A protocol for a Japanese prospective cohort evaluating the features of patients with uncontrolled asthma achieving clinical remission: J-CIRCLE.

BACKGROUND: Increasing expectations that biologics can be used as disease-modifying agents have introduced the concept of clinical remission (CR) in managements of severe asthma. Given the clinical relevance of computed tomography (CT) and blood biomarkers, we hypothesized that further refinement of CR criteria as well as incorporation of CT and blood biomarkers as indicators for structural and biological remission (SR, BR) would enable predicting long-term disease stability in patients with severe asthma treated with biologics. METHODS: This Japanese multicenter prospective observational cohort will enroll patients with severe asthma who will start a new biologic (including a change from another biologic). The enrolled patients will be longitudinally followed up for 3 years. At enrollment, patients will undergo postbronchodilator spirometry, blood tests, fractional exhaled nitric oxide, chest and sinus CT, and patient-reported outcome questionnaires. Follow-up examinations will be performed at 1, 3, 6, 12, 24, and 36 months. The rates of CR resulting from different criteria after 1 year of treatment with biologics will be compared, and factors associated with long-term disease stability after 3 years of biologic treatments will be identified. DISCUSSION: This multicenter study in Japan will provide data that will help establish more appropriate criteria for CR, structural remission, and biological remission to predict long-term disease stability in patients with severe asthma who receive biologic therapy. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of Kyoto University (No. R4419, approval date June 11th, 2024). TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN000053771).

Mast cell MrgprB2 in neuroimmune interaction in IgE-mediated airway inflammation and its modulation by ß-arrestin2.

Introduction: Allergic asthma has been linked to the activation of mast cells (MCs) by the neuropeptide substance P (SP), but the mechanism underlying this neuroimmune interaction is unknown. Substance P produced from cutaneous nociceptors activates MCs via Mas-related G-protein-coupled receptor B2 (MrgprB2) to enhance type 2 immune response in experimental atopic dermatitis in mice. We recently showed that the adapter protein ß-arrestin2 (ß-arr2) contributes to MrgprB2-mediated MC chemotaxis. The goals of this study were to determine if MrgprB2 facilitates neuroimmune interaction in IgE (FcεRI)-mediated allergic airway inflammation (AAI) and to assess if this response is modulated by ß-arr2. Methods: Wild-type (WT), MrgprB2-/- mice and mice with MC-specific deletion of ß-arr2 (Cpa3Cre+ /ß-arr2fl/fl ) were passively sensitized with anti-TNP-IgE and challenged with antigen. The generation of SP and MC recruitment in the lung were determined by immunofluorescence and toluidine blue staining, respectively. The transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokines in lung tissue were assessed by RT-PCR, and the release of selected cytokines in bronchoalveolar lavage (BAL) was determined by ELISA. Eosinophil and neutrophil recruitment in lung tissue and BAL were determined by immunofluorescence staining and flow cytometry, respectively. Goblet cell hyperplasia was determined by periodic acid-Schiff staining. Results: Following IgE sensitization and antigen challenge in WT mice, SP generation, and MC recruitment, transcripts for Tac1, MrgprB2, TNF-α, and Th2 cytokine were upregulated when compared to the control challenge. TNF-α, Th2 cytokine production, eosinophil/neutrophil recruitment, and goblet cell hyperplasia were also increased. These responses were significantly reduced in MrgprB2-/- and Cpa3Cre+ /ß-arr2fl/fl mice. Discussion: The data presented herein suggest that SP-mediated MrgprB2 activation contributes to AAI and goblet cell hyperplasia in mice. Furthermore, these responses are modulated by ß-arr2, which promotes MC recruitment to facilitate their activation through FcεRI.

Expression of Epithelial Alarmin Receptor on Innate Lymphoid Cells Type 2 in Eosinophilic Chronic Obstructive Pulmonary Disease.

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5+ILC2s and TSLPR+ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5+ILC2s, IL-17RB+ILC2s and ST2+ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

Elevated expression of NLRP3 promotes cigarette smoke-induced airway inflammation in chronic obstructive pulmonary disease.

Introduction: NOD-like receptor protein 3 (NLRP3) is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Here, we explored the role of NLRP3 in cigarette smoke (CS)-induced airway inflammation in COPD. Material and methods: NLRP3 expression level was assessed with the microarray data in GEO datasets and validated in serum by ELISA from a case-control cohort. Male C57BL/6J mice were randomly divided into: saline, CS, MCC950 (a specific NLRP3 inhibitor, 10 mg/kg) and CS + MCC950 (5 mg/kg and 10 mg/kg) groups (n = 5 per group). All mice were exposed to CS or air for 4 weeks. Then, broncho-alveolar lavage (BAL) fluid and lung tissues were collected for cell counting, ELISA, HE staining and RNA sequencing with validation by real-time qPCR. Results: Compared to non-smokers, NLRP3 expression was significantly elevated in the lung tissues and sera of COPD smokers. CS remarkably induced airway inflammation in mice, characterized by an increase of inflammatory cells and proinflammatory cytokines in BAL fluid and HE inflammatory score, which were ameliorated by MCC950 treatment dose-dependently. Subsequently, 84 candidate genes were selected following RNA sequencing, and five hub genes (Mmp9, IL-1α, Cxcr2, Cxcl10, Ccr1) were then identified by PPI and MCODE analyses, which were confirmed by real-time qPCR. GO and KEGG analysis suggested that the five genes were enriched in a complicated network of inflammatory processes and signaling pathways. Conclusions: NLRP3 expression is elevated in lungs and sera of COPD smokers. Inhibition of NLRP3 significantly attenuates CS-induced airway inflammation in mice via inactivation of multiple hub genes and their related inflammatory processes and signaling pathways.

Asthma and hypertension: the role of airway inflammation.

Introduction: Asthma is a chronic inflammatory respiratory disease often associated with comorbidities. Among cardiovascular comorbidities, arterial hypertension seems to create an additional health burden in asthmatics. However, evidence on this relationship is lacking. Objective: Our study aims to evaluate the characteristics of hypertensive asthmatics, focusing on the role of inflammation as a possible link between these diseases. Methods: We conducted a monocentric retrospective analysis consecutively including asthmatics who underwent induced sputum (IS) at our asthma referral center. Patients were divided in two groups according to presence or absence of history of hypertension. Clinical, functional, and inflammatory (airway and systemic) data were collected. Results: Data on two hundred and sixty asthmatic patients were analyzed. Seventy-nine (30.4%) of them had a diagnosis of hypertension requiring a specific pharmacological treatment. Asthmatics with hypertension were more frequently male (p = 0.047), older (p < 0.001), and with higher body max index (BMI) (p < 0.001) when compared to normotensive patients. No difference concerning asthma control, severity and pharmacological treatment was observed between the two groups (all p > 0.05); distribution of comorbidities and lung function impairment (forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC); all p < 0.05) were statistically different between groups. Mixed granulocytic airway inflammation was prevalent in the hypertensive asthmatics (p = 0.014). Interestingly, a multivariable analysis revealed that age ≥ 65 years and an increased percentage of sputum neutrophils (≥61%) were independent predictors of hypertensive status (p < 0.001). Conclusion: Our data suggest that neutrophilic airway inflammation (as evaluated by induced sputum) is strictly associated with hypertension. In clinical practice, phenotyping asthmatic patients with comorbidities like hypertension could be useful also from a therapeutic point of view. Additional studies are mandatory to further elucidate the role of neutrophilic airway inflammation in asthma with cardiovascular diseases.

MiR-146a-5p engineered hucMSC-derived extracellular vesicles attenuate Dermatophagoides farinae-induced allergic airway epithelial cell inflammation.

Introduction: Allergic asthma is prevalent in children, with Dermatophagoides farinae as a common indoor allergen. Current treatments for allergic airway inflammation are limited and carry risks. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show promise as a cell-free therapeutic approach. However, the use of engineered MSC-EVs for D. farinae-induced allergic airway epithelial cell inflammation remains unexplored. Methods: We generated miR-146a-5p-engineered EVs from human umbilical cord mesenchymal stem cells (hucMSCs) and established D. farinae-induced mouse and human bronchial epithelial cell allergic models. Levels of IL-1ß, IL-18, IL-4, IL-5, IL-6, IL-10, IL-33, TNF-α and IgE were detected using ELISA. The relative TRAF6 and IRAK1 mRNA expression was quantified using qPCR assay and the NLRP3, NF-κB, IRAK1 and TRAF6 protein expression was determined using Western blotting. The regulatory effect of IRAK1 and TRAF6 by miR-146a-5p was examined using a dual luciferase reporter assay, and the nuclear translocation of NF-κB p65 into 16-HBE cells was evaluated using immunofluorescence assay. Results: Treatment with hucMSC-EVs effectively reduced allergic inflammation, while miR-146a-5p engineered hucMSC-EVs showed greater efficacy. The enhanced efficacy in alleviating allergic airway inflammation was attributed to the downregulation of IRAK1 and TRAF6 expression, facilitated by miR-146a-5p. This downregulation subsequently led to a decrease in NF-κB nuclear translocation, which in turn resulted in reduced activation of the NLRP3 inflammasome and diminished production of inflammatory cytokines, including IL-6, TNF-α, IL-1ß and IL-18. Conclusion: Our study underscores the potential of miR-146a-5p engineered hucMSC-EVs as a cell-free therapeutic strategy for D. farinae-induced allergic airway inflammation, offering a promising avenue for boosting anti-inflammatory responses.

Scutellaria baicalensis ameliorates allergic airway inflammation through agonism and transcriptional regulation of TAS2Rs.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SCB, Huangqin) is a traditional medicinal plant used to treat fever and respiratory diseases. SCB has a good therapeutic effect on asthma and anti-inflammation in traditional clinic use. However, the molecular mechanism and targets of SCB in treating asthma are still unclear. AIM OF THE STUDY: Combining transcriptomic analysis and in vitro experimental validation, this study aimed to reveal the molecular mechanism and targets of SCB in treating asthma. MATERIALS AND METHODS: The anti-asthmatic effects of SCB and its active components, scutellarin and oroxylin A, were evaluated in ovalbumin (OVA)-induced rats by analysis of pulmonary function and pathology. The signaling pathways in rat pulmonary tissue were analyzed using transcriptomics and protein interaction network analysis. Calcium mobilization assay and molecular docking were utilized to discover the active compounds from SCB with agonism activity of type 2 taste receptors (TAS2Rs). The anti-asthmatic effect and transcriptional regulation of TAS2Rs regulated by SCB and its active components were analyzed in vitro. RESULTS: Extracts of SCB (ESB), scutellarin, and oroxylin A ameliorated airway function and inflammation in OVA-induced rats. The anti-asthma mechanism of ESB, scutellarin and oroxylin A was highly related to immune and taste transduction pathways based on transcriptomic analysis, especially the TAS2Rs signaling pathway. ESB was the direct agonist of TAS2R4 and TAS2R14 with EC50 of 209.1 and 217.2 µg/mL based on calcium mobilization assay, respectively. Baicalein was the main active component for TAS2R4 agonism activity, and scutellarin and oroxylin A had weak agonism activity of TAS2R4 and TAS2R14 through calcium mobilization assay and molecular docking. However, scutellarin and oroxylin A significantly upregulated the gene expression of Tas2r108 (the mouse ortholog of the TAS2R4) in lung tissue. ESB, scutellarin, and oroxylin A inhibited LPS-induced lactate dehydrogenase release and gene expression of TNF through transcriptional regulation of TAS2R4 and TAS2R14 on bronchial epithelial cells. ESB and oroxylin A ameliorated IgE-induced ß-hexosaminidase release and gene expression of Il4 and Tnf and upregulated gene expression of Tas2r108. CONCLUSION: These results provided new insight into the anti-asthmatic mechanism of SCB and active components, scutellarin and oroxylin A, through agonism and transcriptional regulation of TAS2Rs to ameliorate allergic airway inflammation.

Curcumin Alleviates Airway Inflammation in Cough-Variant Asthmatic Rats by Modulating M1/M2 Macrophage Polarization.

BACKGROUND: With the increase of environmental pollution and atypical pathogen infections, the incidence of cough variant asthma (CVA) has been increasing annually, making it a pressing issue of the medical community. This study aims to observe the ameliorative effect of curcumin on a rat model of cough variant asthma. METHODS: A rat model of cough variant asthma was induced by sensitization with ovalbumin combined with aluminum hydroxide (Al(OH)3), followed by repeated excitations. The drug was administered on the day of the initial nebulized attack, and gavage was administered for 14 d. Pathological changes in the lung tissues were observed, along with the assessment of cough susceptibility and airway resistance. The number of inflammatory cell eosinophils and leukocytes were determined in alveolar lavage fluid. Additionally, serum inflammatory factors and lung tissues Matrix Metalloproteinase-9 (MMP-9) protein were assessed. The level of M1/M2 macrophages was also detected. RESULTS: Following the administration of curcumin, there was reduced inflammatory infiltration, less disordered arrangement of the lung tissue, and decreased abnormal proliferation of lung tissues in cough variant asthma rats compared to the model group. Curcumin treatment led toa notable reduction in cough frequency, a significant decrease in pro-inflammatory factor concentration levels in serum and inflammatory cell counts in the alveolar lavage fluid, and a marked increase in anti-inflammatory factor levels (p < 0.05). Additionally, curcumin administration led to a significant increase in M2-type macrophage levels, while simultaneously decreasing the levels of M1-type macrophages (p < 0.05). CONCLUSIONS: The administration of curcumin effectively ameliorates ovalbumin-induced airway inflammation in cough-variant asthma rats. This effect is attributed to modulating macrophage polarization towards the anti-inflammatory M2 phenotype, thereby reducing airway inflammation, airway hyperresponsiveness, and lung tissue injury.

The impact of tangeretin combined with whey protein on exercise-induced bronchoconstriction in professional athletes: a placebo-controlled trial.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is highly prevalent in athletes. The objective of this study was to assess the therapeutic efficacy of daily tangeretin combined with whey protein supplementation over a period of 4 weeks in professional athletes with EIB. METHODS: Using a placebo-controlled, double-blind, paired, randomized trial design, a cohort of 30 professional athletes with EIB, consisting of 14 females and 16 males, was divided into two groups: the tangeretin combined with whey protein intervention group (TIG), and the placebo control group (PCG). Both the TIG and PCG underwent exercise challenge tests (ECT) and VO2max tests before (ECT1, V1) and after (ECT2, V2) the intervention. Blood (eosinophils, neutrophils, and basophils) and serum (interleukin-5, IL-5; interleukin-8, IL-8; Clara cell secretory protein-16, CC16; immunoglobulin E, IgE) levels were measured early in the morning of ECT1 and ECT2, respectively. Lung function was assessed immediately before and post-ECT immediately. RESULTS: Tangeretin combined with whey protein use for 4 weeks attenuated the decrease in forced expiratory volume in 1 s (FEV1) post trials (∆FEV1(ECT1-ECT2): mean (SD) TIG -7.51(6.9)% vs. PCG -2.33(11.49)%, p = 0.013). Tangeretin also substantially attenuated IL-5 concentration (∆IL-5(T1-T5): Tangeretin -19.4% vs Placebo + 8.37%, p = 0.022); IL-8 concentration (∆IL-8(T1-T5): Tangeretin -17.28% vs Placebo + 6.1%, p = 0.012); CC16 concentration (∆CC16(T1-T5): Tangeretin -11.77% vs Placebo + 24.19%); and IgE concentration in the serum (∆IgE(T1-T5): Tangeretin -24.1% vs Placebo -3.9%), and significantly decreased neutrophil count (∆N(T1-T5): Tangeretin -11.34% vs Placebo + 0.3%) and eosinophil count in blood (∆N(T1-T5): Tangeretin -38.5% vs Placebo + 4.35%). Compared with V1, VO2max (p = 0.042) and TLim (p = 0.05) of V2 were significantly increased in the TIG, and there was no significant change in the PCG. Meanwhile, six athletes in the TIG and 0 athletes in the PCG became EIB-negative at ECT2; the overall negative conversion rate of EIB was 40.00% in TCG. Additionally, the number of cough symptoms decreased from 9 to 3 and dyspnea from 4 to 2 in the TIG. CONCLUSION: After high-intensity exercise, athletes with EIB achieved significant improvements in lung function and blood inflammatory factors by combining tangeretin and whey protein supplementation. EIB athletes also showed longer exercise endurance and VO2max at 4 weeks after TI. In addition, some patient symptoms disappeared after combination supplementation. The effect of this treatment on professional athletes with EIB was beneficial.

Pioglitazone and asthma: a review of current evidence.

OBJECTIVE: This review aims to present existing evidence on the impact of pioglitazone, a thiazolidinedione class anti-diabetic drug, on asthma control and lung function, providing a comprehensive understanding of its potential as a treatment for asthma. DATA SOURCES: The review draws upon data from preclinical animal studies and clinical trials investigating the effects of pioglitazone on asthma, focusing on its role in reducing airway inflammation, hyperreactivity, and remodeling, and its impact on pulmonary function. STUDY SELECTIONS: Relevant studies were selected based on their examination of pioglitazone's therapeutic effects in asthma, including both animal models and clinical trials involving human asthma patients. RESULTS: Animal studies have suggested that pioglitazone could alleviate inflammation, airway hyperreactivity, and airway remodeling, thereby improving pulmonary function in asthma. However, clinical trials have not demonstrated significant therapeutic benefits, with minimal improvements observed in asthma control and lung function, and the presence of notable side effects. CONCLUSION: Despite promising preclinical data, the efficacy of pioglitazone in treating human asthma remains unproven, with safety concerns and limited clinical benefits observed in trials. Further research is needed to assess the safety and effectiveness of pioglitazone in asthma treatment and to explore its impact on other inflammatory mechanisms.

A reappraisal of IL-9 in inflammation and cancer.

While much is known about the functional effects of type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 in homeostasis and disease, we still poorly understand the functions of IL-9. Chronic inflammation seen in allergic diseases, autoimmunity and cancer is however frequently accompanied by overproduction of this elusive type 2 cytokine. Initially identified as a T cell and mast cell growth factor, and later as the hallmark cytokine defining TH9 cells, we now know that IL-9 is produced by multiple innate and adaptive immune cells. Recent evidence suggests that IL-9 controls discrete aspects of the allergic cascade, cellular responses of immune and stromal cells, cancer progression, tolerance and immune escape. Despite functioning as a pleiotropic cytokine in mucosal environments, like the lungs, the direct and indirect cellular targets of IL-9 are still not well characterized. Here, we discuss IL-9's cellular senders and receivers, focusing on asthma and cancer. Moreover, we review current research directions and the outlook of targeted therapy centered around the biology of IL-9.

Acupoint Autohemotherapy Alleviates Airway Inflammation in Asthmatic Rats via Upregulating Expression of Hemeoxygenase-1.

Importance: Acupoint autohemotherapy (AA), a therapeutic technique involving the subcutaneous injection of autologous blood into acupoints, has been empirically validated as safe and effective for treating asthma by alleviating symptoms and decreasing acute attacks, though its mechanism is not well understood. Objective: The role of heme oxygenase-1 (HO-1) in AA-induced suppression of asthmatic airway inflammation is examined. Methods: Twenty rats were assigned randomly to four groups, namely the Control, OVA, OVA + AA, and (OVA + Snpp) + AA. Rats in the OVA + AA and (OVA + Snpp) + AA received autologous blood injections into acupoints (BL13 and BL23) following OVA challenge. Rats in the (OVA + Snpp) + AA were concurrently subjected to intraperitoneal injections of Snpp, a inhibitor of HO-1. Airway inflammation was evaluated through HE staining, while the concentrations of cytokines in BALF were quantified using ELISA. The mRNA and protein levels of RORγt (Th17-specific transcription factor), Foxp3 (Treg-specific transcription factor), and HO-1 in lung tissue were assessed through qRT-PCR and WB. Results: HE staining indicated that airway inflammation was alleviated in the OVA + AA. The OVA + AA displayed significantly lower counts of total cells and eosinophils in the BALF compared to both the OVA and (OVA + Snpp) + AA. The ELISA demonstrated a significant decrease in levels of pro-inflamatory cytokines (IL-4, IL-17A), and an increase in levels of anti-inflamatory cytokines (IFN-γ, IL-10), in the OVA + AA when compared to both OVA and (OVA + Snpp) + AA. The qRT-PCR and WB analyses revealed an upregulation of HO-1 and Foxp3 expression, and a downregulation of RORγt expression, in the OVA + AA when compared to OVA and (OVA + Snpp) + AA. Conclusions and Relevance: The involvement of HO-1 in the underlying mechanism responsible for the anti-inflammatory effects of AA is evident.

Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma.

BACKGROUND: In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R-/-) mice. METHODS: C57BL/6J WT (Kiss1R+/+) and Kiss1R-/- mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson's Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c. RESULTS: Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R-/- female mice. MA-challenged Kiss1R-/- mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R-/- mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR. CONCLUSIONS: These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

Modification of gut and airway microbiota on ozone-induced airway inflammation.

Ground-level ozone (O3) has been shown to induce airway inflammation, the underlying mechanisms remain unclear. The aim of this study was to determine whether gut and airway microbiota dysbiosis, and airway metabolic alterations were associated with O3-induced airway inflammation. Thirty-six 8-week-old male C57BL/6 N mice were divided into 2 groups: sterile water group and broad-spectrum antibiotics group (Abx). Each group was further divided into two subgroups, filtered air group (Air) and O3 group (O3), with 9 mice in each subgroup. Mice in the Air and O3 groups were exposed to filtered air or 1 ppm O3, 4 h/d for 5 consecutive days, respectively. Mice in Abx + Air and Abx + O3 groups were exposed to filtered air or O3, respectively, after drinking broad-spectrum Abx. 24 h after the final O3 exposure, mouse feces and bronchoalveolar lavage fluids (BALF) were collected and subjected to measurements of airway oxidative stress and inflammation biomarkers, 16S rRNA sequencing and metabolite profiling. Hematoxylin-eosin staining of lung tissues was applied to examine the pathological changes of lung tissue. The results showed that O3 exposure resulted in airway oxidative stress and inflammation, as well as gut and airway microbiota dysbiosis, and airway metabolism alteration. Abx pre-treatment markedly changed gut and airway microbiota and promoted O3-induced metabolic disorder and airway inflammation. Spearman correlation analyses indicated that inter-related gut and airway microbiota dysbiosis and airway metabolic disorder were associated with O3-induced airway inflammation. Together, inhaled O3 causes airway inflammation, which may implicate gut and airway microbiota dysbiosis and airway metabolic alterations.

Anti-astmatic effect of ROCK inhibitor, GSK429286 A, in experimentally induced allergic airway inflammation.

BACKGROUND: Allergic asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, inflammation and remodeling. ROCK inhibitors have now been shown to have the potential to alleviate these symptoms, although the specific effects of a new ROCK inhibitor, GSK429286 A, remain underexplored. OBJECTIVE: The aim of this study was to evaluate the therapeutic effects of a novel ROCK inhibitor, GSK429286 A, which exhibits a high affinity for both ROCK1 and ROCK2 isoforms, on allergic asthma in a guinea pig model, focusing on its effects on airway hyperresponsiveness, inflammation, and remodeling. METHODS: To induce allergic asthma, guinea pigs were sensitized with ovalbumin for 28 days, and in the middle of sensitization they were treated with different doses of the RoCK inhibitor, GSK429286 A. The study evaluated the effect of the administered doses on the reduction of airway hyperresponsiveness, by measuring specific airway resistance (sRaw), and the number of coughs after citric acid inhalation. We also monitored the anti-inflammatory effect by measuring levels of inflammatory cytokines, IL-2, IL-4, IL-5, IL-13, and remodeling markers, such as collagen deposition, and goblet cell hyperplasia. In addition, we monitored the possible anti-remodeling effect of GSK429286 A by histopathological examination. RESULTS: The ROCK inhibitor, GSK429286 A, showed an effect on suppressing airway hyperresponsiveness by reducing sRaw and the number of coughs in treated guinea pigs compared to controls. Our investigated drug suppressed the release of key mediators of inflammation, including IL-2, IL-4, and IL-5, thus demonstrating the effect of this ROCK inhibitor on the suppression of inflammation in the airways. Finally, GSK429286 A reduced markers of airway remodeling such as collagen deposition and goblet cell hyperplasia. CONCLUSION: GSK429286 A, an inhibitor of the ROCK pathway, exhibits significant anti-inflammatory and antiremodeling effects in a guinea pig model of allergic asthma. Indeed, we demonstrate its effect on suppressing airway hyperreactivity and reducing cough frequency. These findings suggest that GSK429286 A may be a promising therapeutic agent for allergic asthma, although further studies are needed to investigate its long-term efficacy, underlying mechanisms, and optimal dosing strategy.

Nebulized Budesonide Prevents Airway Inflammation in Children with High Total IgE Levels After Open Heart Surgery with Cardiopulmonary Bypass: A Prospective Randomized Controlled Trial.

Cardiopulmonary bypass (CPB) is a crucial technique used to repair congenital heart defects (CHD); however, it may induce inflammatory response, leading to airway inflammation and need for prolonged mechanical ventilation. In this study, we aimed to evaluate the effect of budesonide nebulization in children with high serum total immunoglobulin E (tIgE) levels undergoing surgical repair of CHD via CPB. We conducted a randomized, single-center, controlled trial at a tertiary teaching hospital. One-hundred and one children with high tIgE were enrolled and randomized into the budesonide nebulization group (BUD group, n = 50) or the normal saline nebulization group (NS group, n = 51) between January 2020 and December 2020. Budesonide or normal saline was administered through a vibrating mesh nebulizer during mechanical ventilation every 8 h. Blood and bronchoalveolar lavage fluid (BALF) samples were examined and data on airway mechanics and clinical outcomes were recorded. IL-6 and IL-8 levels in the blood and BALF samples significantly increased after CPB in both groups. Budesonide inhalation reduced IL-6 and IL-8 levels in the blood and BALF samples in children with high tIgE (P < 0.05). The mean airway pressure, PCO2, and oxygen index in the BUD group were significantly lower than those in the NS group after the first inhalation dose and persisted until almost 24 h after surgery. The peak inspiratory pressure and drive pressure were lower in the BUD group than in the NS group at nearly 24 h after surgery, with no significant difference at other time points. Additionally, the duration of mechanical ventilation, number of noninvasive ventilations after extubation, and number of patients using aerosol-inhaled bronchodilators after CICU in the BUD group were significantly lower than those in the NS group (P < 0.05). Children with high preoperative tIgE levels are at risk of airway inflammation after cardiopulmonary bypass. Inhaling budesonide during postoperative mechanical ventilation can reduce the intensity of inflammatory reactions, shorten the duration of mechanical ventilation, reduce airway pressure and the utilization of NIV after extubation.

Therapeutic efficacy of JEW-M449, an anti-TCTP monoclonal antibody, administered via the nasal route in a BALB/c mouse model of ovalbumin-induced acute asthma.

Numerous studies have highlighted the role of translationally controlled tumor protein (TCTP) as a key inflammatory mediator of asthma and allergies. Our previous study revealed that blocking the cytokine-like activity of TCTP using JEW-M449, an anti-TCTP monoclonal antibody (mAb), alleviated allergic inflammation in asthmatic mice. This study aimed to determine whether directly delivering JEW-M449 into the respiratory tract is a more effective way of mitigating airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation than delivering this antibody via the intraperitoneal (IP) route. OVA-sensitized mice were intranasally administered JEW-M449 to enable its direct delivery to the respiratory tract before OVA challenge. We evaluated the changes in the levels of bronchoalveolar lavage fluid (BALF) cells, T helper type 2 (Th2) cytokines, OVA-specific immunoglobulin E (IgE), and histopathological alterations in the lung tissues. Intranasal (IN) administration of JEW-M449 significantly ameliorated the pathological changes associated with OVA-induced lung injury, including reduced inflammatory cell infiltration and mucus hypersecretion. Mice IN administered JEW-M449 also showed decreased OVA-mediated induction of Th2 cytokines in BALF and lung homogenates. Importantly, JEW-M449 delivered via the IN route reached the lung tissue more effectively and exerted superior anti-inflammatory effects in OVA-challenged mice than the IP-delivered JEW-M449. This study is the first to demonstrate the efficacy of directly delivering JEW-M449 anti-TCTP mAb into the respiratory tract to alleviate the asthma phenotype in a mouse model, thereby highlighting a potential delivery strategy for novel inhaled mAb therapeutics for human asthma.

Effect of Air Pollutants Particulate Matter PM2.5, PM10, Carbon Monoxide (CO), Nitrogen Dioxide (NO2), Sulfur Dioxide (SO2), and Ozone (O3) on Fractional Exhaled Nitric Oxide (FeNO).

Objectives: This study aimed to investigate the effect of Environmental Pollutants Particulate Matter PM2.5, PM10, Carbon Monoxide (CO), Nitrogen Dioxide (NO2), Sulfur Dioxide (SO2), and Ozone (O3) on lung airway inflammation by assessing the Fractional Exhaled Nitric Oxide (FeNO) in students studying in schools located in or away from air-polluted areas. Methods: This matched case-control cross-sectional study was conducted in the Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia from August 2022 to July 2023. In this study, two schools were selected, one was located near a traffic-polluted area (School #1), and the second was located away from the traffic-polluted area (School #2). A total of 300 students were recruited, 150 (75 male and 75 female) students from the school located in a traffic-polluted area, and 150 students (75 male and 75 female) from the school located away from a traffic-polluted area. Environmental pollutants PM2.5, PM10, CO, NO2, O3, and SO2, were recorded. The Fractional Exhaled Nitric Oxide (FeNO) was measured using a Niox Mino. Results: The mean concentration of PM2.5, PM10, CO, NO2, O3, and SO2 were 35.00±0.65 significantly higher in a school located in motor vehicle polluted area compared to a school located away from a motor vehicle-polluted area (29.95±0.32) (p=0.001). The mean values for FeNO were significantly higher (18.75±0.90) among students studying in a school located in the motor vehicle-polluted area compared to students studying in a school located away from the motor vehicle-polluted area (11.26±0.56) (p=0.001). Conclusions: Environmental pollution can cause lung inflammation among students in schools located in traffic-polluted areas.

4-Hydroxychalcone attenuates ovalbumin-induced allergic airway inflammation and oxidative stress by activating Nrf2/GPx4 pathway.

Asthma is a lung condition characterized by impaired respiratory function and an apparent infiltration of inflammatory cells. Chalcones are substances that have attracted considerable interest in the disciplines of pharmaceutical chemistry and drug discovery due to their diverse biochemical processes, such as antioxidant, anti-inflammatory, anticancer, antibacterial, and others, but whether they can be used in asthma treatment has yet to be investigated. This study aimed to investigate the immunomodulatory effect of 4 hydroxychalcone (4-HC) against allergic asthma in mice. In this research, we investigated how 4-HC affected asthmatic behavior, leukocyte infiltration, histopathological alterations, oxidative stress, immunoglobulin E (IgE) production, and airway inflammation. Moreover, ELISA and immunohistochemistry (IHC) were used to measure the expression of Nrf2 and GPx4. 4-HC treatment significantly decreased lung oxidative stress, inflammatory cell infiltration, and IgE levels. According to our findings, we imply that 4-HC may be utilized as an anti-asthmatic agent through the upregulation of Nrf2/GPx4 signaling pathway.