A New Pathway to Airway Relaxation: Targeting the "Other" Cyclase in Asthma.
Ontology highlight
ABSTRACT:
SUBMITTER: Lam M
PROVIDER: S-EPMC6938138 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E2 signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid β2-adrenoceptor agonist resistance.
| S-EPMC8720283 | biostudies-literature
Project description:Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin ?v?6-deficient mice are protected from airway hyperresponsiveness, due in part to increased expression of the murine ortholog of human chymase. Here, we determined that chymase protects against cytokine-enhanced bronchoconstriction by cleaving fibronectin to impair tension transmission in airway smooth muscle (ASM). Additionally, we identified a pathway that can be therapeutically targeted to mitigate the effects of airway hyperresponsiveness. Administration of chymase to human bronchial rings abrogated IL-13-enhanced contraction, and this effect was not due to alterations in calcium homeostasis or myosin light chain phosphorylation. Rather, chymase cleaved fibronectin, inhibited ASM adhesion, and attenuated focal adhesion phosphorylation. Disruption of integrin ligation with an RGD-containing peptide abrogated IL-13-enhanced contraction, with no further effect from chymase. We identified ?5?1 as the primary fibronectin-binding integrin in ASM, and ?5?1-specific blockade inhibited focal adhesion phosphorylation and IL-13-enhanced contraction, with no additional effect from chymase. Delivery of an ?5?1 inhibitor into murine airways abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. Finally, ?5?1 blockade enhanced the effect of the bronchodilator isoproterenol on airway relaxation. Our data identify the ?5?1 integrin as a potential therapeutic target to mitigate the severity of airway contraction in asthma.
| S-EPMC5199700 | biostudies-literature
Project description:The study of autophagy ('self-eating'), a fundamental cell fate pathway involved in physiological and pathological subcellular processes, opens a new frontier in the continuous search for novel therapies for human asthma. Asthma is a complex syndrome with different disease phenotypes. Autophagy plays a central role in cell physiology, energy and metabolism, and cell survival. Autophagy's hallmark is the formation of double-membrane autophagic autophagosomes, and this process is operational in airway epithelial and mesenchymal cells in asthma. Genetic associations between autophagy genes and asthma have been observed including single nucleotide polymorphisms in Atg5 which correlate with reduced lung function. Immune mechanisms important in asthma such as Th2 cells and eosinophils also manifest autophagy. Lastly, we address the role of autophagy in extracellular matrix deposition and fibrosis in asthmatic airways remodeling, a pathologic process still without effective therapy, and discuss potential pharmacologic inhibitors. We end by offering two opposing but plausible hypotheses as to how autophagy may be directly involved in airway fibrosis.
| S-EPMC4715640 | biostudies-literature
Project description:Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig)E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2-low asthma. Existing biologics target immunological pathways that are downstream in the type 2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, type 2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide (FeNO), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in FeNO The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of "alarmins" thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with type 2-high and type 2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.
| S-EPMC7676874 | biostudies-literature
Project description:Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.
| S-EPMC8453879 | biostudies-literature
Project description:In vivo studies of airway pathology in obstructive lung disease are limited by poor quality of specimens obtained with forceps. Obtainment of cryobiopsies has increased diagnostic yield in cancer and interstitial lung disease but has not been used in patients with asthma. In a recent pilot study, we found mucosal cryobiopsies to be larger and more intact than conventional forceps biopsies. The aim of the present study was to compare quality and safety of mucosal cryobiopsies versus conventional forceps biopsies in patients with asthma. Endobronchial biopsies were obtained with forceps and cryoprobe from patients with asthma not currently treated with inhaled steroids and evaluated histologically. A total of 240 cryobiopsies and 288 forceps biopsies were obtained from 48 patients. Bleeding from the biopsy site was common but self-limiting. No major complications related to the procedure were seen. Cryobiopsy cross areas were four times larger compared with forceps. Stretches of intact epithelium were detected in all cryobiopsies compared to 33% in forceps biopsies. Further, the length of intact epithelium was on average four times longer in the cryobiopsies. Importantly, there was a good preservation of both antigens and mRNA in the cryobiopsies ensuring a suitability and robustness for immunohistochemistry and in situ hybridisation. Obtainment of mucosal cryobiopsies in patients with asthma is safe and yields biopsies that are significantly larger and morphologically better preserved compared with traditional forceps biopsies. The cryotechnique thus seems to be a promising tool for future in vivo studies of airway pathology.
| S-EPMC8943287 | biostudies-literature
Project description:This study explored the effects of microRNA-19b (miR-19b) on airway remodeling, airway inflammation, and degree of oxidative stress in a mouse model of asthma. Bioinformatics analyses and dual luciferase reporter gene assays revealed that thymic stromal lymphopoietin (TSLP) is a direct target of miR-19b. An asthma model was established via ovalbumin (OVA) sensitization and challenge in 72 female BALB/c mice. Mice were then assigned to saline, OVA-sensitized, saline+miR-19b mimics, saline+anti-TSLP, OVA-sensitized+miR-19b mimics, OVA-sensitized+mimics scramble, OVA-sensitized+anti-TSLP, and OVA-sensitized+IgG2a groups. Pathological morphology changes were detected through hematoxylin/eosin, Masson, and periodic acid-Schiff staining. miR-19b was downregulated while TSLP and Stat3 were upregulated in the OVA-sensitized group compared with the saline group. Bronchoalveolar lavage fluid samples from OVA-sensitized mice showed increased total protein, IL-4, IL-5 and IL-6 levels, numbers of inflammatory cells, eosinophils, neutrophils, mononuclear macrophages and lymphocytes, and eosinophil% compared to controls. Lung tissues from sensitized mice exhibited decreased superoxide dismutase activity and increased methane dicarboxylic aldehyde levels. The effects of OVA sensitization were reversed in the OVA-sensitized+miR-19b mimics and OVA-sensitized+anti-TSLP groups. These findings suggest miR-19b reduces airway remodeling, airway inflammation, and degree of oxidative stress by inhibiting Stat3 signaling through TSLP downregulation in a mouse asthma model.
| S-EPMC5564584 | biostudies-other
Project description:PurposeEpithelial cystatin SN (CST1), a type 2 cysteine protease inhibitor, was significantly upregulated in asthma. In this study, we aimed to investigate the potential role and mechanism of CST1 in eosinophilic inflammation in asthma.MethodsBioinformatics analysis on Gene Expression Omnibus datasets were used to explore the expression of CST1 in asthma. Sputum samples were collected from 76 asthmatics and 22 control subjects. CST1 mRNA and protein expression in the induced sputum were measured by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. The possible function of CST1 was explored in ovalbumin (OVA)-induced eosinophilic asthma. Transcriptome sequencing (RNA-seq) was used to predict the possible regulated mechanism of CST1 in bronchial epithelial cells. Overexpression or knockdown of CST1 was further used to verify potential mechanisms in bronchial epithelial cells.ResultsCST1 expression was significantly increased in the epithelial cells and induced sputum of asthma. Increased CST1 was significantly associated with eosinophilic indicators and T helper cytokines. CST1 aggravated airway eosinophilic inflammation in the OVA-induced asthma model. In addition, overexpression of CST1 significantly enhanced the phosphorylation of AKT and the expression of serpin peptidase inhibitor, clade B, member 2 (SERPINB2), while knockdown using anti-CST1 siRNA reversed the trend. Furthermore, AKT had a positive effect on SERPINB2 expression.ConclusionsIncreased sputum CST1 may play a key role in the pathogenesis of asthma through involvement in eosinophilic and type 2 inflammation through activation of the AKT signaling pathway, further promoting SERPINB2 expression. Therefore, targeting CST1 might be of therapeutic value in treating asthma with severe and eosinophilic phenotypes.
| S-EPMC10186126 | biostudies-literature
Project description:Asthma is an inflammatory disease of the airways that may result from exposure to allergens or other environmental irritants, resulting in bronchoconstriction, wheezing, and shortness of breath. The structural changes of the airways associated with asthma, broadly referred to as airway remodeling, is a pathological feature of chronic asthma that contributes to the clinical manifestations of the disease. Airway remodeling in asthma constitutes cellular and extracellular matrix changes in the large and small airways, epithelial cell apoptosis, airway smooth muscle cell proliferation, and fibroblast activation. These pathological changes in the airway are orchestrated by crosstalk of different cell types within the airway wall and submucosa. Environmental exposures to dust, chemicals, and cigarette smoke can initiate the cascade of pro-inflammatory responses that trigger airway remodeling through paracrine signaling and mechanostimulatory cues that drive airway remodeling. In this review, we explore three integrated and dynamic processes in airway remodeling: (1) initiation by epithelial cells; (2) amplification by immune cells; and (3) mesenchymal effector functions. Furthermore, we explore the role of inflammaging in the dysregulated and persistent inflammatory response that perpetuates airway remodeling in elderly asthmatics.
| S-EPMC7253669 | biostudies-literature
Project description: Not available
| S-EPMC9761175 | biostudies-literature