Exposure to particulate matter (PM) can cause airway inflammation and worsen various airway diseases. However, the underlying molecular mechanism by which PM triggers airway inflammation has not been completely elucidated, and effective interventions are lacking. Our study revealed that PM exposure increased the expression of histone deacetylase 9 (HDAC9) in human bronchial epithelial cells and mouse airway epithelium through the METTL3/m6A methylation/IGF2BP3 pathway. Functional assays showed that HDAC9 upregulation promoted PM-induced airway inflammation and activation of MAPK signaling pathway in vitro and in vivo. Mechanistically, HDAC9 modulated the deacetylation of histone 4 acetylation at K12 (H4K12) in the promoter region of dual specificity phosphatase 9 (DUSP9) to repress the expression of DUSP9 and resulting in the activation of MAPK signaling pathway, thereby promoting PM-induced airway inflammation. Additionally, HDAC9 bound to MEF2A to weaken its anti-inflammatory effect on PM-induced airway inflammation. Then, we developed a novel inhaled lipid nanoparticle system for delivering HDAC9 siRNA to the airway, offering an effective treatment for PM-induced airway inflammation. Collectively, we elucidated the crucial regulatory mechanism of HDAC9 in PM-induced airway inflammation and introduced an inhaled therapeutic approach targeting HDAC9. These findings contribute to alleviating the burden of various airway diseases caused by PM exposure.

The airway epithelium is located at the interactional boundary between the external and internal environments of the organism and is often exposed to harmful environmental stimuli. Inflammatory response that occurs after airway epithelial stress is the basis of many lung and systemic diseases. Chloride intracellular channel 4 (CLIC4) is abundantly expressed in epithelial cells. The purpose of this study was to investigate whether CLIC4 is involved in the regulation of lipopolysaccharide (LPS)-induced inflammatory response in airway epithelial cells and to clarify its potential mechanism. Our results showed that LPS induced inflammatory response and decreased CLIC4 levels in vivo and in vitro. CLIC4 silencing aggravated the inflammatory response in epithelial cells, while overexpression of CLIC4 combined with LPS exposure significantly decreased the inflammatory response compared with cells exposed to LPS without CLIC4 overexpression. By labeling intracellular chloride ions with chloride fluorescent probe MQAE, we showed that CLIC4 mediated intracellular chloride ion-regulated LPS-induced cellular inflammatory response.

BACKGROUND: Obese asthma is an asthma phenotype that causes more severe lung inflammation and airway hyperresponsiveness than allergic asthma and it is resistant to conventional therapy. Involucrasin B (IB) is a dihydroflavonoid isolated from Shuteria involucrata (Wall.) Wight & Arn., a traditional \"Dai\" and \"Wa\" medicine was used in southern China to treat the \"phlegm and wetness of sputum\" (obesity disease) as well as lung inflammation. However, whether IB can ameliorate obese asthma remains unclear, and the underlying mechanisms and molecular expression in obese asthma specifically targeted by IB are still not fully understood.
METHODS: An in vivo C57BL/6 J mouse model of obese asthma was established using house dust mites (HDMs) and high-fat diet (HFD) as inducers to evaluate the therapeutic effect of IB. An in vitro cell culture of human THP-1 monocytic cell culture was used to investigate the effect of IB after the treatment with lipopolysaccharide (LPS) and palmitic acid (PA).
RESULTS: In vivo, we found that intervention with IB improved airway hyperresponsiveness and lung histopathology and significantly inhibited the secretion of relevant inflammatory factors, such as interleukin (IL)-1β, IL-17A, and IL-22 in bronchoalveolar lavage fluid, and total-IgE and HDM-IgE in serum compared with the model group (HFD+HDM). The findings indicate that IB could decrease the expression of granulocyte receptor 1 (Gr-1) and neutrophil extracellular traps (NETs) in lung tissue, as well as the expression of NLR family pyrin domain containing 3 (NLRP3) and inducible nitric oxide synthase in M1 macrophages (M1). IB also reduced the population of ILC3/Th17 cells, which are responsible for producing IL-17A, a crucial mediator of neutrophil-mediated inflammation, confirming that the therapeutic effect of IB in obesity-related asthma was related to neutrophils and M1 cells. In addition, IB regulated lipid metabolism and inhibited the production of macrophages in adipose tissue. The in vitro results revealed that IB inhibited the secretion of IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) from THP-1 cells, and the expression of NLRP3-related protein in THP-1 cells compared with the model groups (LPS, PA, and LPS+PA), confirming that the action of IB involved the TLR4-NF-κB-NLRP3 pathway.
CONCLUSIONS: This study demonstrated the therapeutic effect of IB in obese asthma for the first time and further clarified its mechanistic pathway as the TLR4-NF-κB-NLRP3 pathway.

OBJECTIVE: Asthma is a heterogeneous disease characterized by chronic airway inflammation. Huashanshen dripping pills (HSS) are commonly utilized for relieving asthma, relieving cough, and expelling phlegm. At present, the molecular mechanism against airway inflammation remains unclear.
METHODS: In this study, network pharmacology, molecular docking technology, and molecular dynamic simulation were used to predict the therapeutic pathways of HSS for asthma. The ovalbumin-induced mouse model was used to further validate the prediction by RT-qPCR, western blot, immunofluorescence, and related methods.
RESULTS: The findings indicate that HSS improves lung function and relieves lung inflammation by reducing inflammatory cell infiltration around the bronchus and reducing eosinophilic counts in bronchoalveolar lavage fluid (BALF). In addition, it lowers the levels of inflammatory cytokines and the expression levels of interleukin-4, interleukin-5, and interleukin-13 mRNA. HSS also inhibits the phosphorylation and nuclear translocation of NF-κB p65 protein.
CONCLUSIONS: All results suggested that HSS can decrease airway inflammation in asthmatic mice by inhibiting NF-κB signaling pathway. This finding will shed light on how it can be used to treat asthma.

BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear.
METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma.
RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway.
CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.

BACKGROUND: Icariin (ICA) inhibits inflammatory response in various diseases, but the mechanism underlying ICA treating airway inflammation in asthma needs further understood. We aimed to predict and validate the potential targets of ICA against asthma-associated airway inflammation using network pharmacology and experiments.
METHODS: The ovalbumin-induced asthma-associated airway inflammation mice model was established. The effects of ICA were evaluated by behavioral, airway hyperresponsiveness, lung pathological changes, inflammatory cell and cytokines counts. Next, the corresponding targets of ICA were mined via the SEA, CTD, HERB, PharmMapper, Symmap database and the literature. Pubmed-Gene and GeneCards databases were used to screen asthma and airway inflammation-related targets. The overlapping targets were used to build an interaction network, analyze gene ontology and enrich pathways. Subsequently, flow cytometry, quantitative real-time PCR and western blotting were employed for validation.
RESULTS: ICA alleviated the airway inflammation of asthma; 402 targets of ICA, 5136 targets of asthma and 4531 targets of airway inflammation were screened; 216 overlapping targets were matched and predicted ICA possesses the potential to modulate asthmatic airway inflammation by macrophage activation/polarization. Additionally, ICA decreased M1 but elevated M2. Potential targets that were disrupted by asthma inflammation were restored by ICA treatment.
CONCLUSIONS: ICA alleviates airway inflammation in asthma by inhibiting the M1 polarization of alveolar macrophages, which is related to metabolic reprogramming. Jun, Jak2, Syk, Tnf, Aldh2, Aldh9a1, Nos1, Nos2 and Nos3 represent potential targets of therapeutic intervention. The present study enhances understanding of the anti-airway inflammation effects of ICA, especially in asthma.

The health effects of ultrafine particles (UFPs) are of growing global concern, but the epidemiological evidence remains limited. Sleep-disordered breathing (SDB) characterized by hypoxemia is a prevalent condition linked to many debilitating chronic diseases. However, the role of UFPs in the development of SDB is lacking. Therefore, this prospective panel study was performed to specifically investigate the association of short-term exposure to UFPs with SDB parameters in patients with chronic obstructive pulmonary disease (COPD). Ninety-one COPD patients completed 226 clinical visits in Beijing, China. Personal exposure to ambient UFPs of 0-7 days was estimated based on infiltration factor and time-activity pattern. Real-time monitoring of sleep oxygen saturation, spirometry, respiratory questionnaires and airway inflammation detection were performed at each clinical visit. Generalized estimating equation was used to estimate the effects of UFPs. Exposure to UFPs was significantly associated with increased oxygen desaturation index (ODI) and percent of the time with oxygen saturation below 90 % (T90), with estimates of 21.50 % (95%CI: 6.38 %, 38.76 %) and 18.75 % (95%CI: 2.83 %, 37.14 %), respectively, per 3442 particles/cm3 increment of UFPs at lag 0-3 h. Particularly, UFPs\' exposure within 0-7 days was positively associated with the concentration of alveolar nitric oxide (CaNO), and alveolar eosinophilic inflammation measured by CaNO exceeding 5 ppb was associated with 29.63 % and 33.48 % increases in ODI and T90, respectively. In addition, amplified effects on oxygen desaturation were observed in current smokers. Notably, individuals with better lung function and activity tolerance were more affected by ambient UFPs due to longer time spent outdoors. To our knowledge, this is the first study to link UFPs to hypoxemia during sleep and uncover the key role of alveolar eosinophilic inflammation. Our findings provide new insights into the effect spectrum of UFPs and potential environmental and behavioral intervention strategies to protect susceptible populations.

BACKGROUND: Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown.
METHODS: C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF).
RESULTS: The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF.
CONCLUSIONS: These results highlight OAW\'s robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.

OBJECTIVE: To explore the effects of iris xanthin on airway inflammation, airway remodeling, and the high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in asthmatic young mice.
METHODS: Sixty male BALB/c young mice were randomly assigned into six groups: a blank group, a model group, a dexamethasone group, and low, medium, and high dose groups of iris xanthin, with ten mice per group. Asthma models were induced through intraperitoneal injections of a sensitizing agent [ovalbumin (OVA) 20 μg + aluminum hydroxide gel 2 mg], followed by 4% OVA aerosol inhalation. Lung function was measured using a pulmonary function tester to determine lung volume (LV), resting ventilation per minute (VE), and airway reactivity (Penh value). Hematoxylin-eosin (HE) staining was employed to examine and analyze airway remodeling. The contents of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid were quantified using ELISA. Real-time fluorescence quantitative polymerase chain reaction and Western blot analysis were used to assess the expression of HMGB1/TLR4/NF-κB pathway-related mRNA and proteins in lung tissues.
RESULTS: Compared to the model group, the dexamethasone and iris xanthin-treated groups (low, medium, and high doses) exhibited significant increases in LV and VE (P<0.05), with incremental dose-dependent increases observed in the iris xanthin groups. Additionally, Penh values, IL-1β, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, and NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were all reduced (P<0.05) in a dose-dependent manner. When compared to the dexamethasone group, the low and medium dose iris xanthin groups showed decreases in LV and VE (P<0.05), whereas Penh values, IL-1β, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were increased (P<0.05). No significant differences were noted in these indices between the high dose iris xanthin group and the dexamethasone group (P>0.05).
CONCLUSIONS: Iris xanthin can effectively alleviates airway inflammation and inhibits airway remodeling in asthmatic young mice, possibly through the suppression of the HMGB1/TLR4/NF-κB pathway.
目的: 探究鸢尾黄素对哮喘幼鼠气道炎症、气道重塑及高迁移率族蛋白B1（high mobility group box 1 protein, HMGB1）/Toll样受体4（Toll-like receptor 4, TLR4）/核因子κB（nuclear factor-κB, NF-κB）通路的影响。方法: 将60只雄性BALB/c幼鼠随机分为空白组、模型组、地塞米松组，以及鸢尾黄素低、中、高剂量组，每组10只。采用腹腔注射致敏剂［卵清蛋白（ovalbumin, OVA）20 μg+氢氧化铝凝胶2 mg］+4% OVA雾化吸入激发建立幼鼠哮喘模型。肺功能检测仪检测幼鼠肺容积（lung volume, LV）、每分钟静息通气量（resting ventilation per minute, VE）及气道反应性（Penh值）；苏木精-伊红染色观察并分析气道重塑情况；ELISA法检测肺泡灌洗液中白介素（interleukin, IL）-1β、IL-6、肿瘤坏死因子α（tumor necrosis factor alpha, TNF-α）含量；实时定量逆转录聚合酶链反应及Western blot法检测肺组织中HMGB1/TLR4/NF-κB通路相关mRNA及蛋白表达。结果: 与模型组比较，地塞米松组及鸢尾黄素低、中、高剂量组LV、VE均显著升高（P<0.05），其中鸢尾黄素各剂量组随剂量增加LV、VE升高（P<0.05）；地塞米松组及鸢尾黄素低、中、高剂量组Penh值、IL-1β、IL-6、TNF-α、气道重塑指标，以及HMGB1、TLR4、NF-κB p65 mRNA和HMGB1、TLR4、p-NF-κB p65蛋白表达水平均降低（P<0.05），其中鸢尾黄素各剂量组随剂量增加上述指标降低（P<0.05）。与地塞米松组比较，鸢尾黄素低、中剂量组LV、VE均降低（P<0.05），Penh值、IL-1β、IL-6、TNF-α、气道重塑指标，以及HMGB1、TLR4、NF-κB p65 mRNA和HMGB1、TLR4、p-NF-κB p65蛋白表达水平均升高（P<0.05）；鸢尾黄素高剂量组上述指标与地塞米松组比较差异无统计学意义（P>0.05）。结论: 鸢尾黄素能有效减轻哮喘幼鼠气道炎症，抑制气道重塑，可能与抑制HMGB1/TLR4/NF-κB通路有关。.

Chronic cough is a common disorder lasting more than 8 weeks and affecting all age groups. The evidence supporting the role of neutrophils in chronic cough pathology is based on many patients with chronic cough developing airway neutrophilia. How neutrophils influence the development of chronic cough is unknown. However, they are likely involved in multiple aspects of cough etiology, including promoting airway inflammation, airway remodeling, hyper-responsiveness, local neurogenic inflammation, and other possible mechanisms. Neutrophilic airway inflammation is also associated with refractory cough, poor control of underlying diseases (e.g., asthma), and insensitivity to cough suppressant therapy. The potential for targeting neutrophils in chronic cough needs exploration, including developing new drugs targeting one or more neutrophil-mediated pathways or altering the neutrophil phenotype to alleviate chronic cough. How the airway microbiome differs, plays a role, and interacts with neutrophils in different cough etiologies is poorly understood. Future studies should focus on understanding the relationship between the airway microbiome and neutrophils.