Asthmatic Remodeling Research Articles

Targeted Knockdown of Epithelial Estrogen Receptor α to Mitigate Ferroptosis and Epithelial-Mesenchymal Transition in Eosinophilic Asthma.

Estrogen receptor α (ERα) is involved with the hyperresponsiveness and airway remodeling in asthma, but developing therapies targeting ERα remains challenging due to its multifaceted roles in different cell types and the poor efficacy of systemic ERα intervention in asthma. Previously, we uncovered the association of increased ERα expression in airway epithelial cells with poor pulmonary function and epithelial-mesenchymal transition (EMT) in asthma patients. This study further investigated the association of ERα expression with the ferroptosis and EMT levels in a cohort of eosinophilic asthma (EA) patients as well as in an eosinophil-epithelial coculture cell model. By loading small interfering RNA (siRNA) into a mesoporous silica nanoparticle (MSN) and then coating the extracted bronchial epithelial cytomembrane (CM), a bronchial epithelial CM home-targeting nanoplatform (siRNA@MSN@CM) was constructed to selectively decrease the ERα expression in bronchial epithelial cells. The targeting effect of bronchial epithelial cells was confirmed in vitro and in vivo, demonstrating the successful targeted knockdown of ERα expression. Silencing ERα in epithelial cells effectively prevented ferroptosis and EMT induced by coculturing with ferroptotic eosinophils. Targeted intervention of epithelium ERα with intratracheal delivery of siRNA(ERα)@MSN@CM nanoparticle significantly reduced the levels of ferroptosis in bronchial epithelial cells, airway inflammation, and airway remodeling in asthmatic mouse models. This study introduces an innovative nanomaterial for targeted drug delivery to epithelial cells and underscores the potential of targeted knockdown ERα in bronchial epithelial cells as a therapeutic strategy for asthma treatment.

LRP1 regulates asthmatic airway smooth muscle proliferation through FGF2/ERK signaling.

Airway smooth muscle (ASM) hyperplasia is a hallmark of airway remodeling in asthma, which still lacks an effective treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) is involved in regulating the proliferation of various cell types, and the intracellular domain of LRP1 (LRP1-ICD) also exhibits unique biological functions. However, the role of LRP1 in asthma airway remodeling remains unclear. In the present study, LRP1 was increased in ASM cells of mice with OVA-induced chronic asthma, with the elevation in LRP1-ICD protein levels being significantly greater than that of the LRP1 β chain. In vivo experiments demonstrated that inhibiting LRP1 reduced ASM proliferation in these mice. Mechanistically, LRP1 knockdown inhibited the FGF2/ERK signaling pathway, thereby arresting cell cycle progression and suppressing ASM cell proliferation. Additionally, in vitro experiments revealed that the inhibitory effect of LRP1-ICD overexpression on ASM cell proliferation was lost after adjusting the levels of LRP1. LRP1-ICD overexpression inhibited full-length LRP1 protein levels by promoting its protein degradation rather than by suppressing its transcription, thus preventing further exacerbation of asthma. In conclusion, this study clarifies the molecular biological mechanism by which LRP1 regulates ASM proliferation, suggesting targeting full-length LRP1 as a strategy for therapeutic intervention in asthma airway remodeling.

Kv1.3 expression on CD4 (+) T cells promotes interleukin-17A-associated airway inflammation and airway remodeling in asthma.

Kv1.3 expression on CD4 (+) T cells promotes interleukin-17A-associated airway inflammation and airway remodeling in asthma.

Targeting Airway Remodeling in Asthma: Anti-EMT Effects of Xuanfei Pingchuan Prescription via TGFβ1/Smad Pathway Modulation.

Asthma is a chronic airway disease characterized by Airway Remodeling (AR) and persistent inflammation, with Epithelial-Mesenchymal Transition (EMT) playing a crucial role in fibrosis and smooth muscle proliferation. The Transforming Growth Factor-Beta1 (TGFβ1)/Smad pathway is a key driver of EMT in asthma. Current treatments do not effectively prevent AR progression. Traditional Chinese Medicine, particularly the Xuanfei Pingchuan (XFPC) prescription, has shown potential in managing asthma, but its role in EMT regulation remains unclear. This study explored the role of "phlegm and stasis" in airway remodeling (AR) in asthma from the perspective of EMT and investigated the effects and underlying mechanisms of XFPC prescription on EMT in AR. In vitro, human bronchial epithelial (16HBE) cells were induced into EMT with TGFβ1 and treated with XFPC drug-containing serum, with EMT marker expression analyzed via RT-qPCR and Western blot. In vivo, an ovalbumin (OVA)-induced asthma model in Sprague Dawley rats was used to evaluate the effects of different XFPC doses through histopathology, immunofluorescence, and molecular analyses. Additionally, Smurf2 cDNA transfection was conducted to assess the role of Smurf2 in EMT regulation. The results confirmed that XFPC prescription suppressed the pathway of transforming-growth factor-beta1 (TGFβ1)-Smad by reducing Smad ubiquitination regulator 2 (Smurf2), Smad2, Smad3, TGFβ1 receptor (TβRI), N-cadherin, α-SMA, and Vimentin in terms of expressions at messenger ribonucleic acid (mRNA) and protein levels. However, XFPC prescription up-regulated expressions of SnoN and E-cadherin at protein and mRNA levels to inhibit EMT. The result also confirmed that XFPC prescription decreased the ubiquitination of Smad7. XFPC prescription could suppress AR in TGFβ1 induced 16HBE cells and OVA-sensitized animal models through TGFβ1/Smad pathway.

High expression of ITGB3 ameliorates asthma by inhibiting epithelial-mesenchymal transformation through suppressing the activation of NF-kB pathway

Integrin β3 (ITGB3) has been identified as an asthma-associated gene; however, its molecular mechanisms remain poorly understood. Epithelial-mesenchymal transition (EMT) is a critical driver of airway remodeling in asthma, which underpins disease progression. This study aimed to elucidate the role of ITGB3 in asthma pathogenesis by investigating its regulation of EMT. Asthma models were established in vivo using C57BL/6 mice and in vitro with A549 cells, both exposed to house dust mite (HDM) extract. The effects of HDM and ITGB3 modulation on cellular viability, apoptosis, and inflammatory cytokines (IL-4, IL-5, IL-13) were assessed in cultured cells and murine lungs. EMT was evaluated via western blot analysis of E-cadherin, N-cadherin, and vimentin expression. The NF-κB pathway was examined by quantifying phosphorylated p65 and IkBa levels. Lung tissue pathology and ITGB3 expression were assessed using hematoxylin and eosin (H&E) staining and immunohistochemistry. Results demonstrated that HDM exposure reduced A549 cell viability, increased cytotoxicity, apoptosis, and pro-inflammatory cytokine production, while promoting EMT. ITGB3 knockdown exacerbated these effects, whereas ITGB3 overexpression mitigated them. Furthermore, HDM activated the NF-κB pathway, an effect reversed by ITGB3 overexpression. In HDM-challenged cells, NF-κB activation via an agonist counteracted the protective effects of ITGB3 overexpression on apoptosis, inflammation, and EMT. Notably, ITGB3 overexpression suppressed inflammation, EMT, and pathological remodeling in asthmatic mice. Collectively, our findings reveal that ITGB3 exerts protective effects in asthma by inhibiting EMT through suppression of the NF-κB signaling pathway, thereby identifying ITGB3 as a potential therapeutic target for asthma management.

Classification of collagen remodeling in asthma using second-harmonic generation imaging, supervised machine learning and texture-based analysis.

Airway remodeling is present in all stages of asthma severity and has been linked to reduced lung function, airway hyperresponsiveness and increased deposition of fibrillar collagens. Traditional histological staining methods used to visualize the fibrotic response are poorly suited to capture the morphological traits of extracellular matrix (ECM) proteins in their native state, hindering our understanding of disease pathology. Conversely, second harmonic generation (SHG), provides label-free, high-resolution visualization of fibrillar collagen; a primary ECM protein contributing to the loss of asthmatic lung elasticity. From a cohort of 13 human lung donors, SHG-imaged collagen belonging to non-asthmatic (control) and asthmatic donors was evaluated through a custom textural classification pipeline. Integrated with supervised machine learning, the pipeline enables the precise quantification and characterization of collagen, delineating amongst control and remodeled airways. Collagen distribution is quantified and characterized using 80 textural features belonging to the Gray Level Cooccurrence Matrix (GLCM), Gray Level Size Zone Matrix (GLSZM), Gray Level Run Length Matrix (GLRLM), Gray Level Dependence Matrix (GLDM) and Neighboring Gray Tone Difference Matrix (NGTDM). To denote an accurate subset of features reflective of fibrillar collagen formation; filter, wrapper, embedded and novel statistical methods were applied as feature refinement. Textural feature subsets of high predictor importance trained a support vector machine model, achieving an AUC-ROC of 94% ± 0.0001 in the classification of remodeled airway collagen vs. control lung tissue. Combined with detailed texture analysis and supervised ML, we demonstrate that morphological variation amongst remodeled SHG-imaged collagen in lung tissue can be successfully characterized.

Interleukin-4 and interferon gamma in bronchial remodeling in asthma patients with cold airway hyperresponsiveness

Interleukin-4 (IL-4) and interferon gamma (IFNγ) are key participants in the polarization of the immune response toward Th1 or Th2 types in bronchial asthma. However, their role in bronchial remodeling in patients with asthma and cold airway hyperresponsiveness (CAHR) remains unclear. Aim. To study the involvement of IL-4 and IFNγ in the disorganization of bronchial epithelium and the regulation of airway remodeling in asthma with CAHR. Materials and methods. A total of 47 patients with mild persistent asthma were examined. Induced sputum collection, blood sampling for biochemical studies, spirometry, and the isocapnic hyperventilation test with cold (-20 °C) air (IHCA) were performed. The sputum was analyzed for cellular composition (in %), and the cytokine profile (IL-4 and IFNγ in pg / ml) was evaluated in peripheral blood. Results. The patients were divided into groups with CAHR (group 1, 17 patients) and without cold-induced bronchoconstriction (group 2, 30 patients). Forced expiratory volume in 1 sec. (FEV1 ) and maximal mid-expiratory flow (MMEF) in group 1 were lower compared to group 2: 84.0[83.0; 93.0]% and 99.0 [85.0; 105.0]% (p = 0.012); 55.0[51.0;67.0]% and 76.0[59.0;88.0]% (p = 0.021), respectively. The blood content of IL-4 and IFNγ in group 1 was 11.48[10.82;22.48] pg / ml and 26.98[17.24; 73.5] pg / ml, while in group 2, it was 1.88 [0.66; 5.96] (p = 0.003) and 7.24[1.5; 26.98] pg / ml (p = 0.047), respectively. In group 1, an association was found between blood IL-4 and IFNγ levels (Rs = 0.65; p = 0.016), between FEV1 and the number of epithelial cells in sputum (Rs = –0.74; p = 0.0003), and between IL-4 and airway response (ΔFEV1 /Vital Capacity) after the IHCA (Rs = –0.70; p = 0.007). Conclusion. The escalation of the proinflammatory and pro-oxidant function of IFNγ indicates a shift from Th2 immune response activation, regulated by IL-4, toward a Th1 response, which stimulates bronchial remodeling in patients with asthma and CAHR.

Store-operated Ca2+ entry contributes to the ASM phenotype transition in asthma

Aim of the study Phenotype modulation of airway smooth muscle cells (ASMC), characterized by a shift toward a more proliferative and synthetic phenotype from contractile cells, plays a crucial role in airway remodeling in asthma. STIM1 and Orai1, key components of store-operated Ca2+ entry (SOCE), have been demonstrated to enhance ASMC proliferation and migration. This study investigated the impact of STIM1/Orai1-mediated SOCE on ASMC phenotype transition and extracellular matrix (ECM) deposition in asthma. Materials and Methods The ASMCs were treated with PDGF-BB and SOCE inhibitors. Immunocytochemistry staining, enzyme-linked immunosorbent assay, and western blot assay were employed to detect the ASMC’s proliferation as well as the expressions of contractile proteins, inflammatory cytokines and ECM. Moreover, the effect of SOCE repression in ECM deposition were evaluated in an asthmatic mouse model. Results ASMCs from airways of mice were treated with PDGF-BB to induce the ‘proliferative/synthetic’ phenotype. We observed elevated expressions of STIM1 and Orai1 in phenotype-switched ASMCs, along with enhanced SOCE. SKF-96365 and RO2959, which target of STIM1/Orai1, could significantly inhibit SOCE activation in ASMCs. Moreover, these SOCE inhibitors mitigated the elevated proliferation rate, decreased the secretion of inflammatory cytokines and restored the reduced levels of contractile proteins in phenotype-switched ASMCs induced by PDGF-BB. Furthermore, we observed that PDGF-BB-induced ‘proliferative/synthetic’ ASMCs exhibited increased production of ECM components, including collagen I and fibronectin, as well as metalloproteinases (MMPs) such as MMP2 and MMP9, all of which were effectively inhibited by SKF-96365 and RO2959. In vivo experiments also demonstrated that SOCE inhibitors decreased ECM deposition and MMPs production in the asthmatic mouse model. Conclusions These findings underscored the significant role of STIM1/Orai1-mediated SOCE in ASMC phenotype modulation and its impact on the excessive ECM deposition driven by ASMCs. Thus, our findings suggest that STIM1/Orai1-mediated SOCE may contribute to airway remodeling in asthma.

USP22/BRD4 mediated hedgehog pathway activation contributes to airway remodeling in asthma.

USP22/BRD4 mediated hedgehog pathway activation contributes to airway remodeling in asthma.

Advances in pathogenesis of asthma airway remodeling and intervention mechanism of traditional Chinese medicine

Asthma, a chronic inflammatory airway disease with a high global prevalence, has a complex pathogenesis, in which airway remodeling plays a key role in the chronicity of the disease. Airway remodeling involves a series of pathophysiological changes, including airway epithelial damage, proliferation of mucous glands and goblet cells, subepithelial fibrosis, proliferation and migration of airway smooth muscle cells, and epithelial-mesenchymal transition. These complex pathological changes significantly increase airway resistance and responsiveness, forming an important pathological basis for refractory asthma. Currently, the regulatory mechanisms of airway remodeling focus on signaling pathways and regulatory targets. The signaling pathways include phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt), nuclear factor-κB(NF-κB), transforming growth factor-β1(TGF-β1)/Smads, and mitogen-activated protein kinase(MAPK). The regulatory targets include microRNAs(miRNAs), competing endogenous RNAs(ceRNAs), long non-coding RNAs(lncRNAs), and circular RNAs(circRNAs). Key proteins involved in these processes include TGF-β1, silencing information regulator 2-related enzyme 1(SIRT1), chitinase 3-like protein 1(YKL-40), and adenosine deaminase-metalloproteinase 33(ADAM33). In recent years, the potential of traditional Chinese medicine in the treatment of asthma has become increasingly evident. Its active ingredients, extracts, and complexes can inhibit airway remodeling in asthma through multiple pathways, demonstrating a variety of effects, including anti-inflammatory actions, inhibition of smooth muscle cell proliferation and migration, regulation of epithelial-mesenchymal transition, attenuation of fibrosis and basement membrane thickening, reduction of mucus secretion, inhibition of vascular remodeling, modulation of immune imbalance, and antioxidative stress. This paper aims to provide an in-depth analysis of the pathogenesis and therapeutic targets of asthma, offering theoretical support and innovative strategies for clinical research and drug development in the treatment of asthma.

Investigation of the mechanistic impact of CBL0137 on airway remodeling in asthma

BackgroundBronchial asthma, a chronic inflammatory airway disease, is characterized by airway remodeling, including thickening of the airway smooth muscle layer, primarily due to abnormal proliferation of airway smooth muscle cells (ASMCs). CBL0137 (Curaxin-137 hydrochloride), a histone chaperone facilitate chromatin transcription (FACT) inhibitor, has demonstrated anti-tumor properties, including inhibition of proliferation, promotion of apoptosis, and increased autophagy. However, its effects on ASMCs and airway remodeling remain unexplored.MethodsAsthma models were established using ovalbumin (OVA) in female C57BL/6 J mice, with therapeutic interventions using CBL0137 and budesonide. Lung tissues were analyzed using Hematoxylin and eosin (H&E), PAS, Masson’s trichrome, and α-SMA immunofluorescence staining. ASMCs extracted from Sprague–Dawley rats were cultured in vitro experiments, with phenotypic changes assessed via flow cytometry. Gene and protein expressions were analyzed using RT-PCR and Western blotting.ResultsCBL0137 significantly reduced airway resistance, goblet cell proliferation, alveolar collagen deposition, and airway smooth muscle layer thickening in asthmatic mice. In vitro, CBL0137 inhibited ASMC proliferation and induced apoptosis, downregulating cyclin-B1, Cdc2, and Bcl-2 while upregulating caspase-3.ConclusionsCBL0137 mitigates airway remodeling of asthmatic mice by modulating ASMC proliferation and apoptosis, presenting a potential therapeutic strategy for asthma treatment.

Serum neuropilin-1 level may predict airway remodeling based on age and smoking status in asthma

Background: Airway remodeling in asthma is induced by the production of vascular endothelial growth factor, and this process is mediated by neuropilin-1 (NRP-1). Objective: To investigate the association between the serum level of NRP-1 and clinical characteristics in asthma. Methods: We measured the serum level of NRP-1 and performed subgroup analysis of NRP-1 according to the clinical characteristics of 421 asthma patients registered in the Cohort for Reality and Evolution of Adult Asthma in Korea. Results: The serum level of NRP-1 was significantly higher in the group under 65 years of age than in the group over 65 years of age (1628.36 ± 589.51 vs 1416.75 ± 671.42; P < 0.001). Current smokers and ex-smokers had a significantly higher serum NRP-1 level compared with that of never smokers (1647.16 ± 572.34 vs 1528.5 ± 579.37; P = 0.041). Medium- and high-inhaled corticosteroid users had a higher serum NRP-1 level compared with that of low-inhaled corticosteroid users (1589.87 ± 591.7 vs 1436.12 ± 419.21; P = 0.049). The serum NRP-1 level was significantly higher in the group with a forced vital capacity (FVC) of 70% or higher than in the group with an FVC of 70% or lower. In univariate analysis, age was a factor influencing serum NRP-1 with a negative correlation (coefficient=−260.90; P < 0.001). Ex-smokers and current smokers were factors influencing serum NRP-1 with a positive correlation (coefficient = 118.66; P = 0.0412). An FVC of 70% or higher was a factor affecting serum NRP-1 with a positive correlation (coefficient = 173.86; P = 0.0224). Multivariable analysis revealed that age (coefficient = −233.53; P < 0.001) and smoking history (coefficient = −122.4; P = 0.0358) were significant variables affecting serum NRP-1. Conclusion: Serum NRP-1 level was high in asthma patients with a younger age and smoking history, suggesting its potential as a clinical marker for predicting early-stage airway remodeling based on the age and smoking status.

Emerging Concepts in Cytokine Regulation of Airway Remodeling in Asthma.

Asthma, a chronic respiratory condition that has seen a dramatic rise in prevalence over the past few decades, now affects more than 300 million people globally and imposes a significant burden on healthcare systems. The key pathological features of asthma include inflammation, airway hyperresponsiveness, mucus cell metaplasia, smooth muscle hypertrophy, and subepithelial fibrosis. Cytokines released by lung epithelial cells, stromal cells, and immune cells during asthma are critical to pathological tissue remodeling in asthma. Over the past few decades, researchers have made great strides in understanding key cells involved in asthma and the cytokines that they produce. Epithelial cells as well as many adaptive and innate immune cells are activated by environmental signals to produce cytokines, namely, type 2 cytokines (IL-4, IL-5, IL-13), IFN-γ, IL-17, TGF-β, and multiple IL-6 family members. However, the precise mechanisms through which these cytokines contribute to airway remodeling remain elusive. Additionally, multiple cell types can produce the same cytokines, making it challenging to decipher how specific cell types and cytokines uniquely contribute to asthma pathogenesis. This review highlights recent advances and provides a comprehensive overview of the key cells involved in the production of cytokines and how these cytokines modulate airway remodeling in asthma.

The Mechanisms and Therapeutic Implications of PI3K Signaling in Airway Inflammation and Remodeling in Asthma.

Bronchial asthma is a complex and heterogeneous disease with ongoing airway inflammation and increased airway responsiveness. Key characteristics of the disease include persistent airway inflammation, airway hyperresponsiveness, and airway remodeling. Asthma's chronic and recurrent characteristics contribute to airway remodeling and inflammation, which can exacerbate lung damage. Presently, inflammation is predominantly managed with corticosteroids, yet there is a notable absence of treatments specifically addressing airway remodeling. The phosphoinositide 3-kinase (PI3K) signaling pathway is integral to the processes of inflammation, airway remodeling, and immune responses. Pharmacological agents targeting this pathway are currently undergoing clinical evaluation. This review elucidates the role of PI3K in the immune responses, airway inflammation, and remodeling associated with asthma, examining its underlying mechanisms. Furthermore, we synthesize the existing literature on the therapeutic potential of PI3K inhibitors for asthma management, emphasizing immune modulation, airway inflammation, and remodeling, including drug development and ongoing clinical trials. Lastly, we explore how various PI3K-targeted therapies may enhance efficacy and improve tolerance.

Investigating the Relationship between FGF2 Gene Expression and Airway Remodeling in Severe Asthma.

Severe asthma causes chronic airway inflammation and structural changes in the bronchial wall. Fibroblast growth factor 2 (FGF2) plays an inflammatory role in specific pathways in airway remodeling in asthma. Assessing the relationship between sputum pattern, bronchial thickness by high-resolution computed tomography (HRCT) scan, and FGF2 expression level can evaluate the role of FGF2 in asthma remodeling. The study aimed to investigate the correlation between airway wall thickness and FGF2 gene expression in 100 participants with severe asthma. The method involved measuring airway wall thickness using HRCT and analyzing FGF2 gene expression through real-time reverse transcriptase polymerase chain reaction. The participants were divided into 2 groups based on bronchodilator responsiveness and classified into different asthma phenotypes based on sputum cell count. The baseline data did not show a significant difference between the groups. The study found significant differences in airway variables between different asthma subgroups. FGF2 expression was associated with various characteristics of asthma, including body mass index, forced expiratory volume in 1 second (FEV1), and airway wall thickness. The receiver operating characteristic curve analysis showed that a fold change higher than 2.42 in FGF2 expression indicated asthma. Based on our research, FGF2 may play a critical role in airway thickness regardless of inflammation. We found increased FGF2 levels with disease severity and wall thickness in atopic severe persistent asthma patients with FEV1 below 60%. Further research is needed to understand FGF2's role across broader FEV1 ranges and other phenotypes.

Vascular remodeling and TSLP/angiogenin overexpression in severe mixed asthma

BackgroundAsthma with neutrophilic/mixed inflammation is a difficult-to-control clinical phenotype. Currently, vascular and matrix airway remodeling in asthma with neutrophilic/mixed inflammation is not well known. We aimed to evaluate the differences in vascular/smooth muscle/matrix related asthma remodeling in eosinophilic (EOS) and mixed/neutrophilic (MIXED) bronchial phenotypes in relation to asthma severity and exacerbation frequency.MethodsIn this cross-sectional study, α-SMA+ cells (100µM beneath the basement membrane [BM]), BM thickness, vascular remodeling-related biomarkers (angiogenin, vascular endothelial growth factor [VEGF], CD31 and Protease-activated receptor 2 [PAR2]), alarmins (TSLP and Interleukin (IL)-33) were evaluated in bronchial sections from 40 mild-to-severe asthmatics (EOS: N = 19 and mixed/neutrophilic: N = 19/2) and 7 control subjects (CTRL).ResultsThe number of CD31+ and angiogenin+ cells was higher in MIXED than in EOS asthmatics (p < 0.05). In severe MIXED CD31+, TSLP+, α-SMA+, and angiogenin+ cells increased compared to mild MIXED/EOS or severe EOS (p < 0.05), but BM thickness was higher in severe vs. mild EOS (p < 0.05). MIXED frequent exacerbators had higher numbers of CD31+ and TSLP+ cells, whereas MIXED non-exacerbators had increased PAR2+ cells. CD31+ cells correlated with impairment of pulmonary functions, number of exacerbations, ICS dose, bronchial neutrophils, angiogenin, α-SMA, TSLP and IL-33 (p < 0.05). Finally, CD31 > 97.17 cells/mm2, angiogenin > 35.36 cells/mm2, and functional parameters such as FEV1, FEV1/FVC, TLC and FRC (%pred.) were found to be predictors of severe MIXED asthma.ConclusionThe severe or frequent exacerbator asthmatics with bronchial mixed inflammatory profile are characterized by increased number of vessels and overexpression of TSLP and angiogenin, suggesting a pathogenetic link between mixed eosinophilic and neutrophilic inflammation and vascular remodeling.

MiR-186-5p carried by M2 macrophage-derived exosomes downregulates TRPP2 expression in airway smooth muscle to alleviate asthma progression.

MiR-186-5p carried by M2 macrophage-derived exosomes downregulates TRPP2 expression in airway smooth muscle to alleviate asthma progression.

Selective HDAC8 inhibition by PCI-34051 attenuates inflammation and airway remodeling in asthma via miR-381-3p-TGFβ3 axis.

Histone deacetylase (HDAC) families regulate various physical processes and the development of several diseases. The role of HDACs in asthma development and progression worths further investigation. This study aims to evaluate the effect of HDACs in a mouse model of asthma. HDAC8 selective inhibitor PCI-34051 was administered to a mouse model of ovalbumin-sensitized and challenged asthma. Airway responsiveness, serum cytokines, histological changes of the airway, and expression levels of α-SMA, β-actin, VEGFR, VEGF, GAPDH, HDAC8, TGF-β3, CD 105, p-ERK 1/2, ERK 1/2, PI3K, p-AKT, AKT, and PDK1 were evaluated. The miR-381-3p level was also measured. All classic histologic and cellular changes of asthma in inflammation and airway remodeling were altered by HDAC8 inhibitor PCI-34051 via regulation of the miR-381-3p level and its downstream gene, TGF-β3. Inhibition of TGF-β3 further reduced the activation of ERK, PI3K, AKT, and PDK1. In a mouse model, HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling.

Amygdalin Alleviates Airway Inflammation and Remodeling in Asthma Mice: Involvement of TGF-β1/Smads Signaling Pathway.

Asthma is a common respiratory system disease characterized by airway inflammation and airway remodeling. Amygdalin, an active component of the traditional Chinese medicine Bitter Almonds, has been shown to inhibit liver fibrosis via the inactivation of the transforming growth factor-beta 1 (TGF-β1)/Smads pathway. This study aims to investigate the effects of Amygdalin on airway inflammation and remodeling in asthma, as well as its regulatory mechanisms. An asthma mouse model was constructed using ovalbumin (OVA) induction. Mouse bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for in vivo experiments, and airway smooth muscle cells (ASMCs) were isolated from BALB/c mice for in vitro experiments. The mechanism of Amygdalin and the TGF-β1/Smads signaling pathway in the mouse model was analyzed pathologically and molecularly using hematoxylin-eosin (HE) staining, Masson trichrome staining, Western blot, and enzyme-linked immunosorbent assay (ELISA). Amygdalin ameliorated the pathological abnormalities of lung tissues in the OVA-induced mouse model, reducing inflammation by downregulating OVA-specific immunoglobulin E (IgE) and inflammatory factors interleukin (IL)-4, IL-5, and IL-13 (p < 0.001). It also reduced lung tissue fibrosis (p < 0.01). Additionally, Amygdalin inhibited the levels of TGF-β1, p-Smad2, and p-Smad3 proteins (p < 0.05), and downregulated the fibrosis markers alpha-smooth muscle actin (α-SMA), Collagen I, and Collagen III expression in the OVA-induced asthma mouse model (p < 0.01). Amygdalin can regulate the TGF-β1/Smads signaling pathway and alleviate airway inflammation and remodeling in an asthma model in mice.

Spatial phenotyping of human bronchial airways in obstructive lung disease

Chronic respiratory diseases such as asthma and COPD involve interactions between multiple resident and immune cell types within bronchial airways, resulting in structural and functional changes. Thus cellular heterogeneity, arrangements and associated neighborhoods as well as interactions between cells and matrices represent intriguing yet challenging areas of study. Spatial phenotypic profiling facilitates exploration of these issues of the cellular microenvironment and identification of context-dependent cell-cell interactions. Utilizing spatial phenotyping, we interrogated the features and cellular landscape of lungs from non-asthmatics, asthmatics, and COPD in FFPE samples by developing a 10-plex antibody panel for the Akoya PhenoCycler®-Fusion system, focused on immune cells (CD45, CD3, CD4, CD8), proliferative cells (Ki67, PCNA), angiogenesis (CD34), epithelium (E-cadherin), smooth muscle (SMA) and extracellular matrix (collagen). We performed cell segmentation on multiplex immunofluorescence images and quantified marker intensity in each cell. Phenotypes were manually identified after normalization, integration, and clustering cells across samples. The composition, cell profiling, and distribution varied significantly between asthmatics and COPD compared to non-asthmatics emphasizing disease heterogeneity. Spatially agnostic analysis revealed that the matrix cluster was more abundant in COPD compared to non-asthmatics and asthmatics, consistent with a greater role for fibrosis. However, asthmatic patients had a higher proportion of unclassified and CD8 + clusters highlighting immune responses. Co-localization analysis showed near random distribution in non-asthmatics. But strong spatial interaction between T cells and other immune or matrix cells in asthma, and a higher avoidance of smooth muscle and immune cells, and of proliferative markers in both asthmatic and COPD. Niche analysis demonstrated different recurrent cell-cell interactions in asthmatic and COPD cohorts. In COPD, the matrix cell-enriched niche was more abundant, while in asthmatics, the unclassified cell-enriched niche was more prevalent compared to non-asthmatics. These findings provide insights into differential spatial organization of cells and tissues in asthma and COPD, with immune and epithelial mechanisms suggesting active inflammation and remodeling in asthma, but fibrotic processes in COPD, and potential role for vascular processes in both conditions.Graphical abstract