Treatment Of Asthma Research Articles

Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential.

Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP-TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.

Herbal plants: A boon in the treatment of Asthma

Asthma is a common disease that is increasing in prevalence worldwide with the highest prevalence in industrialized countries. Asthma affects around 300 million people worldwide, with more than 100million expected to be affected by 2025. From prehistoric times, plants have been excellent sources of medicine. As current asthma therapy is unsatisfactory due to side effects, many people are turning to complementary and alternative medicine to treat their asthma. Plants are mentioned in Ayurveda and other Indian literature to treat a variety of human ailments. There are around 45000 plant species in India, with thousands of them claiming therapeutic benefits. Recent studies on herbs mentioned in ancient literature or used traditionally for asthma have shown antiasthmatic, antihistaminic, and antiallergic properties. According to this review, various plants and their extracts have antiasthmatic, antihistaminic, anticholinergic, and anti- allergic properties.

Precision care in the treatment of pediatric asthma.

Precision medicine in pediatric asthma involves identification of asthma phenotypes, genetic markers, biomarkers, and biologics that target specific pathways. This review includes a discussion of the efficacy of currently approved biologics for pediatric asthma and most recent advances in biomarker/phenotype identification and genetic associations that affect asthma care. Biologics targeting type-2 mediated pathways have shown success in the treatment of moderate to severe asthma in pediatric and adult patients. In comparative studies, dupilumab, an interleukin-4 (IL-4) alpha receptor inhibitor, and mepolizumab, an IL-5 inhibitor, have shown more improvement in asthma exacerbation rates and lung function compared to other biologics such as tezepelumab, omalizumab and benralizumab. Other methods used to categorize asthma treatment response have been investigated and include use of biomarkers such as fractional exhaled nitric oxide (FeNO). Genomic studies are also emerging in precision care for pediatric asthma. An understanding of underlying immunologic and genetic mechanisms affecting the development of asthma in pediatric patients has resulted in the production of numerous targeted therapies that have led to improvement in lung function and reduced exacerbation burden.

Bioequivalence Between a New Omalizumab Prefilled Syringe With an Autoinjector or with a Needle Safety Device Compared with the Current Prefilled Syringe: A Randomized Controlled Trial in Healthy Volunteers.

Omalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (1) new PFS with autoinjector (PFS-AI), (2) new PFS-NSD configuration, and (3) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80-1.25 range for maximum concentration (Cmax ), area under the concentration-time curve until the last quantifiable measurement (AUClast ), and AUC extrapolated to infinity (AUCinf ). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1×300mg/2mL via new PFS-AI (n = 66), omalizumab 1×300mg/2mL via new PFS-NSD (n = 64), or omalizumab 2×150mg/1mL via current PFS-NSD (n = 63). Comparing new PFS-AI versus current PFS-NSD, the GMRs were: Cmax , 1.085; AUClast , 1.093; AUCinf , 1.100. Comparing new PFS-NSD versus current PFS-NSD, the GMRs were: Cmax , 1.006; AUClast , 1.016; AUCinf , 1.027. The 95% CIs for all GMR parameters were contained within the 0.80-1.25 range. Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD.

Advancing Care in Severe Asthma: The Art of Switching Biologics.

Biologics targeting IgE, IL-5, IL-4/IL-13, and TSLP are crucial in severe asthma treatment. Research, including randomized controlled trials and real-world studies, has been conducted to assess their efficacy and identify patient characteristics that may predict positive responses. The effectiveness of switching biologics, especially given overlaps in treatment eligibility, and the clinical outcomes post-cessation are critical areas of investigation. This work reviews the effects of switching between these biologics and the indicators of treatment success or failure. Insights are primarily derived from real-world experiences, focusing on patients transitioning from one monoclonal antibody to another. Moreover, this review aims to provide insights into the effectiveness, safety, and broader implications of switching biologics, enhancing understanding for clinicians to optimize severe asthma management. The article underlines the importance of a patient-centered approach, biomarker assessment, and the evolving nature of asthma treatment in making informed decisions about biologic therapy.

Bronchial Cryo-Denervation for Severe Asthma: A Pilot Study

Introduction: Targeting the parasympathetic nervous system innervating the airway with pharmacologic products has been proved to improve the clinical outcomes of severe asthma. Bronchial cryo-denervation (BCD) is a novel non-pharmacologic treatment for severe asthma using an endobronchial cryo-balloon administered via bronchoscopy to denervate parasympathetic pulmonary nerves. Preclinical studies have demonstrated that BCD significantly disrupted vagal innervation in the lung. Methods: A total of 15 patients with severe asthma were enrolled in this prospective, single-center pilot study. Patients underwent bifurcated BCD treatment at a 30-day interval after baseline assessment. Follow-up through 12 months included assessment of adverse events, technical feasibility, and changes in pulmonary function; asthma control questionnaire-7 (ACQ-7); and asthma control test (ACT). Results: BCD was performed on all 15 severe asthma patients, with technical feasibility of 96.7%. There were no device-related and 2 procedure-related serious adverse events through 12 months, which resolved without sequelae. The most frequent nonserious procedure-related adverse event was increased cough in 60% (9 of 15) patients. Pulmonary function remained unchanged, and significant improvements from baseline ACQ-7 (mean, −1.19, p = 0.0032) and ACT (mean, 3.18, p = 0.0011) scores were observed since the first month’s follow-up after a single lung airway treatment, with similar trends till the end of the 12-month follow-up. Conclusion: This study provides the first clinical evidence of the safety, feasibility, and initial efficacy of BCD in patients with severe asthma.

Alleviation of allergic asthma by rosmarinic acid via gut-lung axis

BackgroundAsthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PurposeTo investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. MethodsWe used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. ResultsRosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. ConclusionsThe anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.

Alginate aerogels by spray gelation for enhanced pulmonary delivery and solubilization of beclomethasone dipropionate

Aerogel technology is an emerging platform that offers alternative and cost-effective dry carriers with advanced performances for the pharmaceutical industry. The innovative combination of compressed air-assisted spray gelation and “green” supercritical fluid (SCF) technology was used in this study to produce alginate aerogel microparticles with adequate properties for pulmonary drug delivery. Beclomethasone dipropionate (BDP), a poorly water-soluble anti-inflammatory drug for asthma treatment, was loaded into alginate aerogel particles by SCF-assisted impregnation ensuring high loading, as well as the amorphization of the drug. The production of aerogels was optimized through the fine-tuning of parameters in compressed air-assisted spray gelation, specifically adjusting the air flow rate and the pump speed. Alginate aerogels were aimed to be produced with an appropriate aerodynamic diameter from 1 to 5 µm, measured by in vitro deposition tests with Next Generation impactor and potential for deep lung penetration. Nuclear magnetic resonance (NMR) relaxometry was used to assess aerogel hydration and unveiled structure–property relationships leading to the sudden release of the drug. Finally, in vitro cytotoxicity tests in fibroblasts and ex vivo permeability tests were conducted. These biological tests confirmed the excellent biocompatibility of the aerogel formulations and demonstrated the efficient deposition of BDP in porcine bronchial tissues assisted by the porous alginate aerogel carrier.

Jiawei Yanghe Decoction attenuate allergic airway inflammation by suppressing group 2 innate lymphoid cells responses

Ethnopharmacological relevanceJiawei Yanghe Decoction (JWYHD) is modified Yanghe Decoction (YHD). YHD historically utilized as a potent medicinal solution for addressing chronic inflammatory conditions, holds promising therapeutic potential in the treatment of asthma. However, the mechanisms underlying JWYHD's effects on allergic asthma remain unclear. Aim of the studyTo investigate the therapeutic effect as well as the underlying mechanisms of JWYHD on asthmatic mice. Materials and methodsThe ovalbumin (OVA)-induced mouse model was utilized, followed by the administration of JWYHD to allergic asthmatic mice. Subsequently, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and lung tissues were conducted. The levels of various cytokines including interleukin (IL)-4, IL-5, IL-13, IL-33, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in BALF, as well as the total immunoglobulin E (IgE) content in serum, were assessed. Lung function and tissue pathology examinations were performed to assess the protective impacts of JWYHD. The chemical components of JWYHD and its lung prototype compounds (referred to the chemical components present in JWYHD that were observed in the lung) were explored by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). RNA-seq analysis revealed the regulation mechanisms of JWYHD treating asthma. Furthermore, the effect of JWYHD on type 2 innate lymphoid cells (ILC2s) in asthmatic mice was detected by flow cytometry and Smart-RNA-seq analysis. Then molecular docking analysis was used to show the interaction between identified compounds and key targets. ResultsJWYHD significantly attenuated the airway inflammation of asthmatic mice, reduced the levels of inflammatory cells in BALF, as well the levels of the cytokines IL-4, IL-5, IL-13, IL-33, and TNF-α in BALF and IgE in serum. Airway hyperresponsiveness (AHR) and lung inflammation infiltration were also alleviated by JWYHD. Moreover, RNA-seq analysis revealed that JWYHD attenuated airway inflammation in asthmatic mice via regulating immunity. Flow cytometry confirmed that JWYHD could inhibit ILC2 responses. ILC2 Smart-RNA-seq analysis showed that JWYHD impaired the inflammation reaction-related signaling pathways in ILC2s, and neuropilin-1 (Nrp1), endothelial transcription factor 3 (GATA3) and interleukin 1 receptor like protein 1 (ST2) might be the key targets. The molecular docking analysis investigating the connection between the primary targets and JWYHD's prototype compounds in the lung demonstrated that liquiritin apioside, icariin, glycyrrhizic acid, and uralsaponin B, identified through UPLC-Q-TOF/MS, exhibited significant affinity in binding to the mentioned key targets. ConclusionOur results suggested that the mechanism of JWYHD in treating asthma might be related to limiting ILC2 responses. Our findings provided some pharmacological evidence for the clinical application of JWYHD in the treatment of asthma.

Precision medicine in the diagnosis and treatment of asthma

Due to the availability of disease-modifying anti-asthmatic drugs (DMAADs), especially inhaled steroids (alone or in combination with long-acting bronchodilators), biologics and modern allergen immunotherapy, the treatment of asthma has fundamentally changed. The aims of modern asthma precision medicine are prevention of symptoms and the induction and maintenance of asthma remission (long-term asthma control, freedom from exacerbations and stable lung function without the use of systemic steroids). A treat to target approach is used as for other chronic inflammatory diseases in internal medicine: the aim is to achieve remission by an individually tailored treatment with DMAADs; however, the prerequisite for modern asthma precision medicine is asthma phenotyping, including a detailed medical history, lung function testing, allergological diagnostics and measurement of type 2 markers (blood eosinophils and, if available, exhaled nitric oxide, FeNO).

Design, Evaluation and Optimization of Albuterol Sulphate and Theophylline Pulsincap drug delivery system for chronotherapy of Asthma

The aim of the current study was to design and develop and evaluate pulsatile drug delivery system of Albuterol Sulphate and Theophylline for the treatment of Asthma. The capsule body was made water insoluble by cross linked with formaldehyde vaopur. The treatment of Formalin was adopted to modify the gelatin capsule solubility. The formalin residue was carried out by quantitative test. The drug-excipient compatibility is done by FTIR and UV . The pulsincap formulation were prepared by using hydrogel plug of various components. The drug content of the formulation of pulsincap was found to be in the general range. The invitro drug release studies in ph1.2 .6.2 and 7.4 buffern was noticed to be zero percent and capsule was stable for 2 hours drug the studyF5 formulation batch was selected which was best and good formulation and promoted maximum drug release of 96.29% percentage at phosphate buffers when compared with other formulation. Pulsincap formulation can be adopted for optimum delivery of pellets in the treatment as per chronotherapy
 Keywords: Theophylline, quantitative test, invitro drug release studies, phosphate buffers6.2 and 7.4.

Formulation and Evaluation of Pulsatile drug delivery of Albuterol sulphate and Theophylline drugs using modified Pulsincap technology

Albuterol Sulphate and Theophylline are used as anti-asthma agents. The objective of the present investigation was to design develop and evaluate a modified pulsincap drug delivery system of Albuterol Sulphate and Theophylline for the treatment of Asthma. The body of capsule was made insoluble with water by cross linking with formaldehyde. This modified capsule was completely filled with drug with polymer such as HPMCK15M, HPMC K 100M, PVPK-30 to expel the drug after predetermined lag time. A hydrogel plug was inserted in the body of a capsule to obtain desired drug release after a lag time for chronotherapy of asthma. Untreated capsule was attached to the treated body and was released. The drug was exerted to precompression parameter such as Angle of repose, Bulk density, Tapped density, Car’s index Hassner’s ratio. These capsules were subjected to further post formulation studies such as weight variation, drug content, invitro dissolution studies separately. The pre and post formulation parameters were found to be within permissible limit. The mere compatibility of drug, polymer and excipients were determined by Fourier transform infrared analysis (FTIR) and UV-Visible spectroscopy (UV). The results showed that drug was completely compatible with polymer and excipients. In vitro dissolution were carried out by using pH 6 .8 and pH 7.4 buffers. Based on the result obtained F5 Formulation shows good dissolution profile. Higuchi, Hixson crowell. Koresmeyer peppas to evaluate the kinetics and drug release. The drug release follows first order kinetics and the mechanism was found to be NON FICKS DIFFUSION.
 Keywords: Albuterol Sulphate, Theophylline, modified pulsincap drug delivery system, FTIR, Dissolution

Bronchial epithelial transcriptomics and experimental validation reveal asthma severity-related neutrophilc signatures and potential treatments

Airway epithelial transcriptome analysis of asthma patients with different severity was used to disentangle the immune infiltration mechanisms affecting asthma exacerbation, which may be advantageous to asthma treatment. Here we introduce various bioinformatics methods and develop two models: an OVA/CFA-induced neutrophil asthma mouse model and an LPS-induced human bronchial epithelial cell damage model. Our objective is to investigate the molecular mechanisms, potential targets, and therapeutic strategies associated with asthma severity. Multiple bioinformatics methods identify meaningful differences in the degree of neutrophil infiltration in asthma patients with different severity. Then, PTPRC, TLR2, MMP9, FCGR3B, TYROBP, CXCR1, S100A12, FPR1, CCR1 and CXCR2 are identified as the hub genes. Furthermore, the mRNA expression of 10 hub genes is determined in vivo and in vitro models. Reperixin is identified as a pivotal drug targeting CXCR1, CXCR2 and MMP9. We further test the potential efficiency of Reperixin in 16HBE cells, and conclude that Reperixin can attenuate LPS-induced cellular damage and inhibit the expression of them. In this study, we successfully identify and validate several neutrophilic signatures and targets associated with asthma severity. Notably, Reperixin displays the ability to target CXCR1, CXCR2, and MMP9, suggesting its potential therapeutic value for managing deteriorating asthma.

Exploring Perceptions of Biologic Therapies: A Qualitative Study Among Canadians Living with Severe Asthma.

Biologic therapies have demonstrated benefits for individuals with severe asthma, including reduced daily symptoms and severe exacerbations. However, data describing patient perspectives on these treatments are limited. This study sought to understand the preferences and priorities of Canadians with severe asthma in the context of novel biologic treatment options. Semi-structured, qualitative interviews were conducted among Canadians with severe asthma from July to August 2022. Purposeful sampling included individuals with and without biologic therapy experience. All participants described daily life with severe asthma, experiences and priorities related to asthma treatment and their impressions of biologics. Reflexive thematic analysis was used to explore patterns in the data. Among 18 individuals included, 10 were currently taking or had prior experience with biologic treatment for asthma. Those who had never been treated with biologics were unfamiliar with them, considering treatment, or believed that they may not be eligible. Four themes were developed to convey the perspectives of participants on biologics: (1) life-changing benefits, but not for all; (2) navigating barriers to being prescribed and remaining adherent to biologic treatments; (3) treatment administration preferences are not only about convenience; (4) concerns about safety and the unknown as a source of treatment hesitancy. Findings suggest that the clinical benefits of biologics align with patient perceptions of achieving good asthma control. However, treatment gaps persist among individuals who do not experience a meaningful improvement in their asthma symptoms and those who face barriers accessing biologics. People with severe asthma attributed importance to greater availability of at-home treatment options, improved access to financial support to cover treatment costs and support to address safety concerns. This research provides insight into patient-based treatment priorities and preferences for biologics, which may help inform decision-making related to emerging therapies for severe asthma.

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Efficacy of Mepolizumab in the Treatment of Severe Asthma with a Mixed Granulocytic Pattern of Airway Inflammation (Case Report)

This article describes two clinical observations of the use of mepolizumab in patients with severe uncontrolled asthma with a mixed granulocytic pattern of inflammation in the bronchi and comorbid pathology. The mixed granulocytic form of severe asthma is characterized by a combination of T2 endotype and non-T2 endotype. The most common mixed granulocytic pattern of severe asthma occurs in comorbid pathology, in particular, when it is combined with chronic obstructive pulmonary disease (COPD) or bronchiectasis.In the presented observations, both patients had an experience of smoking, a late manifestation of bronchial asthma with the development of centrilobular emphysema and an irreversible decrease in the FEV/FVC ratio as part of the development of COPD. A feature of one of the cases was the presence of cylindrical bronchiectasis in both lungs. The choice of mepolizumab as an additional maintenance agent at GINA stage 5 in both cases was justified by the uncontrolled course of asthma despite the use of a high dose of glucocorticosteroids in combination with other basic drugs and the need for the use of systemic corticosteroids > 50 % of the time per year, a history of recurrent exacerbations in previous 12 months, the presence of persistent blood eosinophilia (>150 cells/μl), as well as a combination of asthma with polypous rhinosinusitis in one of the patients.Overall, the use of mepolizumab 100 mg subcutaneously every four weeks in addition to regular maximum optimized maintenance therapy was characterized by rapid, signifi cant and sustained effi cacy, which was expressed in early achievement of asthma control within the fi rst 16 weeks of therapy.

Acuity of asthma exacerbations in Alberta, Canada is increasing: a population-based study

BackgroundAsthma is a common respiratory illness affecting 2.8 million Canadians, including 9.7% of Albertans. Prior studies showed a substantial decrease in ED visits for asthma in the decade preceding 2010, followed by a stabilization. This was attributed to improvements in the pharmacologic and non-pharmacologic treatments for asthma during that period followed by a balance between epidemiologic drivers and protective factors in the population.MethodsWe assessed whether this trend continued in Alberta from 2010 to 2022 using population level data for the volume of daily ED visits, acuity of asthma exacerbations in the ED, and hospitalization rate.ResultsThe mean number of ED visits decreased from 4.5 to 2.2 per million persons per day, but the acuity of exacerbations and the proportion requiring hospitalization increased. The number of patients presenting with the highest level of acuity increased by over 300%, and the percentage of patients requiring hospitalization increased from 6.8 to 11.3%.ConclusionTotal ED visits for asthma exacerbations continues to decline in Alberta. The reasons for an increase in more severe exacerbations requires further attention.

Anti-CD20 treatment attenuates Th2 cell responses: implications for the role of lung follicular mature B cells in the asthmatic mice.

B cells were believed to act as antigen-presenting cells (APCs) to promote T helper type 2 (Th2) cell responses. However, the role of lung B cells and its subpopulations in Th2 cell responses in asthma remains unclear. We leveraged an anti-CD20 monoclonal antibody (mAb) treatment that has been shown to selectively deplete B cells in mice and investigated whether this treatment modulates Th2 cell responses and this modulation is related to lung follicular mature (FM) B cells in a murine model of asthma. We used a house dust mite (HDM)-induced asthma mouse model and found that anti-CD20 mAb treatment attenuates Th2 cell responses. Meanwhile, anti-CD20 mAb treatment did dramatically reduce the number of B cells, especially FM B cells in the lungs, but did not impact the frequency of other immune cell types, including lung T cells, dendritic cells, natural killer cells, and regulatory T cells in wild-type mice. Moreover, we found that the suppressive effect of anti-CD20 mAb treatment on Th2 cell responses could be reversed upon adoptive transfer of lung FM B cells, but not lung CD19+ B cells without FM B cells in asthmatic mice. These findings reveal that anti-CD20 mAb treatment alleviates Th2 cell responses, possibly by depleting lung FM B cells in a Th2-driven asthma model. This implies a potential therapeutic approach for asthma treatment through the targeting of lung FM B cells.

Rho-Kinase Inhibition of Active Force and Passive Tension in Airway Smooth Muscle: A Strategy for Treating Airway Hyperresponsiveness in Asthma.

Rho-kinase inhibitors have been identified as a class of potential drugs for treating asthma because of their ability to reduce airway inflammation and active force in airway smooth muscle (ASM). Past research has revealed that, besides the effect on the ASM's force generation, rho-kinase (ROCK) also regulates actin filament formation and filament network architecture and integrity, thus affecting ASM's cytoskeletal stiffness. The present review is not a comprehensive examination of the roles played by ROCK in regulating ASM function but is specifically focused on passive tension, which is partially determined by the cytoskeletal stiffness of ASM. Understanding the molecular basis for maintaining active force and passive tension in ASM by ROCK will allow us to determine the suitability of ROCK inhibitors and its downstream enzymes as a class of drugs in treating airway hyperresponsiveness seen in asthma. Because clinical trials using ROCK inhibitors in the treatment of asthma have yet to be conducted, the present review focuses on the in vitro effects of ROCK inhibitors on ASM's mechanical properties which include active force generation, relaxation, and passive stiffness. The review provides justification for future clinical trials in the treatment of asthma using ROCK inhibitors alone and in combination with other pharmacological and mechanical interventions.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma

V-type immunoglobulin domain–containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow–derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.