Chronic Airway Inflammation Research Articles

Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.

Primary ciliary dyskinesia (PCD) is a rare heterogenic genetic disorder associated with perturbed biogenesis or function of motile cilia. Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage. Current approaches to treat PCD are symptomatic, only, indicating an urgent need for curative therapeutic options. Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures. Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.

Prognostic Value of Serum Cholinesterase Levels for In-Hospital Mortality among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Cholinesterase (ChE) is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD), including chronic airway inflammation and oxidation/antioxidant imbalance. However, the relationship between serum ChE levels and survival outcomes of patients hospitalized with acute exacerbations of COPD (AECOPD) is unknown. In this retrospective single-center study, we investigated the ability of the serum ChE level to predict in-hospital death in patients hospitalized with AECOPD. The clinicopathological data, including serum ChE levels as well as clinical and biochemical indicators were extracted for 477 patients from the hospital records and analyzed. Our results demonstrated that AECOPD patients with lower serum ChE levels were associated with increased mortality, frequent hospitalization due to acute exacerbations (AE) in the past year, and longer hospital stay. The optimal cutoff value for the serum ChE level was 4323 U/L. The area under the ROC curve (AUC) values for predicting in-hospital mortality based on the serum ChE level was 0.79 (95% confidence interval (CI), 0.72–0.85). Multivariate logistic regression analysis demonstrated that serum ChE level ≤ 4323 U/L (odds ratio (OR) 9.09, 95% CI 3.43–28.3, p < 0.001), age-adjusted Charlson comorbidity index (aCCI), and the number of hospitalizations due to AE in the past year were independent risk factors for predicting the in-hospital mortality of AECOPD patients. In conclusion, our study demonstrated that low serum ChE levels were associated with significantly higher in-hospital mortality rates of patients hospitalized with AECOPD. Therefore, serum ChE level is a promising prognostic predictor of hospitalized AECOPD patients.

Zi-Su-Zi decoction improves airway hyperresponsiveness in cough-variant asthma rat model through PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways

Ethnopharmacological relevanceCough-variant asthma (CVA) is one of the most common causes of chronic cough. Its pathogenesis is closely related to chronic airway inflammation and airway hyperresponsiveness. CVA belongs to the category of “wind cough” in Traditional Chinese medicine (TCM). Zi-Su-Zi decoction (ZSD) is a Chinese herbal formula that is clinically used for the treatment of cough and asthma, especially CVA. However, the mechanism of action remains unclear. Aim of the studyIn this study, we aimed to explore the potential mechanism by which ZSD improves CVA airway hyperresponsiveness. Materials and methodsThe targets of ZSD in CVA were studied using a Network pharmacology. The main chemical components of ZSD were detected and analyzed using ultra-high-pressure liquid chromatography (UHPLC-MS/MS). In animal experiments, the rat model of CVA was established using Ovalbumin (OVA)/Aluminum hydroxide (AL(OH)3) sensitization. Moreover, the experiment also evaluated cough symptoms, percentage of eosinophils (EOS%), pulmonary function tests, histopathological sections, blood cytokine levels, mRNA and protein levels. ResultsThe results showed that Network pharmacology suggested 276 targets of ZSD and CVA and found that ZSD treatment with CVA was closely related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. UHPLC-MS/MS revealed that ZSD contained 52 main chemical components. Compared with the model group, the cough symptoms of the rats in the different ZSD concentration groups were relieved, the EOS% index was lowered, and body weight was increased. HE staining showed that ZSD reduced airway inflammation, edema and hyperplasia, thereby improving the pathological structure of lung tissue, and the effect of high-dose ZSD was especially significant. Our most important finding was that ZSD blocked the entry of hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription-3 (STAT3) and nuclear factor kappa-B (NF-κB) into the nucleus by interfering with PI3K/AKT1/mechanistic target of rapamycin (mTOR), and janus kinase 2 (JAK2) signaling factors. Consequently, inhibiting the release of cytokines and immunoglobulin-E, thereby reducing airway hyperresponsiveness (AHR) and partially reverses airway remodeling. ConclusionsThis study showed that ZSD can improve airway hyperresponsiveness and partially reverse airway remodeling by inhibiting the PI3K/AKT1/mTOR, JAK2/STAT3 and HIF-1α/NF-κB signaling pathways. Therefore, ZSD is an effective prescription for the treatment of CVA.

To Study the Effectiveness of Inhalation Technique Training in Patients with COPD and Asthma.

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. Lack of knowledge about the correct inhalation techniques leads to poor control of both diseases. This study aimed to study the effectiveness of inhalation technique training in patients with COPD and asthma. A total of 132 patients fulfilling the inclusion criteria were trained with the correct technique of inhalation on day 0 and at the end of 1 and 6 months. Evaluation of technique training was done on these three occasions posttraining. The mean score of devices was obtained, and the mean inhalation technique score of various devices was compared. Out of 132 patients, 65.1% (86/132) patients were using a dry powdered inhaler (DPIs), 26.5% (35/132) patients used metered dose inhalers (MDIs), and 8.4% (11/132) patients used MDI with spacer. The mean scores of patients using MDI at baseline were 5.68 ± 0.83, and after 1 month, 6.68 ± 0.58 (p &lt; 0.000). The inhalation technique mean score of MDI improved after 6 months, 7.02 ± 0.56 as compared to baseline (p &lt; 0.008) mean score of the patients using DPIs improved after 1 month, 5.53 ± 0.58 as compared to baseline 4.37 ± 5.53 (p &lt; 0.000). There was no statistical improvement in the device mean score of DPIs after 6 months, 5.62 ± 0.55 when compared with 1 month, 5.53 ± 0.58 (p &lt; 0.117). Patients who used pressurized metered-dose inhalers (pMDI) with spacers improved their inhalation score after 1 month by 6.90 ± 0.94 as compared to the baseline score of 6.90 ± 0.94 (p &lt; 0.001). The mean score decreased marginally after 6 months, 7.818 ± 0.60, as compared to the score at the end of 1 month of 8.27 ± 0.64 (p &lt; 0.053). Patients showed improvement in the technique of inhalation after educational training, reinstructions, and a standard checklist.

Role of Caspase-11 in house dust mites-mediated lung inflammation

Abstract Asthma is a long-term recurring inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, chronic airway inflammation and bronchial hyper-responsiveness. House dust mites (HDM), such as Dermatophagoides pteronyssinus, are an unsurpassed cause of atopic sensitization and the major causes of allergic asthma worldwide. The multiprotein complexness of the canonical and noncanonical inflammasomes assemble in response to pathogen or danger-associated molecular patterns (PAMPs or DAMPs). We have shown that caspase-11 expression is induced in vitro in response to HDM. Treatment with TH2 cytokines such as IL-4 and IL-13 mediates caspase-11 expression. Additionally, caspase-11−/−macrophages show reduced release of IL-6, IL-12, and KC, and express lower levels of costimulatory molecules (e.g., CD40, CD86 and MHCII) in response to HDM stimulation. Notably, similar level of IgE responses and similar degree of hypothermia in response to nasal HDM challenge were seen in WT and caspase-11−/−mice following HDM sensitization. However, altered inflammatory responses and reduced neutrophilia in bronchiolar alveolar lavage fluid (BALF) and in representative histopathological lung tissues were seen in the caspase-11−/−mice. Therefore, caspase-11 is a regulator of airway inflammation in response to HDM exposure.

Vitamin D mediated mitigation of fibrotic remodeling in asthma is associated with metabolic reprogramming

Vitamin D mediated mitigation of fibrotic remodeling in asthma is associated with metabolic reprogramming Rakhee K. Ramakrishnan1, Zaina Kalaji1, Khuloud Bajbouj1, Rabih Halwani1,2, Qutayba Hamid1,3 1 Sharjah Institute for Medical Research – College of Medicine, University of Sharjah, Sharjah, United Arab Emirates 2 Immunology Research Lab, College of Medicine, King Saud University, Riyadh, Saudi Arabia 3 Meakins-Christie Laboratories, McGill University, Montreal, Quebec, CanadaAsthma is a heterogeneous disorder that is associated with chronic airway inflammation and remodeling of the airways. While vitamin D deficiency has shown correlations with various clinical features of asthma, the mechanisms responsible for this action is poorly understood. This study therefore explored the molecular mechanisms associated with the anti-remodeling potential of vitamin D. We hypothesized that vitamin D induced metabolic reprogramming contributes to its anti-fibrotic activity. To this end, primary lung fibroblasts from asthmatic and non-asthmatic individuals were stimulated with TGF-β1 alone or in combination with the biologically active form of vitamin D, calcitriol. The expression of various fibrotic and metabolic markers was assessed both at the transcript and protein level. While vitamin D receptor (VDR) was constitutively expressed in human lung fibroblasts, calcitriol treatment induced a robust VDR response in asthmatic fibroblasts indicating increased VDR functionality in these cells when compared to normal. TGF-β1 stimulation led to an increase in the expression of several fibrotic markers, including COL1A1, COL3A1, COL5A1, FN1 and ACTA2, which was reversed after calcitriol treatment. These anti-fibrotic effects of calcitriol were associated with dysregulated AMPK signaling and an inhibition of TGF-β1-induced mitochondrial ROS release. Our findings thus, highlight the ability of vitamin D in regulating the cellular mitochondrial metabolism induced by TGF-β1 in lung fibroblasts, suggesting a possible mechanism associated with its anti-fibrotic activity. Since current asthma therapeutics do not effectively target the airway structural changes that are increasingly associated with asthma severity, vitamin D supplementation presents an attractive therapeutic avenue to attenuate subepithelial fibrosis and airway remodeling in asthmatic airways. We would like to acknowledge the funding received from University of Sharjah targeted research grant (ID 2101090295) in conducting this study. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prophylactic and therapeutic use of synthetically glycosylated antigens to limit allergic airway disease

Abstract Asthma is a disease involving chronic airway inflammation affecting more than 300 million people worldwide. There is currently no cure for asthma. While effective, corticosteroids cause broad immune suppression and long-term debilitating disease. Novel immune modulatory therapeutics leave patients vulnerable to infections. Therefore, there is a current need for new therapeutics that target the underlying causes of the disease without triggering detrimental side effects. Through synthetic glycosylation, our platform targets hepatic antigen presenting cells and leverages the liver’s tolerance-inducing mechanisms to limit inflammatory T cell responses, while promoting regulatory T cell (Treg) responses, thus preventing broad immunosuppression. In a model of experimental allergic airway inflammation, prophylactic treatment with synthetically mannosylated OVA (pMan OVA) ameliorated the allergic response to inhaled OVA. Our treatment reduced lung and airway eosinophilia, systemic levels of IgE and OVA-specific IgG1, and airway mucus. Furthermore, pMan OVAtreatment reduced OVA specific lung T H2 cells, and exhibited reduced production of IL-4, IL-5 and IL-13 upon antigen specific restimulation. Treatment with pMan OVAwas accompanied by induction of OVA-specific Tregs, which negatively correlated with features of allergic airway disease. In previously sensitized mice, therapeutic intervention with pMan OVAreduced airway and lung eosinophilia, B cell and CD4 +T cell inflammation. Altogether, these data suggest a potential role for prophylactic and therapeutic intervention with synthetically glycosylated allergens in ameliorating disease severity in a model of allergic airway inflammation.

Monocyte eosinophil ratio and red blood cell distribution width in the diagnosis of asthma

Objective: Bronchial asthma is often associated with chronic airway inflammation and airway hyperresponsiveness in which many cells and mediators are involved. Pulmonary function tests (PFTs) are used in the diagnosis of the disease. Yet PFTs are not available in every healthcare institution or some of the patients cannot cooperate with the procedure. The aim of this study was to determine whether mean platelet volume (MPV), platelet distribution width (PDW), monocyte lymphocyte ratio (MLR), monocyte eosinophil ratio (MER), and platelet lymphocyte ratio (PLR) can be used in the diagnosis of bronchial asthma.&#x0D; &#x0D; Method: Two hundred and twelve patients who were diagnosed with bronchial asthma according to the Global Initiative for Asthma (GINA) criteria and 187 patients who were deemed not to have asthma were included in the study. Two patient groups were compared by examining the hemogram parameters at the time of diagnosis or exclusion of asthma.&#x0D; &#x0D; Results: The levels of MPV, neutrophil-lymphocyte ratio (NLR), and PLR were significantly lower in the Asthma group (p

Delineating asthma according to inflammation phenotypes with a focus on paucigranulocytic asthma.

Asthma is characterized by chronic airway inflammation and airway hyper-responsiveness. However, the differences in pathophysiology and phenotypic symptomology make a diagnosis of "asthma" too broad hindering individualized treatment. Four asthmatic inflammatory phenotypes have been identified based on inflammatory cell profiles in sputum: eosinophilic, neutrophilic, paucigranulocytic, and mixed-granulocytic. Paucigranulocytic asthma may be one of the most common phenotypes in stable asthmatic patients, yet it remains much less studied than the other inflammatory phenotypes. Understanding of paucigranulocytic asthma in terms of phenotypic discrimination, distribution, stability, surrogate biomarkers, underlying pathophysiology, clinical characteristics, and current therapies is fragmented, which impedes clinical management of patients. This review brings together existing knowledge and ongoing research about asthma phenotypes, with a focus on paucigranulocytic asthma, in order to present a comprehensive picture that may clarify specific inflammatory phenotypes and thus improve clinical diagnoses and disease management.

Immunomodulatory effects of modified Liu-Wei-Di-Huang-Wan Traditional Chinese medicine on allergic asthmatic mice

BackgroundAllergic asthma occurs worldwide and is particularly prevalent in westernized countries characterized by chronic airway inflammation resulting in airway hyperresponsiveness. The house dust mites (HDM) including Dermatophagoides pteronyssinus are major sources of sensitization and triggering allergic symptoms in asthmatic patients. The Der p 2 is a major allergen and the predominant source of causative respiratory disorders which induce airway inflammation and bronchial constriction in mite-allergic patients. Few studies evaluate the ameliorating effects of modified Liu-Wei-Di-Huang-Wan (modified LWDHW) on allergic asthma.MethodsThis study aimed to investigate the immunological mechanisms of modified LWDHW on the reductions of airway inflammation, signal transduction, inflammatory cytokine production, Th2 cell proliferation, and bronchial obstruction in Der p 2-induced asthmatic mice.ResultsAt least ten active ingredients were contained in the formula of modified LWDHW- 1217A and 1217B. Results showed that the immunoglobulin generations (Der p 2 specific- IgE and IgG1), inflammatory cytokine productions (IL-5 and IL-13) in the Sera and BALF could be down-regulated, and the Th1-cytokine productions (IL-12 and IFN-γ) be increased after immunotherapy with modified LWDHW of 1217A or 1217B. The inflammatory cell infiltrations (macrophages, eosinophils, and neutrophils) in the airway and the expressions of TH2-related genes (IL-4, IL-5, and IL-13), TH2-related transcription factor (GATA-3), and neutrophil chemotactic chemokine (IL-8) in the lung tissue of asthmatic mice were significantly decreased after the immunotherapy. The Th1/Th2 polarization had been identified that the IL-4+/CD4+ T cells were downregulated and IFN-γ+/CD4+ T cells were increased. The airway hyperresponsiveness to methacholine inhalation of Penh values was significantly decreased in the treated groups. There were significant improvements in the bronchus histopathology after immunotherapy with 1217A or 1217B which were evaluated by tracheal thickness, inflammatory cell count, and tracheal rupture of mouse lung.ConclusionIt revealed that 1217A or 1217B could regulate the immune responses and improve pulmonary function. Data suggests that modified LWDHW of 1217A or 1217B have the potential for use as a therapeutic intervention for the treatment of mite allergen Der p 2-induced allergic asthma.

Calcium-Sensing Receptor Negative Allosteric Modulators Oppose Contraction of Mouse Airways.

Asthma is a heterogeneous chronic airways disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodelling and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared to standard-of-care has not yet been established. Further, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or MCh-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilisation and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse methacholine (MCh)-mediated airway contraction in mouse precision cut lung slices with similar maximal relaxation compared to the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β2 adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target, and NAMs as alternative or adjunct bronchodilators, in asthma.

Differentially expressed microRNAs in peripheral blood cell are associated with downregulated expression of IgE in nonallergic childhood asthma

Childhood asthma is a heterogeneous disease characterized by chronic airway inflammation, leading to a broad range of clinical presentations. Nonallergic asthma is asthma without allergic sensitization. Both clinical manifestations and immunopathological mechanisms of nonallergic childhood asthma were rarely investigated. We aimed to compare the clinical features between nonallergic and allergic childhood asthma and apply microRNA to explore the underlying mechanism of nonallergic childhood asthma. We enrolled 405 asthmatic children (76 nonallergic, 52 allergic with total IgE < 150 IU/mL and 277 allergic with total IgE > 150 IU/mL). Clinical characteristics were compared between groups. Comprehensive miRNA sequencing (RNA-seq) was performed using peripheral blood from 11 nonallergic and 11 allergic patients with elevated IgE, respectively. Differentially expressed miRNA (DEmiRNA) were determined with DESeq2. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed to determine functional pathways involved. Publicly available mRNA expression data was applied to investigate the predicted target mRNA networks via Ingenuity Pathway Analysis (IPA). The average age of nonallergic asthma was significantly younger (5.614 ± 2.743 vs 6.676 ± 3.118 years-old). Higher severity and worse control were more common in nonallergic asthma (two-way ANOVA, P < 0.0001). Long-term severity was higher, and intermittent attacks persisted in nonallergic patients. We identified 140 top DEmiRNAs based on false discovery rate (FDR) q-value < 0.001. Forty predicted target mRNA gene were associated with nonallergic asthma. The enriched pathway based on GO included Wnt signaling pathway. IgE expression was predicted to be downregulated by a network involving simultaneous interaction with IL-4, activation of IL-10 and inhibition of FCER2. Nonallergic childhood asthma were distinct in their younger age, higher long-term severity and more persistent course. Differentially expressed miRNA signatures associate with downregulation of total IgE expression and predicted target mRNA genes related molecular networks contribute to canonical pathways of nonallergic childhood asthma. We demonstrated the negative role of miRNAs involved in regulating IgE expression indicating differences between asthma phenotypes. Identification of biomarkers of miRNAs could contribute to understand the molecular mechanism of endotypes in nonallergic childhood asthma, which can potentially allow delivery of precision medicine to pediatric asthma.

Asthma: The Use of Animal Models and Their Translational Utility

Asthma is characterized by chronic lower airway inflammation that results in airway remodeling, which can lead to a permanent decrease in lung function. The pathophysiology driving the development of asthma is complex and heterogenous. Animal models have been and continue to be essential for the discovery of molecular pathways driving the pathophysiology of asthma and novel therapeutic approaches. Animal models of asthma may be induced or naturally occurring. Species used to study asthma include mouse, rat, guinea pig, cat, dog, sheep, horse, and nonhuman primate. Some of the aspects to consider when evaluating any of these asthma models are cost, labor, reagent availability, regulatory burden, relevance to natural disease in humans, type of lower airway inflammation, biological samples available for testing, and ultimately whether the model can answer the research question(s). This review aims to discuss the animal models most available for asthma investigation, with an emphasis on describing the inciting antigen/allergen, inflammatory response induced, and its translation to human asthma.

Abstract 3947: S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis

Abstract Background: Cigarette smoke-induced chronic airway inflammation increases the risk of lung cancer, and plays a multifaceted role in lung cancer initiation and progression, and RAGE-ligand axis (HMGB1, S100A8/A9) contributes Cigarette smoke-induced persistent and progressive inflammation. The aim of the present study was to determine the inflammatory effect on S100A8/A9-RAGE pathway in smoke-induced carcinogenesis in lung cancer. Methods: Human alveolar adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B) were co-cultured for 24 h with the PBMC and then, cells were incubated in the presence or absence of 1.5% cigarette smoke extract (CSE) for 24 h. The cells transfected with siRNA targeting S100A8/9 or RAGE. The cell viability, colony-forming ability, migration, invasion, metastasis and morphological changes were assessed. Female A/J mice were given a benzo(a)pyrene (100mg/kg) in 0.1 ml corn oil via oral gavage at once a week for 3 weeks, and administrated CSE (1.25 ul/g) via intratracheal (IT) at twice a week for 4 weeks. Tumor load was determined by averaging the total tumor volume in each group. BAL differential cells were counted to analyze inflammatory cells. Results: Cellular growth and colony-forming were promoted by exposure to CSE, and significantly inhibited by S100A8/9 and RAGE-siRNA transfection, especially in A549 cells than BEAS-2B. Cell migration, invasion, MMP-2/9 activities, and the mRNA and protein expression of TLR4, NF-κB, RAGE, S100A8/9 and HMBG1 were higher in CSE exposed A549 cells. S100A8/9 and RAGE-siRNA transfection attenuated those expression, significantly. B(a)P induced an average tumor volume 7.28 mm3 per mouse, and CSE significantly increased tumor volume (8.10 mm3) compared to the B(a)P group. The total cell number and lymphocytes in BAL fluids tended to increase after CSE administration in lung cancer mouse group. Moreover, CSE significantly induced the levels of S100A8/9 and RAGE, p38 and p-ERK, and decreased JNK in serum and tumors with adjacent lung tissues (p &amp;lt; 0.05). Conclusions: We identified cigarette smoke-induced S100A8/A9-RAGE pathway promoted airway inflammation and lung carcinogenesis in vitro and in vivo. Although S100A8/A9 protein contributes to many types of disease, this study will help us gain a better understanding of the complexities of cancer progression. Further studies are needed for therapeutic target of cigarette smoke-induced inflammation and immunosuppression in tumor microenviornment. Citation Format: Hye Seon Kang, In Kyoung Kim, Chang Dong Yeo, Jin Woo Kim, Sang Haak Lee. S100A8/A9-RAGE pathway and chronic airway inflammation in cigarette smoke-induced lung carcinogenesis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3947.

P21 facilitates chronic lung inflammation via epithelial and endothelial cells.

Cellular senescence is a stable state of cell cycle arrest that regulates tissue integrity and protects the organism from tumorigenesis. However, the accumulation of senescent cells during aging contributes to age-related pathologies. One such pathology is chronic lung inflammation. p21 (CDKN1A) regulates cellular senescence via inhibition of cyclin-dependent kinases (CDKs). However, its role in chronic lung inflammation and functional impact on chronic lung disease, where senescent cells accumulate, is less understood. To elucidate the role of p21 in chronic lung inflammation, we subjected p21 knockout (p21-/-) mice to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to chronic bronchitis and accumulation of senescent cells. p21 knockout led to a reduced presence of senescent cells, alleviated the pathological manifestations of chronic lung inflammation, and improved the fitness of the mice. The expression profiling of the lung cells revealed that resident epithelial and endothelial cells, but not immune cells, play a significant role in mediating the p21-dependent inflammatory response following chronic LPS exposure. Our results implicate p21 as a critical regulator of chronic bronchitis and a driver of chronic airway inflammation and lung destruction.

Clinical characteristics of 32 cases of diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) is a chronic airway inflammation with low specificity and its diagnosis is often missed or delayed. This study aims to summarize the clinical characteristics and treatment of DPB in order to improve the understanding and diagnosis of the disease. The clinical data of 32 DPB patients were collected, analyzed and summarized from March 1, 2013 to March 1, 2022 in the Second Xiangya Hospital of Central South University. The basic information, clinical manifestations, laboratory tests, pulmonary function, imaging tests, treatment, and regression of patients were analyzed. A total of 32 patients were enrolled in the final analysis, with a male-to-female ratio at 1.67. The median age at symptom onset was 26.5 (11.0-69.0) years, and the median age of diagnosis was 47.5 (16.0-77.0) years. All patients presented with chronic cough and copious sputum production. A total of 26 patients had post activity shortness of breath and 14 patients had a positive result (blood cold agglutination test titer≥1꞉64). Pulmonary function examination was performed in 31 patients, 18 patients showed mixed pulmonary ventilation dysfunction, 12 patients showed obstructive pulmonary ventilation, and 1 patient had normal pulmonary ventilation function. A total of 31 patients had a bilateral, diffuse, small nodule pattern on chest CT. All patients were treated with macrolides. A total of 31 patients showed improvement, and 20 patients showed improvement in partial pressure of oxygen and blood oxygen saturation compared with before at discharge. A total of 12 patients were re-examined by chest CT after completing macrolides treatment, 6 cases showed less diffuse nodules, 5 cases showed no significant changes, and 1 case showed more diffuse nodules, which indicated the disease progression. Seven patients received pulmonary function tests after completing macrolides treatment, forced expiratory volume in one second (FEV1) and FEV1/forced vital capacitywere improved, but forced expiratory flow at 25% of vital capacity did not change significantly. The clinical manifestations of DPB are nonspecific. Early diagnosis and treatment are very important for the prognosis of patients.

Increased inhaled corticosteroids for treating acute asthma exacerbations

Increased inhaled corticosteroids for treating acute asthma exacerbations

S100A8/A9-RAGE pathway and chronic airway inflammation in smoke-induced lung carcinogenesis

S100A8/A9-RAGE pathway and chronic airway inflammation in smoke-induced lung carcinogenesis

Physical training in adults with asthma: An integrative approach on strategies, mechanisms, and benefits.

Asthma is a chronic airway disease characterized by airflow limitation and respiratory symptoms associated with chronic airway and systemic inflammation, bronchial hyperreactivity (BHR), and exercise-induced bronchoconstriction (EIB). Asthma is a heterogeneous disease classified according to distinct airway and systemic inflammation. Patients commonly present with several comorbidities, including anxiety, depression, poor sleep quality, and reduced physical activity levels. Individuals with moderate to severe asthma often have more symptoms and difficulty achieving adequate clinical control, which is associated with poor quality of life, despite proper pharmacological treatment. Physical training has been proposed as an adjunctive therapy for asthma. Initially, it was suggested that the effect of physical training might be attributed to the improved oxidative capacity and reduced production of exercise metabolites. However, in the last decade, there has been evidence that aerobic physical training promotes anti-inflammatory effects in asthma patients. Physical training improves BHR and EIB, asthma symptoms, clinical control, anxiety, and depression levels, sleep quality, lung function, exercise capacity, and dyspnea perception. Furthermore, physical training reduces medication consumption. The most commonly used exercise strategies are moderate aerobic and breathing exercises; however, other techniques, such as high-intensity interval training, have shown promising effects. In the present study, we reviewed the strategies and beneficial effects of exercise on clinical and pathophysiological asthma outcomes.

Dexmedetomidine Protects against Airway Inflammation and Airway Remodeling in a Murine Model of Chronic Asthma through TLR4/NF-κB Signaling Pathway.

Asthma is a common respiratory disease characterized by chronic airway inflammation. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, has been shown to participate in regulating inflammatory states and thus exert organ protective actions. However, the potential of DEX in asthma is still unknown. This study is aimed at investigating the role of DEX in a mouse model of house dust mite- (HDM-) induced asthma and exploring its underlying mechanism. Here, we found that DEX treatment significantly ameliorated airway hyperresponsiveness, airway inflammation, and airway remodeling in the asthmatic mice, which were similar to the efficacy of the reference anti-inflammatory drug dexamethasone. In addition, DEX reversed the increased expression of toll-like receptor 4 (TLR4) and its downstream signaling adaptor molecule nuclear factor-κB (NF-κB) in the lung tissue of asthmatic mice. Furthermore, these protective effects of DEX were abolished by yohimbine, an α2 adrenergic receptor antagonist. These results indicate that DEX is capable of ameliorating airway inflammation and remodeling in asthmatic mice, and this protective effect is associated with the inhibition of the TLR4/NF-κB signaling pathway.