically, HDAC10 interacts with P62 and mediates P62 deacetylation at lysine 165 (K165), by which it promotes P62 expression and increases inflammatory cytokines production. Importantly, we identified that Salvianolic acid B (SAB), an HDAC10 inhibitor, reduces lung inflammatory response in LPS-stimulated ALI. CONCLUSION: These results uncover a previously unknown role for HDAC10 in regulating P62 deacetylation and aggravating lung inflammation in LPS-induced ALI, implicating that targeting HDAC10 is an effective therapy for LPS-exposed ALI.

Promising Intestinal Microbiota Associated with Clinical Characteristics of COPD Through Integrated Bioinformatics Analysis.

Introduction: Chronic obstructive pulmonary disease (COPD), an incurable chronic respiratory disease, has become a major public health problem. The relationship between the composition of intestinal microbiota and the important clinical factors affecting COPD remains unclear. This study aimed to identify specific intestinal microbiota with high clinical diagnostic value for COPD. Methods: The fecal microbiota of patients with COPD and healthy individuals were analyzed by 16S rDNA sequencing. Random forest classification was performed to analyze the different intestinal microbiota. Spearman correlation was conducted to analyze the correlation between different intestinal microbiota and clinical characteristics. A microbiota-disease network diagram was constructed using the gut MDisorder database to identify the possible pathogenesis of intestinal microorganisms affecting COPD, screen for potential treatment, and guide future research. Results: No significant difference in biodiversity was shown between the two groups but significant differences in microbial community structure. Fifteen genera of bacteria with large abundance differences were identified, including Bacteroides, Prevotella, Lachnospira, and Parabacteroides. Among them, the relative abundance of Lachnospira and Coprococcus was negatively related to the smoking index and positively related to lung function results. By contrast, the relative abundance of Parabacteroides was positively correlated with the smoking index and negatively correlated with lung function findings. Random forest classification showed that Lachnospira was the genus most capable of distinguishing between patients with COPD and healthy individuals suggesting it may be a potential biomarker of COPD. A Lachnospira disease network diagram suggested that Lachnospira decreased in some diseases, such as asthma, diabetes mellitus, and coronavirus disease 2019 (COVID-19), and increased in other diseases, such as irritable bowel syndrome, hypertension, and bovine lichen. Conclusion: The dominant intestinal microbiota with significant differences is related to the clinical characteristics of COPD, and the Lachnospira has the potential value to identify COPD.

Emerging roles and therapeutic implications of HDAC2 and IL-17A in steroid-resistant asthma.

Steroid resistance represents a major clinical problem in the treatment of severe asthma, and therefore a better understanding of its pathogenesis is warranted. Recent studies indicated that histone deacetylase 2 (HDAC2) and interleukin 17A (IL-17A) play important roles in severe asthma. HDAC2 activity is reduced in patients with severe asthma and smoking-induced asthma, perhaps accounting for the amplified expression of inflammatory genes, which is associated with increased acetylation of glucocorticoid receptors. Neutrophilic inflammation contributes to severe asthma and may be related to T helper (Th) 17 rather than Th2 cytokines. IL-17A levels are elevated in severe asthma and correlate with the presence of neutrophils. Restoring the activity of HDAC2 or targeting the Th17 signaling pathway is a potential therapeutic approach to reverse steroid insensitivity.

The Burden of COPD in China and Its Provinces: Findings From the Global Burden of Disease Study 2019.

In China, chronic obstructive pulmonary disease (COPD) was accounted for a quarter of the global COPD population and has become a large economic burden. However, the comprehensive picture of the COPD burden, which could inform health policy, is not readily available for all of the provinces of China. Here, we aimed to describe the burden of COPD in China, providing an up-to-date and comprehensive analysis at the national and provincial levels, and time trends from 1990 to 2019. Following the methodology framework and general analytical strategies used in the GBD 2019, we analyzed the incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years with life lost (YLLs) attributable to COPD across China and the corresponding time trends from 1990 to 2019, stratified by age and province. In order to quantify the secular trends of the burden of COPD, the estimated annual percentage changes were calculated by the linear regression model of age-standardized rates (ASRs) and calendar years. We also presented the contribution of risk factors to COPD-related mortality and DALYs. The association between COPD burden and socio-demographic index (SDI) were also evaluated. From 1990 to 2019, the incidence and prevalence numbers of COPD increased by 61.2 and 67.8%, respectively, whereas the number of deaths and DALYs owing to COPD decreased. The ASRs of COPD burden, including incidence, prevalence, mortality, DALYs, YLDs, and YLLs continuously decreased from 1990 to 2019. The crude rates of COPD burden dramatically increased with age and reached a peak in the older than 95 years age group. In 2019, the leading risk factor for COPD mortality and DALYs was tobacco use in the whole population, but ambient particulate matter pollution was the most significant risk factor in females. At the provincial level, the ASRs of COPD burden was significantly associated with the SDIs, with the highest ASRs in the western provinces with low SDIs. Collectively, our study indicated that COPD remains an important public health problem in China. Geographically targeted considerations should be developed to enhance COPD health and reduce the COPD burden throughout China and in specific provinces.