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.

Comprehensive analysis and identification of subtypes and hub genes of high immune response in lung adenocarcinoma.

BACKGROUND: The advent of immunotherapy targeting immune checkpoints has conferred significant clinical advantages to patients with lung adenocarcinoma (LUAD); However, only a limited subset of patients exhibit responsiveness to this treatment. Consequently, there is an imperative need to stratify LUAD patients based on their response to immunotherapy and enhance the therapeutic efficacy of these treatments. METHODS: The differentially co-expressed genes associated with CD8 + T cells were identified through weighted gene co-expression network analysis (WGCNA) and the Search Tool for the Retrieval of Interacting Genes (STRING) database. These gene signatures facilitated consensus clustering for TCGA-LUAD and GEO cohorts, categorizing them into distinct immune subtypes (C1, C2, C3, and C4). The Tumor Immune Dysfunction and Exclusion (TIDE) model and Immunophenoscore (IPS) analysis were employed to assess the immunotherapy response of these subtypes. Additionally, the impact of inhibitors targeting five hub genes on the interaction between CD8 + T cells and LUAD cells was evaluated using CCK8 and EDU assays. To ascertain the effects of these inhibitors on immune checkpoint genes and the cytotoxicity mediated by CD8 + T cells, flow cytometry, qPCR, and ELISA methods were utilized. RESULTS: Among the identified immune subtypes, subtypes C1 and C3 were characterized by an abundance of immune components and enhanced immunogenicity. Notably, both C1 and C3 exhibited higher T cell dysfunction scores and elevated expression of immune checkpoint genes. Multi-cohort analysis of Lung Adenocarcinoma (LUAD) suggested that these subtypes might elicit superior responses to immunotherapy and chemotherapy. In vitro experiments involved co-culturing LUAD cells with CD8 + T cells and implementing the inhibition of five pivotal genes to assess their function. The inhibition of these genes mitigated the immunosuppression on CD8 + T cells, reduced the levels of PD1 and PD-L1, and promoted the secretion of IFN-γ and IL-2. CONCLUSIONS: Collectively, this study delineated LUAD into four distinct subtypes and identified five hub genes correlated with CD8 + T cell activity. It lays the groundwork for refining personalized therapy and immunotherapy strategies for patients with LUAD.

Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line in vitro and an airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1ß in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.

Global, regional and national disability-adjusted life years due to HIV from 1990 to 2019: findings from the Global Burden of Disease Study 2019.

OBJECTIVES: Increasing life expectancy and decreasing mortality in patients with HIV infection are well documented. However, details of how many of the years of healthy life are damaged by HIV infection vs. good health have not been understood. We conducted this study to provide a comprehensive assessment of the levels and trends of the global burden, as measured by disability-adjusted life years (DALYs), of HIV infection. METHODS: Data on HIV-related DALY were obtained from the Global Burden of Disease Study 2019. The absolute numbers and age-standardised rates of DALYs due to HIV were reported between 1990 and 2019. Estimated annual percentage changes in age-standardised rates by sex, region and nation were calculated to quantify the temporal trends in HIV burden. RESULTS: Global HIV infection caused 47.63 million DALYs in 2019, presenting a 1.28-fold increase from 1990 to 2019. In 2019, years of life lost contributed to most of the total DALYs, but the increases in HIV-related years lived with disability have outpaced increases in years of life lost. The age-standardised rates of HIV-related DALYs in 2019 decreased as the sociodemographic indexes increased. The highest age-standardised rates were observed in sub-Saharan Africa, and the greatest increments over time were detected in Oceania. CONCLUSIONS: Globally, HIV continues to cause enormous healthy life loss. The first and foremost strategy for controlling the HIV burden is still the reduction of premature deaths, and much effort needs to be exerted to mitigate the harm of comorbidities.

HB-EGF-induced IL-8 secretion from airway epithelium leads to lung fibroblast proliferation and migration.

BACKGROUND: We have reported that heparin-binding epidermal growth factor (HB-EGF) is increased in patients with chronic obstructive pulmonary disease (COPD) and associated with collagen deposition, but the mechanisms remain unclear. In the present study, we aimed to investigated the inflammatory cytokines secreted by bronchial epithelial cells following exposure to HB-EGF that promoted proliferation and migration of human lung fibroblast. METHODS: HB-EGF-induced inflammatory cytokines were assayed in two airway epithelial cells (primary human bronchial epithelial cells [HBECs] and BEAS-2B cells). Moreover, the culture supernatants derived from HB-EGF-treated HBECs and BEAS-2B cells were added to human primary lung fibroblasts. The effect of culture supernatants on proliferation and migration of fibroblasts was assessed. RESULTS: IL-8 expression was significantly increased in bronchial epithelial cells treated with HB-EGF, which was at least partially dependent on NF-kB pathways activation. HB-EGF-induced IL-8 was found to further promote lung fibroblasts proliferation and migration, and the effects were attenuated after neutralizing IL-8. CONCLUSIONS: These findings suggest that HB-EGF may be involved in the pathology of airway fibrosis by induction of IL-8 from airway epithelium, subsequently causing lung fibroblasts proliferation and migration. Thus, inhibition of HBEGF and/or IL-8 production could prevent the development of airway fibrosis by modulating fibroblast activation.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

Bergenin-activated SIRT1 inhibits TNF-α-induced proinflammatory response by blocking the NF-κB signaling pathway.

BACKGROUND: Bergenin, a type of polyphenol compound, exhibits antiulcerogenic, anti-inflammatory, antitussive, and burn wound-healing properties. However, its therapeutic effect on tumor necrosis factor α (TNF-α)-induced proinflammatory responses in the airway and potential mechanisms of actions are still unclear. This study aimed to investigate the anti-inflammatory effects and mechanism of bergenin in TNF-α-stimulated human bronchial epithelial (16-HBE) cells. METHODS: Cell Counting Kit-8 was used to evaluate cytotoxicity. Cytokine expression was analyzed by reverse transcription-quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay. Immunofluorescence, western blot, and sirtuin-1 (SIRT1) activity assays were employed to investigate potential molecular mechanisms. RESULTS: Bergenin obviously decreased both mRNA and protein expression levels of interleukins 6 and 8 (IL-6 and IL-8) in TNF-α-stimulated 16-HBE cells. Bergenin blocked TNF-α-mediated activation of nuclear factor κB (NF-κB) signaling and NF-κB nuclear translocation. Interestingly, RT-qPCR and western blotting results revealed that bergenin did not affect SIRT1 expression, but significantly increased its activity. Bergenin-mediated SIRT1 activation was further confirmed by results indicating decreased acetylation levels of NF-κB-p65 and p53. Moreover, the inhibitory effects of bergenin on mRNA and protein expression levels of IL-6 and IL-8 were reversed by a SIRT1 inhibitor. In addition, combining bergenin and dexamethasone (DEX) yielded additive effects on the reduction of IL-6 and IL-8 expression. CONCLUSIONS: These findings demonstrate that bergenin could suppress TNF-α-induced proinflammatory responses by augmenting SIRT1 activity to block the NF-κB signaling pathway, which may provide beneficial effects for the treatment of airway inflammation associated with asthma.

MTOR Suppresses Cigarette Smoke-Induced Epithelial Cell Death and Airway Inflammation in Chronic Obstructive Pulmonary Disease.

Airway epithelial cell death and inflammation are pathological features of chronic obstructive pulmonary disease (COPD). Mechanistic target of rapamycin (MTOR) is involved in inflammation and multiple cellular processes, e.g., autophagy and apoptosis, but little is known about its function in COPD pathogenesis. In this article, we illustrate how MTOR regulates cigarette smoke (CS)-induced cell death, airway inflammation, and emphysema. Expression of MTOR was significantly decreased and its suppressive signaling protein, tuberous sclerosis 2 (TSC2), was increased in the airway epithelium of human COPD and in mouse lungs with chronic CS exposure. In human bronchial epithelial cells, CS extract (CSE) activated TSC2, inhibited MTOR, and induced autophagy. The TSC2-MTOR axis orchestrated CSE-induced autophagy, apoptosis, and necroptosis in human bronchial epithelial cells; all of which cooperatively regulated CSE-induced inflammatory cytokines IL-6 and IL-8 through the NF-κB pathway. Mice with a specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly augmented airway inflammation and airspace enlargement in response to CS exposure, accompanied with enhanced levels of autophagy, apoptosis, and necroptosis in the lungs. Taken together, these data demonstrate that MTOR suppresses CS-induced inflammation and emphysema-likely through modulation of autophagy, apoptosis, and necroptosis-and thus suggest that activation of MTOR may represent a novel therapeutic strategy for COPD.

HDAC2 attenuates airway inflammation by suppressing IL-17A production in HDM-challenged mice.

Histone deacetylase (HDAC)2 is expressed in airway epithelium and plays a pivotal role in inflammatory cells. However, the role of HDAC2 in allergic airway inflammation remains poorly understood. In the present study, we determined the role of HDAC2 in airway inflammation using in vivo models of house dust mite (HDM)-induced allergic inflammation and in vitro cultures of human bronchial epithelial (HBE) cells exposed to HDM, IL-17A, or both. We observed that HDM-challenged Hdac2+/- mice exhibited substantially enhanced infiltration of inflammatory cells. Higher levels of T helper 2 cytokines and IL-17A expression were found in lung tissues of HDM-challenged Hdac2+/- mice. Interestingly, IL-17A deletion or anti-IL-17A treatment reversed the enhanced airway inflammation induced by HDAC2 impairment. In vitro, HDM and IL-17A synergistically decreased HDAC2 expression in HBE cells. HDAC2 gene silencing further enhanced HDM- and/or IL-17A-induced inflammatory cytokines in HBE cells. HDAC2 overexpresion or blocking IL-17A gene expression restored the enhanced inflammatory cytokines. Collectively, these results support a protective role of HDAC2 in HDM-induced airway inflammation by suppressing IL-17A production and might suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of allergic airway inflammation.

Heparin-binding epidermal growth factor contributes to COPD disease severity by modulating airway fibrosis and pulmonary epithelial-mesenchymal transition.

Although airway fibrosis and epithelial-mesenchymal transition (EMT) contribute to airway remodeling in chronic obstructive pulmonary disease (COPD), the mechanisms underlying their development have not been fully elucidated. In the present study, we aimed to assess heparin-binding epidermal growth factor (HB-EGF) expression in the airways of patients with COPD and to elucidate the possible role of HB-EGF in the pathology of COPD. Sputum and lung tissue HB-EGF expression was evaluated in control subjects and patients with COPD. The relationships between HB-EGF expression, disease severity, collagen deposition (fibrosis), and EMT were investigated. In vitro, human bronchial epithelial (HBE) cells and lung fibroblast cells exposed to the recombinant HB-EGF, collagen deposition and EMT were assessed. We found that sputum HB-EGF expression was significantly increased in patients with COPD compared with non-smokers and smokers without COPD. There was a significant positive correlation between sputum HB-EGF and COPD assessment test (CAT) score. HB-EGF expression was significantly increased in the lung tissue samples of patients with COPD and associated with collagen deposition and N- and E-cadherin, and vimentin expression. In vitro, HB-EGF promoted collagen production in lung fibroblasts. Moreover, HB-EGF induced the EMT process through induction of N-and E-cadherin, and vimentin expression in HBE cells. Collectively, HB-EGF induces airway remodeling by modulating airway fibrosis and pulmonary EMT, and contributes to the COPD severity. The current data may provide insight into the underlying pathogenesis of COPD, in which HB-EGF has an important pathogenic role.

Proteomic analysis of sputum reveals novel biomarkers for various presentations of asthma.

BACKGROUND: It is now recognized that asthma can present in different forms. Typically, asthma present with symptoms of wheeze, breathlessness and cough. Atypical forms of asthma such as cough variant asthma (CVA) or chest tightness variant asthma (CTVA) do not wheeze. We hypothesize that these different forms of asthma may have distinctive cellular and molecular features. METHODS: 30 patients with typical or classical asthma (CA), 27 patients with CVA, 30 patients with CTVA, and 30 healthy control adults were enrolled in this prospective study. We measured serum IgE, lung function, sputum eosinophils, nitric oxide in exhaled breath (FeNO). We performed proteomic analysis of induced-sputum supernatants by mass spectrometry. RESULTS: There were no significant differences in atopy and FEV1 among patients with CA, CVA, and CTVA. Serum IgE, sputum eosinophil percentages, FeNO, anxiety and depression scores were significantly increased in the three presentations of asthmatic patients as compared with healthy controls but there was no difference between the asthmatic groups. Comprehensive mass spectrometric analysis revealed more than a thousand proteins in the sputum from patients with CA, CVA, and CTVA, among which 23 secreted proteins were higher in patients than that in controls. CONCLUSIONS: Patients with CA, CVA, or CTVA share common clinical characteristics of eosinophilic airway inflammation. And more importantly, their sputum samples were composed with common factors with minor distinctions. These findings support the concept that these three different presentations of asthma have similar pathogenetic mechanism in terms of an enhanced Th2 associated with eosinophilia. In addition, this study identified a pool of novel biomarkers for diagnosis of asthma and to label its subtypes. Trial registration http://www.chictr.org.cn (ChiCTR-OOC-15006221).

YKL-40 expression in chronic obstructive pulmonary disease: relation to acute exacerbations and airway remodeling.

BACKGROUND: Recent studies suggest that YKL-40, also called chitinase-3-like-1 protein, has been implicated in the pathogenesis of various inflammatory diseases. It is currently unknown, however, whether YKL-40 plays a role in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and airway remodeling. METHODS: We evaluated serum YKL-40 levels in patients with AECOPD (n = 37) and stable COPD (n = 44), as well as in controls (n = 47). The association between YKL-40 expression and airway remodeling was analyzed. The effects of YKL-40 on collagen synthesis of primary human lung fibroblasts were also evaluated. RESULTS: Serum YKL-40 levels were elevated at AECOPD onset as compared to stable disease (median [interquartile range], 78.6 [52.3-122.2] ng/ml versus 46.7 [31.2-75.5] ng/ml; p = 0.0005). The ideal cutoff point for distinguishing patients with AECOPD from those with stable COPD was 64.7 ng/ml (AUC: 0.71; 95%CI: 0.596 to 0.823). YKL-40 expression correlated with airflow obstruction, C-reactive protein, and collagen deposition. Stimulation with YKL-40 promoted collagen production in lung fibroblasts through ERK- and p38-dependent mechanisms. CONCLUSIONS: YKL-40 expression is up-regulated in patients with COPD and correlates with exacerbation attacks and may contribute to airway remodeling by acting on lung fibroblasts. The current data may provide insight into the underlying pathogenesis of COPD, in which YKL-40 has an important pathogenic role. TRIAL REGISTRATION: ChiCTR-OCC-13003567.

Increases in peripheral SIRT1: a new biological characteristic of asthma.

BACKGROUND AND OBJECTIVE: Silent information regulator 1 (SIRT1) is a class III histone deacetylase that exerts both anti-inflammatory and anti-aging effects. However, no data are available regarding SIRT1 expression in patients with asthma. Here, we studied SIRT1 levels in the serum of patients with asthma and analysed the distribution of SIRT1 in both the serum and the lungs in an asthmatic mouse model to determine its clinical significance. METHODS: Serum SIRT1 levels, total immunoglobulin E (IgE) levels and peripheral blood eosinophil percentages as well as pulmonary function were quantified in 97 patients with asthma and 118 healthy volunteers. BALB/c mice were sensitized and challenged using ovalbumin (OVA) to produce the asthmatic model, and SIRT1 levels in both the serum and the lung tissues were subsequently measured. RESULTS: The serum SIRT1 levels were significantly elevated in the patients with asthma compared with the controls. Serum SIRT1 levels positively correlated with total IgE levels and negatively correlated with pulmonary function. In the OVA-sensitized and challenged mice, an increased serum SIRT1 level was confirmed, whereas decreased SIRT1 expression was observed in the lung tissues. CONCLUSIONS: These data indicate that lung SIRT1 expression decreased while serum SIRT1 increased in the setting of asthma. Serum SIRT1 levels correlate positively with both IgE levels and negatively with pulmonary function, suggesting that increased peripheral SIRT1 levels represent a new biological characteristic of asthma. Increased serum SIRT1 may be an auxiliary index for the diagnosis of asthma and elevating lung SIRT1 levels may be a new strategy for asthma therapy.

YKL-40 is correlated with FEV1 and the asthma control test (ACT) in asthmatic patients: influence of treatment.

BACKGROUND: YKL-40 is also called chitinase-3-like-1 (CHI3L1) protein and may be a marker for asthma. The aims of the present study were to investigate whether serum YKL-40 levels are stable or decreased in patients with asthma after appropriate treatment and to evaluate the correlation of YKL-40 levels with lung function and asthma control test (ACT) results. METHODS: A total of 103 asthmatic patients (mean age 33.1 ± 0.9 years) with diagnosed asthma were enrolled in our study. All patients underwent a detailed clinical examination and completed the ACT questionnaire, serum YKL-40 measurement, and spirometry before (visit 1) and 8 weeks after initiation of treatment (visit 2). RESULTS: At the follow-up, the median serum YKL-40 level was significantly decreased compared to the levels at visit 1 (75.2 [55.8-86.8] ng/ml versus 54.5 [46.4-58.4] ng/ml, p < 0.001). The serum YKL-40 level was negatively correlated with %FEV1 (r = -0.37, p < 0.001) and ACT score (r = -0.26, p = 0.007) at visit 1. The change in serum YKL-40 levels between the visits was significantly correlated with changes in FEV1 (r = -0.28, p = 0.006) and ACT score (r = -0.22, p = 0.037). Patients with elevated YKL-40 levels had significantly greater corticosteroid use than patients with lower levels. CONCLUSIONS: YKL-40 was reduced in the serum of asthmatic patients after appropriate treatment, and the levels correlated with improvements in %FEV1 and ACT. High levels of serum YKL-40 may be refractory to current asthma treatments. TRIAL REGISTRATION: ChiCTR-OCC-13003316.

[Distribution of influenza A (H5N1) virus and pathological lesions in major organ tissues of experimentally infected rhesus macaques].

OBJECTIVE: To investigate the pathological changes and viral invasion in the main organs of rhesus macaques after experimental infection with H5N1 virus. METHODS: The rhesus macaques were infected with H5N1 virus (AF148678/ACGoose/Guangdong/11961H5N1) by nasal inoculation under anesthesia. One rhesus macaque was killed respectively at 1, 3, 6, 14 days after infection. The pathologic changes of the main organs were observed using HE staining and the characteristics of the viral invasion in the body were analyzed using viral isolation, RT-PCR andimmunohistochemistry. RESULTS: The influenza virus replicated only in the lung tissues characterized by diffuse alveolar damage in the infected rhesus macaques, mainly involving alveolar epithelial cells and pulmonary macrophages. The pathological changes showed 3 phases including exudative inflammation, hyperplasia and fibrosis. Extra-pulmonary organs also showed different degree of pathological changes such as degeneration and necrosis, but virus was not isolated in the corresponding organs. CONCLUSIONS: Acute diffuse lung injury was a central part of the pathogenesis in H5N1 avian influenza virus infection. The lung was the main target organ in H5N1 viral infection, and H5N1 virus cannot replicate in other organs, which may be one of the obstacles to H5N1 viral transmission from person to person.

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.

Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

Myeloid-Specific SIRT6 Deletion Protects Against Particulate Matter (PM2.5)-Induced Airway Inflammation.

Purpose: Particulate matter (PM2.5) is a common risk factor for airway inflammation. Alveolar macrophages play a critical role in airway inflammation. Sirtuin 6 (SIRT6) is a class Ill histone deacetylase that exerts an anti-inflammatory effect in airway diseases. However, the role of SIRT6 on PM2.5-induced airway inflammation in macrophages remains unclear. We aimed to determine whether SIRT6 protects against PM2.5-induced airway inflammation in macrophages. Methods: The effect of SIRT6 on PM2.5-induced airway inflammation was assessed by using THP1 cells or bone marrow-derived macrophages (BMDMs) exposed to PM2.5 in vitro and myeloid cell-specific SIRT6 conditional knockout mice (Sirt6fl/fl-LysMCre) in vivo. Results: PM2.5 increased SIRT6 expression in THP1 cells, but SIRT6 gene silencing decreased PM2.5 induced inflammatory cytokines in THP1 cells. Moreover, the expression of SIRT6 and inflammatory cytokines was also decreased in BMDMs with myeloid-specific deletion of SIRT6 after stimulation of PM2.5. In vivo, Sirt6fl/fl-LysMCre mice substantially decreased airway inflammation in response to PM2.5 exposure. Conclusion: Our results revealed that SIRT6 promotes the PM2.5-induced airway inflammation in macrophages and indicated that inhibition of SIRT6 in macrophages may represent therapeutic strategy for airway disorders induced by airborne particulate pollution.