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Biomedicines
Special Issues
Pathogenesis and Novel Therapeutics in Asthma
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Pathogenesis and Novel Therapeutics in Asthma

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 30282

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Stanislawa Bazan-Socha

E-Mail Website
Guest Editor
Department of Internal Medicine, Jagiellonian University Medical College, 30-688 Kraków, Małopolskie, Poland
Interests: allergy; asthma; airway remodeling; autoimmune diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Asthma is a prevalent chronic inflammatory disease of the airways with complex etiology, mechanistic pathways, and variable clinical presentation. Such heterogeneity renders the search for targeted therapies. Currently, the best-known disease phenotype with tailored biological treatment is eosinophilic asthma. However, even in some of these patients, anti-IL5 treatment is ineffective. Furthermore, about a quarter of patients, especially those with a severe phenotype, develop progressive and irreversible airway obstruction, leading to persistent symptoms despite optimized treatment. Therefore, new therapeutic approaches are still needed, particularly in severe asthma. The Special Issue focuses on asthma research referring to modern personalized therapeutic opportunities. Particular interest is directed to novel asthma biomarkers, including molecular and epigenetic ones, providing new light on pathogenesis, phenotyping, and customized therapy in various airway inflammatory patterns of that disease. In addition, research articles on airway epithelial cell dysfunction, airway remodeling, and the overlap between asthma and chronic obstructive pulmonary disease are welcomed.

Dr. Stanislawa Bazan-Socha
Guest Editor

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Keywords

  • asthma
  • pathogenesis
  • biomarkers
  • epithelial cells
  • airway remodeling
  • asthma/COPD overlap
  • biologics
  • new therapies

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Published Papers (11 papers)

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Editorial

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4 pages, 202 KiB  
Editorial
Editorial to the Special Issue “Pathogenesis and Novel Therapeutics in Asthma”
by Stanisława Bazan-Socha and Bogdan Jakieła
Biomedicines 2023, 11(2), 268; https://doi.org/10.3390/biomedicines11020268 - 19 Jan 2023
Cited by 1 | Viewed by 1329
Abstract
In recent years, substantial progress has been made in our understanding of asthma pathomechanisms, especially phenotyping [...] Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)

Research

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14 pages, 5465 KiB  
Article
Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation
by Dong-Wook Kwak, Donghwan Park and Jae-Hong Kim
Biomedicines 2022, 10(11), 2979; https://doi.org/10.3390/biomedicines10112979 - 19 Nov 2022
Cited by 4 | Viewed by 1828
Abstract
Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an [...] Read more.
Granulocyte colony-stimulating factor (G-CSF) has been suggested to be closely associated with neutrophilic asthma pathogenesis. However, little is known about the factors regulating the production of G-CSF in neutrophilic asthma. We previously reported that a leukotriene B4 receptor 2, BLT2, played an important role in neutrophilic airway inflammation. Therefore, in the current study, we investigated whether BLT2 plays a role in the production of G-CSF in lipopolysaccharide/ovalbumin (LPS/OVA)-induced steroid-resistant neutrophilic asthma. The data showed that BLT2 critically mediated G-CSF production, contributing to the progression of neutrophilic airway inflammation. We also observed that 12-lipoxygenase (12-LO), which catalyzes the synthesis of the BLT2 ligand 12(S)-HETE, was also necessary for G-CSF production. Together, these results suggest that the 12-LO-BLT2-linked signaling network is critical for the production of G-CSF, contributing to the development of neutrophilic airway inflammation. Our findings can provide a potential new target for the therapy of severe neutrophilic asthma. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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10 pages, 1338 KiB  
Article
Assessing the Anti-Inflammatory Effects of an Orally Dosed Enzymatically Liberated Fish Oil in a House Dust Model of Allergic Asthma
by Crawford Currie, Bomi Framroze, Dave Singh, Simon Lea, Christian Bjerknes and Erland Hermansen
Biomedicines 2022, 10(10), 2574; https://doi.org/10.3390/biomedicines10102574 - 14 Oct 2022
Cited by 3 | Viewed by 2171
Abstract
Eosinophils are a major driver of inflammation in a number of human diseases, including asthma. Biologic therapies targeting IL-5 have enabled better control of severe eosinophilic asthma, but no such advances have been made for enhancing the control of moderate asthma. However, a [...] Read more.
Eosinophils are a major driver of inflammation in a number of human diseases, including asthma. Biologic therapies targeting IL-5 have enabled better control of severe eosinophilic asthma, but no such advances have been made for enhancing the control of moderate asthma. However, a number of moderate asthma sufferers remain troubled by unresolved symptoms, treatment side effects, or both. OmeGo, an enzymatically liberated fish oil, has demonstrated antioxidant and anti-inflammatory properties including the reduction of eosinophilia. A house dust mite model of induced asthma in mice was utilized in this study, and OmeGo showed a significant reduction in eosinophilic lung and systemic inflammation and reduced lung remodelling compared to cod liver oil. The CRTH2 antagonist fevipiprant showed an anti-inflammatory profile similar to that of OmeGo. OmeGo has the potential to be a pragmatic, cost-effective co-treatment for less severe forms of eosinophilic asthma. Proof-of-concept studies are planned. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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17 pages, 3748 KiB  
Article
Bcl10 Regulates Lipopolysaccharide-Induced Pro-Fibrotic Signaling in Bronchial Fibroblasts from Severe Asthma Patients
by Rakhee K. Ramakrishnan, Khuloud Bajbouj, Maha Guimei, Surendra Singh Rawat, Zaina Kalaji, Mahmood Y. Hachim, Bassam Mahboub, Saleh M. Ibrahim, Rifat Hamoudi, Rabih Halwani and Qutayba Hamid
Biomedicines 2022, 10(7), 1716; https://doi.org/10.3390/biomedicines10071716 - 15 Jul 2022
Cited by 2 | Viewed by 3018
Abstract
Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. Current asthma medications have limited efficacy in treating fibrosis, particularly in patients with severe asthma, necessitating a deeper understanding of the fibrotic mechanisms. The NF-κB pathway is key to airway inflammation in [...] Read more.
Subepithelial fibrosis is a characteristic hallmark of airway remodeling in asthma. Current asthma medications have limited efficacy in treating fibrosis, particularly in patients with severe asthma, necessitating a deeper understanding of the fibrotic mechanisms. The NF-κB pathway is key to airway inflammation in asthma, as it regulates the activity of multiple pro-inflammatory mediators that contribute to airway pathology. Bcl10 is a well-known upstream mediator of the NF-κB pathway that has been linked to fibrosis in other disease models. Therefore, we investigated Bcl10-mediated NF-κB activation as a potential pathway regulating fibrotic signaling in severe asthmatic fibroblasts. We demonstrate here the elevated protein expression of Bcl10 in bronchial fibroblasts and bronchial biopsies from severe asthmatic patients when compared to non-asthmatic individuals. Lipopolysaccharide (LPS) induced the increased expression of the pro-fibrotic cytokines IL-6, IL-8 and TGF-β1 in bronchial fibroblasts, and this induction was associated with the activation of Bcl10. Inhibition of the Bcl10-mediated NF-κB pathway using an IRAK1/4 selective inhibitor abrogated the pro-fibrotic signaling induced by LPS. Thus, our study indicates that Bcl10-mediated NF-κB activation signals increased pro-fibrotic cytokine expression in severe asthmatic airways. This reveals the therapeutic potential of targeting Bcl10 signaling in ameliorating inflammation and fibrosis, particularly in severe asthmatic individuals. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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16 pages, 3118 KiB  
Article
Increased Oxidative Stress in Asthma—Relation to Inflammatory Blood and Lung Biomarkers and Airway Remodeling Indices
by Stanisława Bazan-Socha, Krzysztof Wójcik, Magdalena Olchawa, Tadeusz Sarna, Jakub Pięta, Bogdan Jakieła, Jerzy Soja, Krzysztof Okoń, Jacek Zarychta, Lech Zaręba, Michał Stojak, Daniel P. Potaczek, Jan G. Bazan and Magdalena Celińska-Lowenhoff
Biomedicines 2022, 10(7), 1499; https://doi.org/10.3390/biomedicines10071499 - 24 Jun 2022
Cited by 10 | Viewed by 2726
Abstract
Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using [...] Read more.
Airway inflammation in asthma is related to increased reactive oxygen species generation, potentially leading to tissue injury and subsequent airway remodeling. We evaluated oxidative stress in peripheral blood from asthmatic subjects (n = 74) and matched controls (n = 65), using recently developed real-time monitoring of the protein hydroperoxide (HP) formation by the coumarin boronic acid (CBA) assay. We also investigated the relation of the systemic oxidative stress response in asthma to disease severity, lung function, airway remodeling indices (lung computed tomography and histology), and blood and bronchoalveolar lavage fluid (BAL) inflammatory biomarkers. We documented enhanced systemic oxidative stress in asthma, reflected by 35% faster and 58% higher cumulative fluorescent product generation in the CBA assay (p < 0.001 for both). The dynamics of HP generation correlated inversely with lung function but not with asthma severity or histological measures of airway remodeling. HP generation was associated positively with inflammatory indices in the blood (e.g., C-reactive protein) and BAL (e.g., interleukin [IL]-6, IL-12p70, and neutrophil count). Bronchial obstruction, thicker airway walls, increased BAL IL-6, and citrullinated histone 3 in systemic circulation independently determined increased HP formation. In conclusion, a real-time CBA assay showed increased systemic HP generation in asthma. In addition, it was associated with inflammatory biomarkers, suggesting that proper disease control can also lead to a decrease in oxidative stress. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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15 pages, 3057 KiB  
Article
The Mediating Effect of Cytokines on the Association between Fungal Sensitization and Poor Clinical Outcome in Asthma
by Ching-Hsiung Lin, Yi-Rong Li, Chew-Teng Kor, Sheng-Hao Lin, Bin-Chuan Ji, Ming-Tai Lin and Woei-Horng Chai
Biomedicines 2022, 10(6), 1452; https://doi.org/10.3390/biomedicines10061452 - 19 Jun 2022
Cited by 5 | Viewed by 2296
Abstract
Sensitization to fungal allergens is one of the proposed phenotypes in asthma. An association between fungal sensitization and worse clinical outcomes is apparent. Moreover, fungal sensitization in asthma that is associated with different type of immunological mechanism has been reported. How the role [...] Read more.
Sensitization to fungal allergens is one of the proposed phenotypes in asthma. An association between fungal sensitization and worse clinical outcomes is apparent. Moreover, fungal sensitization in asthma that is associated with different type of immunological mechanism has been reported. How the role of cytokines mediates the association between fungal sensitization and poorer asthmatic outcomes remains unclear. We aimed to determine role of cytokines in the relationship between fungal sensitization and worse clinical outcomes in asthma. Method: We conducted a prospective study to recruit adult patients with asthma. Data including age, sex, height, weight, smoking history, medication, emergency visit and admission, pulmonary function testing result, and Asthma Control Test (ACT) scores were collected. We used the automated BioIC method to measure fungal allergen sIgE in sera. Serum levels of Interleukin (IL) -4, IL-13, IL-6, IL-9, IL-10, IL-17 A, IL-22, Interferon (IFN) -γ, Immunoglobulin E (IgE), Tumor necrosis factor-α (TNF-α), and Transforming growth factor-β (TGF-β) were measured using ELISA. Result: IL-6 and IL-17A had a significant positive correlation between sensitization and most fungi species compared to IgE. Sensitization to Candida albicans had strongly positive association both with IL-6 and IL-17A. However, only IL-17A had significant relationship with ED visit times. The mediation analysis result indicates that IL-17A had a significant positively mediating effect (ME) on the association between Candida albicans and ED visit times. Conclusion: IL-17A is a potential mediator to link Candida albicans sensitization and ED visits for asthma. We suggest that patients with fungal sensitization, such as Candida albicans, have poorer outcomes associated with Th17-mediated immune response rather than Th2. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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16 pages, 2622 KiB  
Article
Predictive Response to Immunotherapy Score: A Useful Tool for Identifying Eligible Patients for Allergen Immunotherapy
by Ilaria Mormile, Francescopaolo Granata, Aikaterini Detoraki, Daniela Pacella, Francesca Della Casa, Felicia De Rosa, Antonio Romano, Amato de Paulis and Francesca Wanda Rossi
Biomedicines 2022, 10(5), 971; https://doi.org/10.3390/biomedicines10050971 - 22 Apr 2022
Cited by 5 | Viewed by 2144
Abstract
A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible [...] Read more.
A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible patients. A total of 110 patients diagnosed with allergic rhinitis with or without concomitant asthma were enrolled in this study. Before beginning sublingual immunotherapy (SLIT), patients were evaluated by analyzing clinical and laboratory parameters. A specific rating was assigned to each parameter to be combined in a total score named PRIS. At baseline (T0) and follow-up [after 12 (T12) and 24 months (T24) of SLIT], a Visual Analogue Scale (VAS) was used to calculate a mean symptom score (MSS). Finally, the percentage variation between the MSS at T0 and at T12 [ΔMSS-12(%)] and T24 [ΔMSS-24 (%)] was measured. We observed a significant improvement of symptoms at T12 and T24 compared to T0 in all groups undergoing SLIT. PRIS was effective in predicting ΔMSS-24 (%) in patients treated with single-allergen SLIT. In addition, PRIS was effective in predicting ΔMSS-24 (%) in both patients with only rhinitis and with concomitant asthma. PRIS assessment can represent a useful tool to individuate potential responders before SLIT prescription. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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17 pages, 3134 KiB  
Article
Side-Directed Release of Differential Extracellular Vesicle-associated microRNA Profiles from Bronchial Epithelial Cells of Healthy and Asthmatic Subjects
by Viktoria E. M. Schindler, Fahd Alhamdan, Christian Preußer, Lukas Hintz, Bilal Alashkar Alhamwe, Andrea Nist, Thorsten Stiewe, Elke Pogge von Strandmann, Daniel P. Potaczek, Clemens Thölken and Holger Garn
Biomedicines 2022, 10(3), 622; https://doi.org/10.3390/biomedicines10030622 - 7 Mar 2022
Cited by 13 | Viewed by 3520
Abstract
Extracellular vesicles (EVs) are released by virtually all cells and may serve as intercellular communication structures by transmitting molecules such as proteins, lipids, and nucleic acids between cells. MicroRNAs (miRNAs) are an abundant class of vesicular RNA playing a pivotal role in regulating [...] Read more.
Extracellular vesicles (EVs) are released by virtually all cells and may serve as intercellular communication structures by transmitting molecules such as proteins, lipids, and nucleic acids between cells. MicroRNAs (miRNAs) are an abundant class of vesicular RNA playing a pivotal role in regulating intracellular processes. In this work, we aimed to characterize vesicular miRNA profiles released in a side-directed manner by bronchial epithelial cells from healthy and asthmatic subjects using an air−liquid interface cell culture model. EVs were isolated from a culture medium collected from either the basolateral or apical cell side of the epithelial cell cultures and characterized by nano-flow cytometry (NanoFCM) and bead-based flow cytometry. EV-associated RNA profiles were assessed by small RNA sequencing and subsequent bioinformatic analyses. Furthermore, miRNA-associated functions and targets were predicted and miRNA network analyses were performed. EVs were released at higher numbers to the apical cell side of the epithelial cells and were considerably smaller in the apical compared to the basolateral compartment. EVs from both compartments showed a differential tetraspanins surface marker expression. Furthermore, 236 miRNAs were differentially expressed depending on the EV secretion side, regardless of the disease phenotype. On the apical cell side, 32 miRNAs were significantly altered in asthmatic versus healthy conditions, while on the basolateral cell side, 23 differentially expressed miRNAs could be detected. Downstream KEGG pathway analysis predicted mTOR and MAPK signaling pathways as potential downstream targets of apically secreted miRNAs. In contrast, miRNAs specifically detected at the basolateral side were associated with processes of T and B cell receptor signaling. The study proves a compartmentalized packaging of EVs by bronchial epithelial cells supposedly associated with site-specific functions of cargo miRNAs, which are considerably affected by disease conditions such as asthma. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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Review

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12 pages, 584 KiB  
Review
The Potential Role of Serum and Exhaled Breath Condensate miRNAs in Diagnosis and Predicting Exacerbations in Pediatric Asthma
by Natalia Kierbiedź-Guzik and Barbara Sozańska
Biomedicines 2023, 11(3), 763; https://doi.org/10.3390/biomedicines11030763 - 2 Mar 2023
Cited by 4 | Viewed by 2059
Abstract
Asthma is the most common chronic disease of the respiratory system in children and the number of new cases is constantly increasing. It is characterized by dyspnea, wheezing, tightness in the chest, or coughing. Due to diagnostic difficulties, disease monitoring, and the selection [...] Read more.
Asthma is the most common chronic disease of the respiratory system in children and the number of new cases is constantly increasing. It is characterized by dyspnea, wheezing, tightness in the chest, or coughing. Due to diagnostic difficulties, disease monitoring, and the selection of safe and effective drugs, it has been shown that among the youngest patients, miRNAs fulfilling the above roles can be successfully used in common clinical practice. These biomolecules, by regulating the expression of the body’s genes, influence various biological processes underlying the pathogenesis of asthma, such as the inflammatory process, remodeling, and intensification of airway obstruction. They can be detected in blood serum and in exhaled breath condensate (EBC). Among children, common factors responsible for the onset or exacerbation of asthma, such as infections, allergens, air pollution, or tobacco smoke present in the home environment, cause a change the concentration of miRNAs in the body. This is related to their significant impact on the modulation of the disease process. In the following paper, we review the latest knowledge on miRNAs and their use, especially as diagnostic markers in assessing asthma exacerbation, with particular emphasis on the pediatric population. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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9 pages, 848 KiB  
Review
Prostacyclin Regulation of Allergic Inflammation
by Kunj Patel and R. Stokes Peebles, Jr.
Biomedicines 2022, 10(11), 2862; https://doi.org/10.3390/biomedicines10112862 - 9 Nov 2022
Cited by 3 | Viewed by 4342
Abstract
Prostacyclin is a metabolic product of the cyclooxygenase pathway that is constitutively expressed and can be induced during inflammatory conditions. While prostacyclin and its analogs have historically been considered effective vasodilators and used in treating pulmonary hypertension, prostacyclin has demonstrated potent anti-inflammatory effects [...] Read more.
Prostacyclin is a metabolic product of the cyclooxygenase pathway that is constitutively expressed and can be induced during inflammatory conditions. While prostacyclin and its analogs have historically been considered effective vasodilators and used in treating pulmonary hypertension, prostacyclin has demonstrated potent anti-inflammatory effects in animal models of allergic airway inflammation. In vitro studies reveal that prostacyclin directly inhibits type 2 cytokine production from CD4+ Th2 cells and ILC2 and reduces the ability of dendritic cells to generate Th2 cytokine production from CD4+ T cells in an antigen-specific manner. Thus, there is strong evidence that prostacyclin may be an additional therapeutic target for treating allergic inflammation and asthma in human subjects. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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Other

24 pages, 1296 KiB  
Systematic Review
Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma
by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Elena Pistocchini, Beatrice Ludovica Ritondo, Paola Rogliani and Alfredo Chetta
Biomedicines 2022, 10(9), 2330; https://doi.org/10.3390/biomedicines10092330 - 19 Sep 2022
Cited by 6 | Viewed by 3315
Abstract
Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really [...] Read more.
Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M3 receptor muscarinic antagonists/β2-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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