2025 |
Yang XY, Li F, Zhang G, Foster PS, Yang M, 'The role of macrophages in asthma-related fibrosis and remodelling', Pharmacology and Therapeutics, 269 (2025) [C1]
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2024 |
Tu M, Lu C, Jia H, Chen S, Wang Y, Li J, Cheng J, Yang M, Zhang G, 'SULF1 expression is increased and promotes fibrosis through the TGF-ß1/SMAD pathway in idiopathic pulmonary fibrosis', JOURNAL OF TRANSLATIONAL MEDICINE, 22 (2024) [C1]
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor progno... [more]
Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease of unknown etiology. Despite the increasing global incidence and poor prognosis, the exact pathogenic mechanisms remain elusive. Currently, effective therapeutic targets and treatment methods for this disease are still lacking. This study tried to explore the pathogenic mechanisms of IPF. We found elevated expression of SULF1 in lung tissues of IPF patients compared to normal control lung tissues. SULF1 is an enzyme that modifies heparan sulfate chains of heparan sulfate proteoglycans, playing a critical role in biological regulation. However, the effect of SULF1 in pulmonary fibrosis remains incompletely understood. Our study aimed to investigate the impact and mechanisms of SULF1 in fibrosis. Methods: We collected lung specimens from IPF patients for transcriptome sequencing. Validation of SULF1 expression in IPF patients was performed using Western blotting and RT-qPCR on lung tissues. ELISA experiments were employed to detect SULF1 concentrations in IPF patient plasma and TGF-ß1 levels in cell culture supernatants. We used lentiviral delivery of SULF1 shRNA to knock down SULF1 in HFL1 cells, evaluating its effects on fibroblast secretion, activation, proliferation, migration, and invasion capabilities. Furthermore, we employed Co-Immunoprecipitation (Co-IP) to investigate the regulatory mechanisms involved. Results: Through bioinformatic analysis of IPF transcriptomic sequencing data (HTIPF) and datasets GSE24206, and GSE53845, we identified SULF1 may potentially play a crucial role in IPF. Subsequently, we verified that SULF1 was upregulated in IPF and predominantly increased in fibroblasts. Furthermore, SULF1 expression was induced in HFL1 cells following exposure to TGF-ß1. Knockdown of SULF1 suppressed fibroblast secretion, activation, proliferation, migration, and invasion under both TGF-ß1-driven and non-TGF-ß1-driven conditions. We found that SULF1 catalyzes the release of TGF-ß1 bound to TGFßRIII, thereby activating the TGF-ß1/SMAD pathway to promote fibrosis. Additionally, TGF-ß1 induces SULF1 expression through the TGF-ß1/SMAD pathway, suggesting a potential positive feedback loop between SULF1 and the TGF-ß1/SMAD pathway. Conclusions: Our findings reveal that SULF1 promotes fibrosis through the TGF-ß1/SMAD pathway in pulmonary fibrosis. Targeting SULF1 may offer a promising therapeutic strategy against IPF.
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Open Research Newcastle |
2024 |
Yuan L, Qin Q, Yao Y, Chen L, Liu H, Du X, Ji M, Wu X, Wang W, Qin Q, Xiang Y, Qing B, Qu X, Yang M, Qin X, Xia Z, Liu C, 'Increased expression of cathepsin C in airway epithelia exacerbates airway remodeling in asthma', JCI INSIGHT, 9 (2024) [C1]
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2024 |
Yao Y, Yang Y, Ji M, Qin Q, Xu K, Xia Z, Liu H, Yuan L, Yuan Y, Qin L, Du X, Wang L, Zhou K, Wu X, Wang W, Qing B, Xiang Y, Qu X, Yang M, Qin X, Liu C, 'Airway epithelial-derived exosomes induce acute asthma exacerbation after respiratory syncytial virus infection', MEDCOMM, 5 (2024) [C1]
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Open Research Newcastle |
2024 |
Qin L, Yao Y, Wang W, Qin Q, Liu J, Liu H, Yuan L, Yuan Y, Du X, Zhao B, Wu X, Qing B, Huang L, Wang G, Xiang Y, Qu X, Zhang X, Yang M, Xia Z, Liu C, 'Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma', BRITISH JOURNAL OF PHARMACOLOGY, 181, 3700-3716 (2024) [C1]
Background and Purpose: Airway epithelial cells (AECs) regulate the activation of epithelial¿mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signa... [more]
Background and Purpose: Airway epithelial cells (AECs) regulate the activation of epithelial¿mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure. Experimental Approach: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma. Key Results: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling. Conclusion and Implications: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.
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Open Research Newcastle |
2024 |
Wang W, Zhou K, Wang L, Qin Q, Liu H, Qin L, Yang M, Yuan L, Liu C, 'Aging in chronic lung disease: Will anti-aging therapy be the key to the cure?', EUROPEAN JOURNAL OF PHARMACOLOGY, 980 (2024) [C1]
Chronic lung disease is the third leading cause of death globally, imposing huge burden of death, disability and healthcare costs. However, traditional pharmacotherapy has relativ... [more]
Chronic lung disease is the third leading cause of death globally, imposing huge burden of death, disability and healthcare costs. However, traditional pharmacotherapy has relatively limited effects in improving the cure rate and reducing the mortality of chronic lung disease. Thus, new treatments are urgently needed for the prevention and treatment of chronic lung disease. It is particularly noteworthy that, multiple aging-related phenotypes were involved in the occurrence and development of chronic lung disease, such as blocked proliferation, telomere attrition, mitochondrial dysfunction, epigenetic alterations, altered nutrient perception, stem cell exhaustion, chronic inflammation, etc. Consequently, senescent cells induce a series of pathological changes in the lung, such as immune dysfunction, airway remodeling, oxidative stress and regenerative dysfunction, which is a critical issue that needs special attention in chronic lung diseases. Therefore, anti-aging interventions may bring new insights into the treatment of chronic lung diseases. In this review, we elaborate the involvement of aging in chronic lung disease and further discuss the application and prospects of anti-aging therapy.
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Open Research Newcastle |
2023 |
Zhou K, Yuan L, Liu H, Du X, Yao Y, Qin L, Yang M, Xu K, Wu X, Wang L, Xiang Y, Qu X, Qin X, Liu C, 'ITGB4 deficiency in airway epithelia enhances HDM-induced airway inflammation through hyperactivation of TLR4 signaling pathway', JOURNAL OF LEUKOCYTE BIOLOGY, 113, 216-227 (2023) [C1]
Airway epithelial cells (AECs) are the first cell barrier of the respiratory system against external stimuli that play a critical role in the development of asthma. It is known th... [more]
Airway epithelial cells (AECs) are the first cell barrier of the respiratory system against external stimuli that play a critical role in the development of asthma. It is known that AECs play a key role in asthma susceptibility and severity. ITGB4 is a downregulated adhesion molecule in the airway epithelia of asthma patients, which was involved in the exaggerated lung inflammation after allergy stimulation. Toll-like receptor 4 (TLR4) in AECs has also been shown to play a crucial role in the development of lung inflammation in asthma patients. However, the specific intrinsic regulatory mechanism of TLR4 in AECs are still obscure. In this article, we demonstrated that ITGB4 deficiency in AECs enhances HDM-induced airway inflammation through hyperactivation of the TLR4 signaling pathway, which is mediated by inhibition of FYN phosphorylation. Moreover, TLR4-antagonist treatment or blockade of FYN can inhibit or exaggerate lung inflammation in HDM-stressed ITGB4-deficient mice, separately. Together, these results demonstrated that ITGB4 deficiency in AECs enhances HDM-induced lung inflammatory response through the ITGB4-FYN-TLR4 axis, which may provide new therapeutic approaches for the management of lung inflammation in asthma.
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Open Research Newcastle |
2023 |
Yuan L, Liu H, Du X, Yao Y, Qin L, Xia Z, Zhou K, Wu X, Yuan Y, Qing B, Xiang Y, Qu X, Qin X, Yang M, Liu C, 'Airway epithelial ITGB4 deficiency induces airway remodeling in a mouse model', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 151, 431-+ (2023) [C1]
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Open Research Newcastle |
2023 |
Zhang C, Xu H, Netto KG, Sokulsky LA, Miao Y, Mo Z, Meng Y, Du Y, Wu C, Han L, Zhang L, Liu C, Zhang G, Li F, Yang M, 'Inhibition of ?-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation', FRONTIERS IN IMMUNOLOGY, 14 (2023) [C1]
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Open Research Newcastle |
2022 |
Zhang H, Liu S, Li Y, Li J, Ni C, Yang M, Dong J, Wang Z, Qin Z, 'Dysfunction of S100A4+ effector memory CD8+ T cells aggravates asthma', EUROPEAN JOURNAL OF IMMUNOLOGY, 52, 978-993 (2022) [C1]
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Open Research Newcastle |
2022 |
Du X, Yuan L, Yao Y, Yang Y, Zhou K, Wu X, Wang L, Qin L, Li W, Xiang Y, Qu X, Liu H, Qin X, Yang M, Liu C, 'ITGB4 Deficiency in Airway Epithelium Aggravates RSV Infection and Increases HDM Sensitivity', FRONTIERS IN IMMUNOLOGY, 13 (2022) [C1]
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Open Research Newcastle |
2022 |
Yao Y, Liu H, Yuan L, Du X, Yang Y, Zhou K, Wu X, Qin L, Yang M, Xiang Y, Qu X, Qin X, Liu C, 'Integrins are double-edged swords in pulmonary infectious diseases', BIOMEDICINE & PHARMACOTHERAPY, 153 (2022) [C1]
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Open Research Newcastle |
2022 |
Xu K, Yao Y, Liu H, Yang M, Yuan L, Du X, Yang Y, Qin L, Wang W, Zhou K, Wu X, Liu C, 'ITGB4 deficiency induces DNA damage by downregulating HDAC1 in airway epithelial cells under stress stimulation', PEDIATRIC ALLERGY AND IMMUNOLOGY, 33 (2022) [C1]
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Open Research Newcastle |
2022 |
Liu X, Netto KG, Sokulsky LA, Zhou L, Xu H, Liu C, Wang M, Wang H, Li H, Zhang G, Foster PS, Li F, Yang M, 'Single-cell RNA transcriptomic analysis identifies Creb5 and CD11b-DCs as regulator of asthma exacerbations', MUCOSAL IMMUNOLOGY, 15, 1363-1374 (2022) [C1]
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Open Research Newcastle |
2022 |
Liu X, Li X, Chen L, Hsu AC-Y, Asquith KL, Liu C, Laurie K, Barr I, Foster PS, Yang M, 'Proteomic Analysis Reveals a Novel Therapeutic Strategy Using Fludarabine for Steroid-Resistant Asthma Exacerbation', FRONTIERS IN IMMUNOLOGY, 13 (2022) [C1]
Virus-induced asthma exacerbation is a health burden worldwide and lacks effective treatment. To better understand the disease pathogenesis and find novel therapeutic targets, we ... [more]
Virus-induced asthma exacerbation is a health burden worldwide and lacks effective treatment. To better understand the disease pathogenesis and find novel therapeutic targets, we established a mouse model of steroid (dexamethasone (DEX)) resistant asthma exacerbation using ovalbumin (OVA) and influenza virus (FLU) infection. Using liquid chromatography-tandem mass spectrometry (LC-MC/MS), we performed a shotgun proteomics assay coupled with label-free quantification to define all dysregulated proteins in the lung proteome of asthmatic mice. Compared to control, 71, 89, and 30 proteins were found significantly upregulated by at least two-fold (p-value = 0.05) in OVA-, OVA/FLU-, and OVA/FLU/DEX-treated mice, respectively. We then applied a Z-score transformed hierarchical clustering analysis and Ingenuity Pathway Analysis (IPA) to highlight the key inflammation pathways underlying the disease. Within all these upregulated proteins, 64 proteins were uniquely highly expressed in OVA/FLU mice compared to OVA mice; and 11 proteins were DEX-refractory. IPA assay revealed two of the most enriched pathways associated with these over-expressed protein clusters were those associated with MHC class I (MHC-I) antigen-presentation and interferon (IFN) signaling. Within these pathways, signal-transducer-and-activator-of-transcription-1 (STAT1) protein was identified as the most significantly changed protein contributing to the pathogenesis of exacerbation and the underlying steroid resistance based on the label-free quantification; and this was further confirmed by both Parallel Reaction Monitoring (PRM) proteomics assay and western blots. Further, the pharmacological drug Fludarabine decreased STAT1 expression, restored the responsiveness of OVA/FLU mice to DEX and markedly suppressed disease severity. Taken together, this study describes the proteomic profile underpinning molecular mechanisms of FLU-induced asthma exacerbation and identifies STAT1 as a potential therapeutic target, more importantly, we provided a novel therapeutic strategy that may be clinically translated into practice.
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Open Research Newcastle |
2022 |
Du X, Yang Y, Yang M, Yuan L, Wang L, Wu M, Zhou K, Li W, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells', INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, 18, 349-359 (2022) [C1]
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Open Research Newcastle |
2021 |
Yuan F, Jiang L, Li Q, Sokulsky L, Wanyan Y, Wang L, Liu X, Zhou L, Tay HL, Zhang G, Yang M, Li F, 'A Selective alpha 7 Nicotinic Acetylcholine Receptor Agonist, PNU-282987, Attenuates ILC2s Activation and Alternaria-Induced Airway Inflammation', FRONTIERS IN IMMUNOLOGY, 11 (2021) [C1]
Background: The anti-inflammatory effect of an a7nAChR agonist, PNU-282987, has previously been explored in the context of inflammatory disease. However, the effects of PNU-282987... [more]
Background: The anti-inflammatory effect of an a7nAChR agonist, PNU-282987, has previously been explored in the context of inflammatory disease. However, the effects of PNU-282987 on type 2 innate lymphoid cells (ILC2s)-mediated allergic airway inflammation has not yet been established. Aims: To determine the effects of PNU-282987 on the function of ILC2s in the context of IL-33¿ or Alternaria Alternata (AA)¿ induced airway inflammation. Methods: PNU-282987 was administered to mice that received recombinant IL-33 or AA intranasal challenges. Lung histological analysis and flow cytometry were performed to determine airway inflammation and the infiltration and activation of ILC2s. The previously published a7nAChR agonist GTS-21 was employed as a comparable reagent. ILC2s were isolated from murine lung tissue and cultured in vitro in the presence of IL-33, IL-2, and IL-7 with/without either PNU-282987 or GTS-21. The expression of the transcription factors GATA3, IKK, and NF-¿B were also determined. Results: PNU-282987 and GTS-21 significantly reduced goblet cell hyperplasia in the airway, eosinophil infiltration, and ILC2s numbers in BALF, following IL-33 or AA challenge. In vitro IL-33 stimulation of isolated lung ILC2s showed a reduction of GATA3 and Ki67 in response to PNU-282987 or GTS-21 treatments. There was a significant reduction in IKK and NF-¿B phosphorylation in the PNU-282987¿treated group when compared to the GTS-21¿treated ILC2s. Conclusion: PNU-282987 inhibits ILC2-associated airway inflammation, where its effects were comparable to that of GTS-21.
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Open Research Newcastle |
2021 |
Yang Y, Yuan L, Du X, Zhou K, Qin L, Wang L, Yang M, Wu M, Zheng Z, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'Involvement of epithelia-derived exosomes in chronic respiratory diseases', BIOMEDICINE & PHARMACOTHERAPY, 143 (2021) [C1]
Exosomes are tiny membrane lipid bilayer vesicles (f40¿100 nm) formed by the fusion of multivesicular bodies with plasma membrane, which are released extracellular by exocytosis. ... [more]
Exosomes are tiny membrane lipid bilayer vesicles (f40¿100 nm) formed by the fusion of multivesicular bodies with plasma membrane, which are released extracellular by exocytosis. As natural nanocarriers, exosomes contain a variety of signal substances of the mother cell: nucleic acids, proteins and lipids, etc., which always play a vital role in the transmission of signal molecules between different cells. Epithelial cells are the first-line defense system against various inhaled allergens causing chronic respiratory diseases (CRD), such as asthma and chronic obstructive pulmonary disease (COPD). It's noted that increasing literature shows the exosomes derived from epithelial cells are involved in the pathogenesis of CRD. Moreover, the correlations between exosome cargo and the disease phenotypes show a high potential of using exosomes as biomarkers of CRD. In this review, we mainly focus on the physiological functions of epithelial-derived exosomes and illustrate the involved mechanism of epithelial-derived exosomes in common CRD.
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Open Research Newcastle |
2021 |
Duan Z, Liu M, Yuan L, Du X, Wu M, Yang Y, Wang L, Zhou K, Yang M, Zou Y, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'Innate lymphoid cells are double-edged swords under the mucosal barrier', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 25, 8579-8587 (2021) [C1]
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Open Research Newcastle |
2021 |
Netto KG, Foster PS, Li F, Yang M, 'Understanding scRNA-seq data in the context of the tissue microenvironment requires clinical relevance', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118 (2021)
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2021 |
Collison AM, Sokulsky LA, Kepreotes E, de Siqueira AP, Morten M, Edwards MR, Walton RP, Bartlett NW, Yang M, Nguyen TH, Johnston SL, Foster PS, Mattes J, 'miR-122 promotes virus-induced lung disease by targeting SOCS1', JCI INSIGHT, 6 (2021) [C1]
Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the c... [more]
Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.
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Open Research Newcastle |
2021 |
Li W, Du X, Yang Y, Yuan L, Yang M, Qin L, Wang L, Zhou K, Xiang Y, Qu X, Liu H, Qin X, Xiao G, Liu C, 'miRNA-34b/c regulates mucus secretion in RSV-infected airway epithelial cells by targeting FGFR1', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 25, 10565-10574 (2021) [C1]
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Open Research Newcastle |
2021 |
Wang L, Netto KG, Zhou L, Liu X, Wang M, Zhang G, Foster PS, Li F, Yang M, 'Single-cell transcriptomic analysis reveals the immune landscape of lung in steroid-resistant asthma exacerbation', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 118 (2021) [C1]
Exaggerated airway hyperresponsiveness and inflammation are hallmarks of asthma, and lipopolysaccharide (LPS) exposure is linked to the severity of the disease and steroid resista... [more]
Exaggerated airway hyperresponsiveness and inflammation are hallmarks of asthma, and lipopolysaccharide (LPS) exposure is linked to the severity of the disease and steroid resistance. To investigate the mechanisms underlying asthma exacerbation, we established a mouse model of LPS-induced steroid-resistant exacerbation on the background of house dust mite (HDM)-induced asthma to profile the immune cells in lung by using single-cell RNA deep sequencing. Twenty immune subsets were identified by their molecular and functional properties. Specific cell clusters of basophils, type 2 innate lymphoid cells (ILC2), and CD8+ memory T cells were the predominant sources of interleukin (IL)-4 and IL-13 transcripts whose expressions were dexamethasone resistant. Production of IL-13 by these cells was validated by IL-13-reporter mice. Neutralization of IL-13 abolished HDM/LPS-induced airway hyperresponsiveness, airway inflammation, and decreased mucus hypersecretion. Furthermore, using Ingenuity Pathway Analysis systems, we identified canonical pathways and upstream regulators that regulate the activation of basophils, ILC2, and CD8+ memory T cells. Our study provides mechanistic insights and an important reference resource for further understanding of the immune landscape during asthma exacerbation.
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Open Research Newcastle |
2021 |
Yang Y, Yuan L, Yang M, Du X, Qin L, Wang L, Zhou K, Wu M, He R, Feng J, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'Aberrant Methylation of Aging-Related Genes in Asthma', FRONTIERS IN MOLECULAR BIOSCIENCES, 8 (2021) [C1]
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Open Research Newcastle |
2021 |
Li H, Wang H, Sokulsky L, Liu S, Yang R, Liu X, Zhou L, Li J, Huang C, Li F, Lei X, Jia H, Cheng J, Li F, Yang M, Zhang G, 'Single-cell transcriptomic analysis reveals key immune cell phenotypes in the lungs of patients with asthma exacerbation', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 147, 941-954 (2021) [C1]
Background: Asthma exacerbations are associated with heightened asthma symptoms, which can result in hospitalization in severe cases. However, the molecular immunologic processes ... [more]
Background: Asthma exacerbations are associated with heightened asthma symptoms, which can result in hospitalization in severe cases. However, the molecular immunologic processes that determine the course of an exacerbation remain poorly understood, impeding the progression of development of effective therapies. Objective: Our aim was to identify candidate genes that are strongly associated with asthma exacerbation at a cellular level. Methods: Subjects with asthma exacerbation and healthy control subjects were recruited, and bronchoalveolar lavage fluid was isolated from these subjects via bronchoscopy. Cells were isolated through fluorescence-activated cell sorting, and single-cell RNA sequencing was performed on enriched cell populations. Results: We showed that the levels of monocytes, CD8+ T cells, and macrophages are significantly elevated in the bronchoalveolar lavage fluid of patients. A set of cytokines and intracellular transduction regulators are associated with asthma exacerbations and are shared across multiple cell clusters, forming a complicated molecular framework. An additional group of core exacerbation-associated modules is activated, including eukaryotic initiation factor 2 signaling, ephrin receptor signaling, and C-X-C chemokine receptor type 4 signaling in the subpopulations of CD8+ T cells (C1-a) and monocyte clusters (C7 clusters), which are associated with infection. Conclusion: Our study identified a significant number of severe asthma¿associated genes that are differentially expressed by multiple cell clusters.
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Open Research Newcastle |
2021 |
Yuan L, Wang L, Du X, Qin L, Yang M, Zhou K, Wu M, Yang Y, Zheng Z, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma (vol 18, 467, 2020)', JOURNAL OF TRANSLATIONAL MEDICINE, 19 (2021)
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2021 |
Liu X, Nguyen TH, Sokulsky L, Li X, Netto KG, Hsu AC-Y, Liu C, Laurie K, Barr I, Tay H, Eyers F, Foster PS, Yang M, 'IL-17A is a common and critical driver of impaired lung function and immunopathology induced by influenza virus, rhinovirus and respiratory syncytial virus', RESPIROLOGY, 26, 1049-1059 (2021) [C1]
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Open Research Newcastle |
2020 |
Yuan L, Wang L, Du X, Qin L, Yang M, Zhou K, Wu M, Yang Y, Zheng Z, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma', JOURNAL OF TRANSLATIONAL MEDICINE, 18 (2020) [C1]
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Open Research Newcastle |
2020 |
Sokulsky LA, Garcia-Netto K, Nguyen TH, Girkin JLN, Collison A, Mattes J, Kaiko G, Liu C, Bartlett NW, Yang M, Foster PS, 'A critical role for the CXCL3/CXCL5/CXCR2 neutrophilic chemotactic axis in the regulation of type 2 responses in a model of rhinoviral-induced asthma exacerbation', Journal of Immunology, 205, 2468-2478 (2020) [C1]
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Open Research Newcastle |
2020 |
Sokulsky LA, Goggins B, Sherwin S, Eyers F, Kaiko GE, Board PG, et al., 'GSTO1-1 is an upstream suppressor of M2 macrophage skewing and HIF-1a-induced eosinophilic airway inflammation', CLINICAL AND EXPERIMENTAL ALLERGY, 50 609-624 (2020) [C1]
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Open Research Newcastle |
2020 |
Wu M, Yang Y, Yuan L, Yang M, Wang L, Du X, Qin L, Wu S, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'DNA methylation down-regulates integrin ß4 expression in asthmatic airway epithelial cells', Clinical and Experimental Allergy, 50, 1127-1139 (2020) [C1]
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Open Research Newcastle |
2020 |
Yuan L, Zhang X, Yang M, Du X, Wang L, Wu S, Wu M, Duan Z, Xiao G, Zou Y, Xiang Y, Qu X, Liu H, Qin L, Qin Q, Qin X, Liu C, 'Airway epithelial integrin beta 4 suppresses allergic inflammation by decreasing CCL17 production', CLINICAL SCIENCE, 134, 1735-1749 (2020) [C1]
Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway ep... [more]
Airway epithelial cells (AECs) play a key role in asthma susceptibility and severity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is down-regulated in the airway epithelium of asthma patients. Although a few studies hint toward the role of ITGB4 in asthmatic inflammation pathogenesis, their specific resultant effects remain unexplored. In the present study, we determined the role of ITGB4 of AECs in the regulation of Th2 response and identified the underpinning molecular mechanisms. We found that ITGB4 deficiency led to exaggerated lung inflammation and AHR with higher production of CCL17 in house dust mite (HDM)-treated mice. ITGB4 regulated CCL17 production in AECs through EGFR, ERK and NF-¿B pathways. EFGR-antagonist treatment or the neutralization of CCL17 both inhibited exaggerated pathological marks in HDM-challenged ITGB4-deficient mice. Together, these results demonstrated the involvement of ITGB4 deficiency in the development of Th2 responses of allergic asthma by down-regulation of EGFR and CCL17 pathway in AECs.
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Open Research Newcastle |
2020 |
Du X, Yang Y, Xiao G, Yang M, Yuan L, Qin L, He R, Wang L, Wu M, Wu S, Feng J, Xiang Y, Qu X, Liu H, Qin X, Liu C, 'Respiratory syncytial virus infection-induced mucus secretion by down-regulation of miR-34b/c-5p expression in airway epithelial cells', JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 24, 12694-12705 (2020) [C1]
Severe RSV infection is the main cause of hospitalization to children under the age of five. The regulation of miRNAs on the severity of RSV infection is unclear. The aim of the s... [more]
Severe RSV infection is the main cause of hospitalization to children under the age of five. The regulation of miRNAs on the severity of RSV infection is unclear. The aim of the study was to identify the critical differential expression miRNAs (DE miRNAs) that can regulate the pathological response in RSV-infected airway epithelial cells. In this study, miRNA and mRNA chips of RSV-infected airway epithelia from Gene Expression Omnibus (GEO) were screened and analysed, separately. DE miRNAs-targeted genes were performed for further pathway and process enrichment analysis. DE miRNA-targeted gene functional network was constructed on the basis of miRNA-mRNA interaction. The screened critical miRNA was also investigated by bioinformatics analysis. Then, RSV-infected human bronchial epithelial cells (HBECs) were constructed to verify the expression of the DE miRNAs. Finally, specific synthetic DE miRNAs mimics were used to confirm the effect of DE miRNAs on the RSV-infected HBECs. 45 DE miRNAs were identified from GEO62306 dataset. Our results showed that hsa-mir-34b-5p and hsa-mir-34c-5p decreased significantly in HBECs after RSV infection. Consistent with the biometric analysis, hsa-mir-34b/c-5p is involved in the regulation of mucin expression gene MUC5AC. In RSV-infected HBECs, the inducement of MUC5AC production by decreased hsa-mir-34b/c-5p was partly mediated through activation of c-Jun. These findings provide new insights into the mechanism of mucus obstruction after RSV infection and represent valuable targets for RSV infection and airway obstruction treatment.
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Open Research Newcastle |
2020 |
Hadjigol S, Netto KG, Maltby S, Tay HL, Nguyen TH, Hansbro NG, Eyers F, Hansbro PM, Yang M, Foster PS, 'Lipopolysaccharide induces steroid-resistant exacerbations in a mouse model of allergic airway disease collectively through IL-13 and pulmonary macrophage activation', CLINICAL AND EXPERIMENTAL ALLERGY, 50, 82-94 (2020) [C1]
Background: Acute exacerbations of asthma represent a major burden of disease and are often caused by respiratory infections. Viral infections are recognized as significant trigge... [more]
Background: Acute exacerbations of asthma represent a major burden of disease and are often caused by respiratory infections. Viral infections are recognized as significant triggers of exacerbations; however, less is understood about the how microbial bioproducts such as the endotoxin (lipopolysaccharide (LPS)) trigger episodes. Indeed, increased levels of LPS have been linked to asthma onset, severity and steroid resistance. Objective: The goal of this study was to identify mechanisms underlying bacterial-induced exacerbations by employing LPS as a surrogate for infection. Methods: We developed a mouse model of LPS-induced exacerbation on the background of pre-existing type-2 allergic airway disease (AAD). Results: LPS-induced exacerbation was characterized by steroid-resistant airway hyperresponsiveness (AHR) and an exaggerated inflammatory response distinguished by increased numbers of infiltrating neutrophils/macrophages and elevated production of lung inflammatory cytokines, including TNFa, IFN¿, IL-27 and MCP-1. Expression of the type-2 associated inflammatory factors such as IL-5 and IL-13 were elevated in AAD but not altered by LPS exposure. Furthermore, AHR and airway inflammation were no longer suppressed by corticosteroid (dexamethasone) treatment after LPS exposure. Depletion of pulmonary macrophages by administration of 2-chloroadenosine into the lungs suppressed AHR and reduced IL-13, TNFa and IFN¿ expression. Blocking IL-13 function, through either IL-13-deficiency or administration of specific blocking antibodies, also suppressed AHR and airway inflammation. Conclusions & Clinical Relevance: We present evidence that IL-13 and innate immune pathways (in particular pulmonary macrophages) contribute to LPS-induced exacerbation of pre-existing AAD and provide insight into the complex molecular processes potentially underlying microbial-induced exacerbations.
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Open Research Newcastle |
2018 |
Liu C, Yuan L, Zou Y, Yang M, Chen Y, Qu X, Liu H, Jiang J, Xiang Y, Qin X, 'ITGB4 is essential for containing HDM-induced airway inflammation and airway hyperresponsiveness', JOURNAL OF LEUKOCYTE BIOLOGY, 103, 897-908 (2018) [C1]
Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to in... [more]
Airway epithelial cells play a significant role in the pathogenesis of asthma. Although the structural and functional defects of airway epithelial cells have been postulated to increase asthma susceptibility and exacerbate asthma severity, the mechanism and implication of these defects remain uncertain. Integrin ß4 (ITGB4) is a structural adhesion molecule that is downregulated in the airway epithelium of asthma patients. In this study, we demonstrated that ITGB4 deficiency leads to severe allergy-induced airway inflammation and airway hyper-responsiveness (AHR) in mice. After house dust mite (HDM) challenge, epithelial cell-specific ITGB4-deleted mice showed increased lymphocyte, eosinophil, and neutrophil infiltration into lung compared with that of the wild-type mice. ITGB4 deficiency also resulted in increased expression of the Th2 cytokine IL-4, IL-13, and the Th17 cytokine IL-17A in the lung tissue and in the T cells after HDM challenge. The aggravated inflammation in ITGB4 defect mice was partly caused by enhanced disrupted epithelial barrier integrity after HDM stress, which induced the increased thymic stromal lymphopoietin secretion from airway epithelial cells. This study therefore demonstrates that ITGB4 plays a pivotal role in containing allergen-mediated lung inflammation and airway hyper-responsiveness in allergic asthma.
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Open Research Newcastle |
2018 |
Thi HN, Liu X, Su ZZ, Hsu AC-Y, Foster PS, Yang M, 'Potential Role of MicroRNAs in the Regulation of Antiviral Responses to influenza infection', FRONTIERS IN IMMUNOLOGY, 9 (2018) [C1]
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Open Research Newcastle |
2018 |
Thi HN, Maltby S, Tay HL, Eyers F, Foster PS, Yang M, 'Identification of IFN-¿ and IL-27 as Critical Regulators of Respiratory Syncytial Virus-Induced Exacerbation of Allergic Airways Disease in a Mouse Model', JOURNAL OF IMMUNOLOGY, 200, 237-247 (2018) [C1]
Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exa... [more]
Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exacerbations are the main cause of morbidity and mortality associated with asthma, and significantly contribute to asthma-associated healthcare costs. Although glucocorticoids are used to manage exacerbations, some patients respond to them poorly. The underlying mechanisms associated with steroid-resistant exacerbations remain largely unknown. We have previously established a mouse model of RSV-induced exacerbation of allergic airways disease, which mimics hallmark clinical features of asthma. In this study, we have identified key roles for macrophage IFN-¿ and IL-27 in the regulation of RSV-induced exacerbation of allergic airways disease. Production of IFN-¿ and IL-27 was steroid-resistant, and neutralization of IFN-¿ or IL-27 significantly suppressed RSV-induced steroid-resistant airway hyperresponsiveness and airway inflammation. We have previously implicated activation of pulmonary macrophage by TNF-a and/or MCP-1 in the mechanisms of RSV-induced exacerbation. Stimulation of pulmonary macrophages with TNF-a and/or MCP-1 induced expression of both IFN-¿ and IL-27. Our findings highlight critical roles for IFN-¿ and IL-27, downstream of TNF-a and MCP-1, in the mechanism of RSV-induced exacerbation. Thus, targeting the pathways that these factors activate may be a potential therapeutic approach for virus-induced asthma exacerbations.
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Open Research Newcastle |
2017 |
Maltby S, Tay HL, Yang M, Foster PS, 'Mouse models of severe asthma: Understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation', RESPIROLOGY, 22, 874-885 (2017) [C1]
Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for indiv... [more]
Severe asthma has significant disease burden and results in high healthcare costs. While existing therapies are effective for the majority of asthma patients, treatments for individuals with severe asthma are often ineffective. Mouse models are useful to identify mechanisms underlying disease pathogenesis and for the preclinical assessment of new therapies. In fact, existing mouse models have contributed significantly to our understanding of allergic/eosinophilic phenotypes of asthma and facilitated the development of novel targeted therapies (e.g. anti-IL-5 and anti-IgE). These therapies are effective in relevant subsets of severe asthma patients. Unfortunately, non-allergic/non-eosinophilic asthma, steroid resistance and disease exacerbation remain areas of unmet clinical need. No mouse model encompasses all features of severe asthma. However, mouse models can provide insight into pathogenic pathways that are relevant to severe asthma. In this review, as examples, we highlight models relevant to understanding steroid resistance, chronic tissue remodelling and disease exacerbation. Although these models highlight the complexity of the immune pathways that may underlie severe asthma, they also provide insight into new potential therapeutic approaches.
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Open Research Newcastle |
2017 |
Foster PS, Maltby S, Rosenberg HF, Tay HL, Hogan SP, Collison AM, Yang M, Kaiko GE, Hansbro PM, Kumar RK, Mattes J, 'Modeling TH2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma', IMMUNOLOGICAL REVIEWS, 278, 20-40 (2017) [C1]
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Open Research Newcastle |
2016 |
Thi HN, Maltby S, Simpson JL, Eyers F, Baines KJ, Gibson PG, Foster PS, Yang M, 'TNF-a and Macrophages Are Critical for Respiratory Syncytial Virus-Induced Exacerbations in a Mouse Model of Allergic Airways Disease', JOURNAL OF IMMUNOLOGY, 196, 3547-3558 (2016) [C1]
Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation... [more]
Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-a, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVAsensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-a, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-a levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-a and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-a and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management.
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Open Research Newcastle |
2016 |
Xiang Y, Eyers F, Herbert C, Tay HL, Foster PS, Yang M, 'MicroRNA-487b is a negative regulator of macrophage activation by targeting IL-33 production', Journal of Immunology, 196, 3421-3428 (2016) [C1]
MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the functio... [more]
MicroRNAs (miRNAs) are short noncoding RNAs that regulate a broad spectrum of biological processes, including immune responses. Although the contributions of miRNAs to the function of immune cells are beginning to emerge, their specific roles remain largely unknown. IL-33 plays an important role in macrophage activation for innate host defense and proinflammatory responses. In this study, we report that miR-487b can suppress the levels of mRNA and protein for IL-33 during the differentiation of bone marrow-derived macrophages (BMDMs). This results in inhibition of IL-33-induced expression of Ag-presenting and costimulatory molecules and proinflammatory mediators. A luciferase assay showed that miR-487b binds to the IL-33 39-untranslated region. We also confirmed that IL-33 directly promotes the activation of BMDMs by increasing the expression of MHC class I, MHC class II, CD80/CD86, and inducible NO synthase (iNOS) in a dose-dependent manner. Exposure of BMDMs to the TLR4 ligand, LPS, decreased miR-487b expression, increased IL-33 transcript levels, and induced the production of proinflammatory mediators (e.g., iNOS, IL-1b, IL-6, and TNF-a). Treatment with a specific inhibitor of miR-487b function also resulted in increased levels of IL-33 mRNA, which augmented LPS-induced expression of these inflammatory mediators in macrophages. Collectively, our results indicate that miR-487b plays a negative regulatory role in macrophages by controlling the levels of IL-33 transcript and protein to fine-tune innate immune host defense and proinflammatory responses of these cells. Thus, miR-487b plays an important role in the regulation of macrophage homeostasis and activation by targeting IL-33 transcripts.
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Open Research Newcastle |
2016 |
Zhou H, Zhang J, Eyers F, Xiang Y, Herbert C, Tay HL, Foster PS, Yang M, 'Identification of the microRNA networks contributing to macrophage differentiation and function', Oncotarget, 7, 28806-28820 (2016) [C1]
Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associ... [more]
Limited evidence is available about the specific miRNA networks that regulate differentiation of specific immune cells. In this study, we characterized miRNA expression and associated alterations in expression with putative mRNA targets that are critical during differentiation of macrophages. In an effort to map the dynamic changes in the bone marrow (BM), we profiled whole BM cultures during differentiation into macrophages. We identified 112 miRNAs with expression patterns that were differentially regulated 5-fold or more during BMDM development. With TargetScan and MeSH databases, we identified 1267 transcripts involved in 30 canonical pathways linked to macrophage biology as potentially regulated by these specific 112 miRNAs. Furthermore, by employing miRanda and Ingenuity Pathways Analysis (IPA) analysis systems, we identified 18 miRNAs that are temporally linked to the expression of CSF1R, CD36, MSR1 and SCARB1; 7 miRNAs linked to the regulation of the transcription factors RUNX1 and PU.1, and 14 miRNAs target the nuclear receptor PPARa and PPAR¿. This novel information provides an important reference resource for further study of the functional links between miRNAs and their target mRNAs for the regulation of differentiation and function of macrophages.
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Open Research Newcastle |
2016 |
Thi HN, Maltby S, Eyers F, Foster PS, Yang M, 'Bromodomain and Extra Terminal (BET) Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation', PLOS ONE, 11 (2016) [C1]
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Open Research Newcastle |
2015 |
Tay HL, Kaiko GE, Plank M, Li J, Maltby S, Essilfie AT, Jarnicki A, Yang M, Mattes J, Hansbro PM, Foster PS, 'Correction: Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung', PLoS Pathogens, 11 (2015) [O1]
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2015 |
Li JJ, Tay HL, Maltby S, Xiang Y, Eyers F, Hatchwell L, Zhou H, Toop HD, Morris JC, Nair P, Mattes J, Foster PS, Yang M, 'MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity', Journal of Allergy and Clinical Immunology, 136, 462-473 (2015) [C1]
Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells. Levels of IFN-¿ and LPS are often increased in these patients.... [more]
Background Steroid-resistant asthma is a major clinical problem that is linked to activation of innate immune cells. Levels of IFN-¿ and LPS are often increased in these patients. Cooperative signaling between IFN-¿/LPS induces macrophage-dependent steroid-resistant airway hyperresponsiveness (AHR) in mouse models. MicroRNAs (miRs) are small noncoding RNAs that regulate the function of innate immune cells by controlling mRNA stability and translation. Their role in regulating glucocorticoid responsiveness and AHR remains unexplored. Objective IFN-¿ and LPS synergistically increase the expression of miR-9 in macrophages and lung tissue, suggesting a role in the mechanisms of steroid resistance. Here we demonstrate the role of miR-9 in IFN-¿/LPS-induced inhibition of dexamethasone (DEX) signaling in macrophages and in induction of steroid-resistant AHR. Methods MiRNA-9 expression was assessed by means of quantitative RT-PCR. Putative miR-9 targets were determined in silico and confirmed in luciferase reporter assays. miR-9 function was inhibited with sequence-specific antagomirs. The efficacy of DEX was assessed by quantifying glucocorticoid receptor (GR) cellular localization, protein phosphatase 2A (PP2A) activity, and AHR. Results Exposure of pulmonary macrophages to IFN-¿/LPS synergistically induced miR-9 expression; reduced levels of its target transcript, protein phosphatase 2 regulatory subunit B (B56) d isoform; attenuated PP2A activity; and inhibited DEX-induced GR nuclear translocation. Inhibition of miR-9 increased both PP2A activity and GR nuclear translocation in macrophages and restored steroid sensitivity in multiple models of steroid-resistant AHR. Pharmacologic activation of PP2A restored DEX efficacy and inhibited AHR. MiR-9 expression was increased in sputum of patients with neutrophilic but not those with eosinophilic asthma. Conclusion MiR-9 regulates GR signaling and steroid-resistant AHR. Targeting miR-9 function might be a novel approach for the treatment of steroid-resistant asthma.
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Open Research Newcastle |
2015 |
Tay HL, Kaiko GE, Plank M, Li JJ, Maltby S, Essilfie A-T, Jarnicki A, Yang M, Mattes J, Hansbro PM, Foster PS, 'Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung', PLoS Pathogens, 11 (2015) [C1]
Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibio... [more]
Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.
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Open Research Newcastle |
2014 |
Yang M, Eyers F, Xiang Y, Guo M, Young IG, Rosenberg HF, Foster PS, 'Expression profiling of differentiating eosinophils in bone marrow cultures predicts functional links between microRNAs and their target mRNAs', PLoS ONE, 9 (2014) [C1]
Background: MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks underpin immune responses. However, little is known about the specific miRN... [more]
Background: MicroRNAs (miRNAs) are small non-coding RNAs that regulate complex transcriptional networks underpin immune responses. However, little is known about the specific miRNA networks that control differentiation of specific leukocyte subsets. In this study, we profiled miRNA expression during differentiation of eosinophils from bone marrow (BM) progenitors (bmEos), and correlated expression with potential mRNA targets involved in crucial regulatory functions. Profiling was performed on whole BM cultures to document the dynamic changes in miRNA expression in the BM microenvironment over the differentiation period. miRNA for network analysis were identified in BM cultures enriched in differentiating eosinophils, and chosen for their potential ability to target mRNA of factors that are known to play critical roles in eosinophil differentiation pathways or cell identify. Methodology/Principal Findings: We identified 68 miRNAs with expression patterns that were up- or down- regulated 5-fold or more during bmEos differentiation. By employing TargetScan and MeSH databases, we identified 348 transcripts involved in 30 canonical pathways as potentially regulated by these miRNAs. Furthermore, by applying miRanda and Ingenuity Pathways Analysis (IPA), we identified 13 specific miRNAs that are temporally associated with the expression of IL-5Ra and CCR3 and 14 miRNAs associated with the transcription factors GATA-1/2, PU.1 and C/EBPe. We have also identified 17 miRNAs that may regulate the expression of TLRs 4 and 13 during eosinophil differentiation, although we could identify no miRNAs targeting the prominent secretory effector, eosinophil major basic protein. Conclusions/Significance: This is the first study to map changes in miRNA expression in whole BM cultures during the differentiation of eosinophils, and to predict functional links between miRNAs and their target mRNAs for the regulation of eosinophilopoiesis. Our findings provide an important resource that will promote the platform for further understanding of the role of these non-coding RNAs in the regulation of eosinophil differentiation and function. © 2014 Yang et al.
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Open Research Newcastle |
2014 |
Xiang Y, Eyers F, Young IG, Rosenberg HF, Foster PS, Yang M, 'Identification of MicroRNAs regulating the developmental pathways of bone marrow derived mast cells', PLoS ONE, 9 (2014) [C1]
Background: MicroRNAs (miRNAs) play important roles in leukocyte differentiation, although those utilised for specific programs and key functions remain incompletely characterised... [more]
Background: MicroRNAs (miRNAs) play important roles in leukocyte differentiation, although those utilised for specific programs and key functions remain incompletely characterised. As a global approach to gain insights into the potential regulatory role of miRNA in mast cell differentiation we characterised expression in BM cultures from the initiation of differentiation. In cultures enriched in differentiating mast cells we characterised miRNA expression and identified miRNA targeting the mRNA of putative factors involved in differentiation pathways and cellular identity. Detailed pathway analysis identified a unique miRNA network that is intimately linked to the mast cell differentiation program. Methodology/Principal Findings: We identified 86 unique miRNAs with expression patterns that were up- or down-regulated at 5-fold or more during bone marrow derived mast cells (BMMC) development. By employing TargetScan and MeSH databases, we identified 524 transcripts involved in 30 canonical pathways as potentially regulated by these specific 86 miRNAs. Furthermore, by applying miRanda and IPA analyses, we predict that 7 specific miRNAs of this group are directly associated with the expression of c-Kit and FceRIa and likewise, that 18 miRNAs promote expression of Mitf, GATA1 and c/EBPa three core transcription factors that direct mast cell differentiation. Furthermore, we have identified 11 miRNAs that may regulate the expression of STATs-3, -5a/b, GATA2 and GATA3 during differentiation, along with 13 miRNAs that target transcripts encoding Ndst2, mMCP4 and mMCP6 and thus may regulate biosynthesis of mast cell secretory mediators. Conclusions/ Significance: This investigation characterises changes in miRNA expression in whole BM cultures during the differentiation of mast cells and predicts functional links between miRNAs and their target mRNAs for the regulation of development. This information provides an important resource for further investigations of the contributions of miRNAs to mast cell differentiation and function. © 2014 Xiang et al.
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Open Research Newcastle |
2014 |
Wang X, Evans GM, Stevenson P, 'Flooding in a Vertically Rising Gas-Liquid Foam', INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH, 53, 6150-6156 (2014)
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Open Research Newcastle |
2013 |
Eftekhari P, Hajizadeh S, Raoufy MR, Masjedi MR, Yang M, Hansbro N, Li JJ, Foster PS, 'Preventive effect of N-Acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma', EXCLI JOURNAL, 12, 184-192 (2013) [C1]
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acety... [more]
Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyperresponsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.
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Open Research Newcastle |
2013 |
Beckett EL, Stevens RL, Jarnicki AG, Kim RY, Hanish I, Hansbro NG, Deane A, Keely S, Horvat JC, Yang M, Oliver BG, Van Rooijen N, Inman MD, Adachi R, Soberman RJ, Hamadi S, Wark PA, Foster PS, Hansbro PM, 'A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis', The Journal of Allergy and Clinical Immunology, 131, 752-762 (2013) [C1]
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Open Research Newcastle |
2013 |
Foster PS, Plank M, Collison A, Tay HL, Kaiko GE, Li J, Johnston SL, Hansbro PM, Kumar RK, Yang M, Mattes J, 'The emerging role of microRNAs in regulating immune and inflammatory responses in the lung', Immunological Reviews, 253, 198-215 (2013) [C1]
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Open Research Newcastle |
2013 |
Hansbro PM, Scott GV, Essilfie A-T, Kim RY, Starkey MR, Nguyen D, Allen PD, Kaiko GE, Yang M, Horvat JC, Foster PS, 'Th2 cytokine antagonists: Potential treatments for severe asthma', Expert Opinion on Investigational Drugs, 22, 49-69 (2013) [C1]
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Open Research Newcastle |
2013 |
Li JJ, Tay HL, Plank M, Essilfie AT, Hansbro PM, Foster PS, Yang M, 'Activation of olfactory receptors on mouse pulmonary macrophages promotes monocyte chemotactic protein-1 production', PLoS ONE, 8 (2013) [C1]
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Open Research Newcastle |
2012 |
Yang M, Kumar RK, Hansbro PM, Foster PS, 'Emerging roles of pulmonary macrophages in driving the development of severe asthma', Journal of Leukocyte Biology, 91, 557-569 (2012) [C1]
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Open Research Newcastle |
2012 |
Kumar RK, Yang M, Herbert C, Foster PS, 'Interferon-¿, pulmonary macrophages and airway responsiveness in asthma', Inflammation and Allergy - Drug Targets, 11, 292-297 (2012) [C1]
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Open Research Newcastle |
2011 |
Wang W, Hansbro PM, Foster PS, Yang M, 'An alternate STAT6-independent pathway promotes eosinophil influx into blood during allergic airway inflammation', PLoS ONE, 6 (2011) [C1]
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Open Research Newcastle |
2010 |
Li J, Wang W, Baines KJ, Bowden NA, Hansbro PM, Gibson PG, Kumar RK, Foster PS, Yang M, 'IL-27/IFN-y induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages', Journal of Immunology, 185, 4401-4409 (2010) [C1]
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Open Research Newcastle |
2010 |
Yang M, Kumar RK, Foster PS, 'Interferon-Y and pulmonary macrophages contribute to the mechanisms underlying prolonged airway hyperresponsiveness', Clinical and Experimental Allergy, 40, 163-173 (2010) [C1]
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Open Research Newcastle |
2010 |
Hardy CL, Lemasurier JS, Olsson F, Dang T, Yao J, Yang M, Plebanski M, Phillips DJ, Mollard R, Rolland JM, O'Hehir RE, 'Interleukin-13 regulates secretion of the tumor growth factor-beta superfamily cytokine activin A in allergic airway inflammation', American Journal of Respiratory Cell and Molecular Biology, 42, 667-675 (2010) [C1]
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Open Research Newcastle |
2010 |
Wang W, Li J, Foster PS, Hansbro PM, Yang M, 'Potential therapeutic targets for steroid-resistant asthma', Current Drug Targets, 11, 957-970 (2010) [C1]
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Open Research Newcastle |
2009 |
Yang M, Kumar RK, Foster PS, 'Pathogenesis of steroid-resistant airway hyperresponsiveness: Interaction between IFN-gamma and TLR4/MyD88 pathways', Journal of Immunology, 182, 5107-5115 (2009) [C1]
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Open Research Newcastle |
2008 |
Yang M, Mattes J, 'Discovery, biology and therapeutic potential of RNA interference, microRNA and antagomirs', Pharmacology & Therapeutics, 117, 94-104 (2008) [C1]
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Open Research Newcastle |
2007 |
Mattes J, Yang M, Foster PS, 'Regulation of microRNA by antagomirs: a new class of pharmacological antagonists for the specific regulation of gene function?', American Journal of Respiratory and Cellular Molecular Biology, 36, 8-12 (2007) [C1]
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2007 |
Webb DC, Yang M, Matthaei (Ext) K, Foster PS, 'Comparative roles of IL-4, IL-13, and IL-4Ralpha in dendritic cell maturation and CD4+ Th2 cell function', Journal of Immunology, 178, 219-227 (2007) [C1]
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2006 |
Yang M, Rangasamy D, Matthaei KI, Frew AJ, Zimmmermann N, Mahalingam S, Webb DC, Tremethick DJ, Thompson PJ, Hogan SP, Rothenberg ME, Cowden WB, Foster PS, 'Inhibition of arginase I activity by RNA interference attenuates IL-13-induced airways hyperresponsiveness', Journal of Immunology, 177, 5595-5603 (2006) [C1]
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Open Research Newcastle |
2006 |
Yang M, Mattes J, Hansbro PM, Foster PS, 'Employment of microRNA profiles and RNA interference and antagomirs for the characterization and treatment of respiratory disease', Drug Discovery Today: Therapeutic Strategies, 3, 325-332 (2006) [C1]
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Open Research Newcastle |
2006 |
Yang M, Rangasamy D, Matthaei K, Frew A, Zimmmermann N, Mahalingham S, et al., 'Inhibition of arginase I activity by RNA interference attenuates interleukin-13 induced airways hyperresponsiveness', ACTA PHARMACOLOGICA SINICA, 27 266-266 (2006) |
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2006 |
Siegle JS, Hansbro NG, Herbert C, Yang M, Foster PS, Kumar RK, 'Airway hyperreactivity in exacerbation of chronic asthma is independent of elosinophilic inflammation', American Journal of Respiratory Cell and Molecular Biology, 35, 565-570 (2006) [C1]
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2004 |
Forbes E, Smart VE, D'Aprile A, Henry P, Yang M, Matthaei KI, Rothenburg ME, Foster PS, Hogan SP, 'T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice', Gastroenterology, 127, 105-118 (2004) [C1]
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2004 |
Forbes E, Murase T, Yang M, Matthaei KI, Lee JJ, Lee NA, Foster PS, Hogan SP, 'Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase', Journal of Immunology, 172, 5664-5675 (2004) [C1]
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2004 |
Fulkerson PC, Zimmerman N, Brandt EB, Muntel EE, Doepker MP, Kavanaugh JL, Mishra A, Witte DP, Zhang H, Farber JM, Yang M, Foster PS, Rothenburg ME, 'Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9)', Proceedings of the National Academy of Sciences of USA, 101, 1987-1992 (2004) [C1]
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Open Research Newcastle |
2003 |
Foster PS, Yang M, Mattes J, Kumar R, Webb D, 'Interleukin-13 and allergy', Modern Aspects of Immunobiology, 3 (2003)
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2003 |
Zimmerman N, King NE, Laporte J, Yang M, Mishra A, Pope S, Muntel EE, Witte DP, Pegg AA, Foster PS, Hamid Q, Rothenburg ME, 'Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis', Journal of Clinical Investigation, 111, 1863-1874 (2003) [C1]
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2003 |
Kumar RK, Herbert C, Thomas PS, Wollin L, Beume R, Yang M, Webb DC, Foster PS, 'Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma', Journal of Pharmacology and Experimental Therapeutics, 307, 349-355 (2003) [C1]
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2003 |
Yang M, Hogan SP, Mahalingam S, Pope SM, Zimmerman N, Fulkerson P, Dent LA, Young IG, Matthaei KI, Rothenburg ME, Foster PS, 'Eotaxin-2 and interleukin-5 cooperate in the lung to regulate interleukin-13 production and airways eosinophilia and hypereactivity', Journal of Allergy and Clinical Immunology, 112, 935-943 (2003) [C1]
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2003 |
Foster PS, Webb DC, Yang M, Herbert C, Kumar RK, 'Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma', Clinical and Experimental Allergy, 33, 688-695 (2003) [C1]
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2002 |
Mattes J, Yang M, Mahalinggam S, Kuehr J, Webb DC, Simson L, Hogan SP, Koskinen A, McKenzie AN, Dent LA, Rothenburg ME, Matthaei KI, Young IG, Foster PS, 'Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and cotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.', J Exp Med. 195:1433-44, 1433-1444 (2002) [C1]
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2002 |
Foster PS, Yang M, Herbert C, Kumar R, 'CD4+ T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma', Laboratory Investigation, 82, 455-462 (2002) [C1]
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2002 |
Foster PS, Hogan S, Yang M, Mattes J, Young I, Matthaei K, Kumar R, Mahalingam S, Webb D, 'Interleukin-5 and eosinophils as therapeutic targets for asthma', Trends in Molecular Medicine, 8, 162-167 (2002) [C2]
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2002 |
Kumar R, Herbert C, Yang M, Koskinen A, McKenzie A, Foster PS, 'Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma', Clinical and Experimental Allergy, 32, 1104-1111 (2002) [C1]
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2002 |
Foster PS, Yang M, Herbert C, Kumar RK, 'CD4+ T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma', Laboratory Investigation, 82, 455-462 (2002)
Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma... [more]
Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4+ T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4+ T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin- synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4+ T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.
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2002 |
Yang M, Hogan SP, Henry P, Matthaei KI, McKenzie ANJ, Young IG, et al., 'Interleukin-(IL)-13 mediates biphasic airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 109 S360-S360 (2002)
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2001 |
Mattes J, Yang M, Siqueira A, Clark K, Mackenzie J, McKenzie A, Webb D, Matthaei K, Foster PS, 'IL-13 induces airways hyperreactivity independently of the IL-4R{alpha} chain in the allergic lung', Journal of Immunology, 167, 1683-1692 (2001) [C1]
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2001 |
Foster PS, Mould A, Yang M, Mackenzie J, Mattes J, Hogan S, Mahalingam S, McKenzie A, Rothenberg M, Young I, Matthaei K, Webb D, 'Elemental signals regulating eosinophil accumulation in the lung', Immunological Reviews, 179, 173-181 (2001) [C2]
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2001 |
Yang M, Hogan S, Henry P, Matthaei K, McKenzie A, Young I, et al., 'Interleukin-13 mediates airways hyperreactivity through the IL-4 receptor-alpha chain and STAT-6 independently of IL-5 and eotaxin', American Journal of Respiratory Cell and Molecular Biology, 25 522-530 (2001) [C1]
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2000 |
Webb D, McKenzie A, Koskinen A, Yang M, Mattes J, Foster PS, 'Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity', Journal of Immunology, 165, 108-113 (2000) [C1]
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2000 |
Foster PS, Ming Y, Matthei K, Young I, Temelkovski J, Kumar R, 'Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma', Laboratory Investigation, 80, 655-662 (2000) [C1]
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Li J, Li Y, Wang X, Zhou Z, Li X, Yue S, Wang H, Yang M, Zhang G, 'Germline alteration analysis reveals EPHB4R91H mutation as a key player in multiple primary lung tumors', CARCINOGENESIS [C1]
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