ABSTRACT
Asthma and chronic obstructive pulmonary disease (COPD) represent chronic inflammatory respiratory disorders that, despite having distinct pathophysiological underpinnings, both feature airflow obstruction and respiratory symptoms. A critical component in the pathogenesis of each condition is the transforming growth factor-ß (TGF-ß), a multifunctional cytokine that exerts varying influences across these diseases. In asthma, TGF-ß is significantly involved in airway remodeling, a key aspect marked by subepithelial fibrosis, hypertrophy of the smooth muscle, enhanced mucus production, and suppression of emphysema development. The cytokine facilitates collagen deposition and the proliferation of fibroblasts, which are crucial in the structural modifications within the airways. In contrast, the role of TGF-ß in COPD is more ambiguous. It initially acts as a protective agent, fostering tissue repair and curbing inflammation. However, prolonged exposure to environmental factors such as cigarette smoke causes TGF-ß signaling malfunction. Such dysregulation leads to abnormal tissue remodeling, marked by excessive collagen deposition, enlargement of airspaces, and, thus, accelerated development of emphysema. Additionally, TGF-ß facilitates the epithelial-to-mesenchymal transition (EMT), a process contributing to the phenotypic alterations observed in COPD. A thorough comprehension of the multifaceted role of TGF-ß in asthma and COPD is imperative for elaborating precise therapeutic interventions. We review several promising approaches that alter TGF-ß signaling. Nevertheless, additional studies are essential to delineate further the specific mechanisms of TGF-ß dysregulation and its potential therapeutic impacts in these chronic respiratory diseases.
Subject(s)
Asthma , Pulmonary Disease, Chronic Obstructive , Transforming Growth Factor beta , Humans , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Transforming Growth Factor beta/metabolism , Asthma/metabolism , Asthma/pathology , Animals , Airway Remodeling , Signal Transduction , Epithelial-Mesenchymal TransitionABSTRACT
Bronchial airways and lung parenchyma undergo both static and dynamic stretch in response to normal breathing but also in the context of insults such as mechanical ventilation (MV) or in diseases such as asthma and COPD which lead to airway remodeling involving increased extracellular matrix (ECM) production. Here, the role of fibroblasts is critical, but the relationship between stretch and fibroblast induced ECM remodeling under these conditions is not well-explored. Piezo (PZ) channels play a role in mechanotransduction in many cell and organ systems, but their role in mechanical stretch-induced airway remodeling is not known. To explore this, we exposed human lung fibroblasts to 10% static stretch on a background of 5% oscillations for 48 hours, with no static stretch considered controls. Collagen I, Fibronectin, α-SMA, and Piezo 1 (PZ1) expression were determined in the presence or absence of Yoda1 (PZ1 agonist) or GsMTx4 (PZ1 inhibitor). Collagen I, Fibronectin, and α-SMA expression was increased by stretch and Yoda1 while pretreatment with GsMTx4 or knockdown of PZ1 by siRNA blunted this effect. Acute stretch in the presence and absence of Yoda1 demonstrated activation of ERK pathway but not Smad. Measurement of [Ca2+] i responses to histamine showed significantly greater responses following stretch: effects that were blunted by knockdown of PZ1.Our findings identify an essential role for PZ1 in mechanical stretch-induced production of ECM mediated by ERK phosphorylation and Ca2+ influx in lung fibroblasts. Targeting PZ channels in fibroblasts may constitute a novel approach to ameliorate airway remodeling by decreasing ECM deposition.
ABSTRACT
PURPOSE: Asthma, an airway inflammatory disease, involves multiple tumor necrosis factors (TNF). TNF ligand superfamily member 11 (TNFSF11) and its known receptor, TNF receptor superfamily 11A (TNFRSF11A), has been implicated in asthma; however, the related mechanisms remain unknown. METHODS: The serum and bronchial airway of patients with asthma and healthy subjects were examined. The air-liquid interface of primary human bronchial epithelial (HBE) cells, and Tnfsf11+/- mouse, Tnfrsf11a+/- mouse, and a humanized HSC-NOG-EXL mouse model were established. This study constructed short hairpin RNA (shRNA) of TNFSF11, TNFRSF11A, transforming growth factor ß1 (TGFß1), and transforming growth factor ß receptor type 1 (TGFßR1) using lentivirus to further examine the ability of TNFSF11 protein. RESULTS: This study was the first to uncover TNFSF11 overexpression in the airway and serum of asthmatic human subjects, and the TNFSF11 in serum was closely correlated with lung function. The TNFSF11/TNFRSF11A axis deficiency in Tnfsf11+/- or Tnfrsf11a+/- mice remarkably attenuated the house dust mite (HDM)-induced signal transducer and activator of transcription 3 (STAT3) action and remodeling protein expression. Similarly, the HDM-induced STAT3 action and remodeling protein expression in HBE cells decreased after pretreatment with TNFSF11 or TNFRSF11A shRNA. Meanwhile, the expression of the remodeling proteins induced by TNFSF11 significantly decreased after pretreatment with-stattic (inhibitor of STAT3 phosphorylation) in HBE cells. The STAT3 phosphorylation and remodeling protein expression induced by TNFSF11 obviously decreased after pretreatment with TGFß1 or TGFßR1 shRNA in HBE cells. The above results also verified that blocking TNFSF11 with denosumab alleviated airway remodeling via the TGFß1/STAT3 signaling in the humanized HSC-NOG-EXL mice with HDM-induced asthma. CONCLUSIONS: TGFß1/STAT3 action was closely correlated with TNFSF11/TNFRSF11A axis-mediated airway remodeling. This study presented a novel strategy that blocks the TNFSF11/TNFRSF11A axis to exert a protective effect against asthma.
ABSTRACT
Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-ß1, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-ß1 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincR-PPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-ß1 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-ß1 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.
ABSTRACT
Cigarette smoke (CS) is a prevalent chemical indoor air contaminant known to be the primary cause of EMT during airway remodeling in COPD. While some evidence indicates the involvement of SMAD4 in EMT across certain diseases, its specific role in CS-induced EMT in airway remodeling associated with COPD is not established. In our research, we observed a substantial upregulation in SMAD4 expression, O-GlcNAcylation and EMT in patients with COPD, as well as in vitro and in vivo COPD models induced by CS, than those of the controls. Downregulation of SMAD4 resulted in a reduction in CS-induced EMT in vitro and in vivo. As a post-translational modification of proteins, O-GlcNAcylation is dynamically controlled by the duo of enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA). We further discovered the enhancement of O-GlcNAcylation levels induced by CS was due to an elevated OGT expression, as the expression of OGA remained unchanged. Using an OGT inhibitor (OSMI-1) counteracted the effects of SMAD4 on EMT. Whereas, overexpressing OGT increased SMAD4 expression and promoted EMT. OGT-mediated SMAD4 O-GlcNAcylation shielded SMAD4 from proteasomal degradation by reducing its ubiquitination, thereby aiding in SMAD4 stabilization in response to EMT induced by CS. Overall, this research uncovers a fresh pathway for CS-induced EMT in the airway remodeling of COPD and offers valuable insights.
ABSTRACT
Shortening of airway smooth muscle and bronchoconstriction are pathognomonic for asthma. Airway shortening occurs through calcium-dependent activation of myosin light chain kinase, and RhoA-dependent calcium sensitization, which inhibits myosin light chain phosphatase. The mechanism through which pro-contractile stimuli activate calcium sensitization is poorly understood. Our review of the literature suggests that pro-contractile G protein coupled receptors likely signal through G12/13 to activate RhoA and mediate calcium sensitization. This hypothesis is consistent with the effects of pro-contractile agonists on RhoA and Rho kinase activation, actin polymerization and myosin light chain phosphorylation. Recognizing the likely role of G12/13 signaling in the pathophysiology of asthma rationalizes the effects of pro-contractile stimuli on airway hyperresponsiveness, immune activation and airway remodeling, and suggests new approaches for asthma treatment.
Subject(s)
Asthma , Signal Transduction , Asthma/metabolism , Asthma/physiopathology , Asthma/drug therapy , Humans , Signal Transduction/physiology , Animals , GTP-Binding Protein alpha Subunits, G12-G13/metabolism , Muscle, Smooth/metabolism , Muscle, Smooth/physiopathology , Muscle, Smooth/drug effects , Airway Remodeling/physiologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Shegan-Mahuang Decoction (SMD) is a classical formula that has been used to effectively treat cold-induced asthma (CA) for 1800 years. Airway smooth muscle cells (ASMCs) play a crucial role in airway remodeling of CA and can be modulated through bitter taste-sensing type 2 receptors (TAS2Rs). Given that SMD contains numerous bitter herbs and TAS2R10 expression in ASMCs remains consistently high, it is pertinent to explore whether SMD regulates ASMCs via TAS2R10 to exert its CA mechanism. AIM OF THE STUDY: This study investigated the efficacy as well as the potential mechanism of SMD in CA. MATERIALS AND METHODS: In this study, experiments in vivo were conducted using the CA rat model induced by ovalbumin (OVA) along with cold stimulation. The effects of SMD and TAS2R10 expression in CA rats were evaluated using the following methods: clinical symptoms, weights, pathological staining, immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB). Assays in vitro including cell counting Kit-8 (CCK-8), ELISA, flow cytometry, TUNEL staining, RT-qPCR and WB were performed to investigate potential mechanism of SMD on the proliferation and apoptosis of ASMCs through upregulation of TAS2R10. RESULTS: The administration of SMD resulted in a notable improvement in the symptoms, trends in weight, airway inflammation and airway remodeling observed in CA rats with upregulated TAS2R10. Mechanistically, we furtherly confirmed that SMD inhibits p70S6K/CyclinD1 pathway by upregulating TAS2R10. SMD furthermore blocked the G0/G1 phase, suppressed the proliferation and inducted apoptosis in ASMCs induced by platelet-derived growth factor-BB (PDGF-BB). Erythromycin (EM), a TAS2R10 agonist, can intensify these effects. CONCLUSIONS: SMD significantly ameliorates CA by upregulating TAS2R10 and inhibiting the p70S6K/CyclinD1 pathway, thereby modulating ASMCs' proliferation and apoptosis. Inspired by the Five Flavors Theory of Traditional Chinese Medicine, this study provides an updated treatment perspective for treating CA.
Subject(s)
Apoptosis , Asthma , Cell Proliferation , Drugs, Chinese Herbal , Myocytes, Smooth Muscle , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled , Animals , Apoptosis/drug effects , Asthma/drug therapy , Cell Proliferation/drug effects , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Drugs, Chinese Herbal/pharmacology , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Rats , Cold Temperature , Male , Ovalbumin , Airway Remodeling/drug effects , Disease Models, Animal , Anti-Asthmatic Agents/pharmacology , Cells, CulturedABSTRACT
Asthma is a widely prevalent chronic disease that brings great suffering to patients and may result in death if it turns severe. Jolkinolide B (JB) is one diterpenoid component separated from the dried roots of Euphorbia fischeriana Steud (Euphorbiaceae), and has anti--inflammatory, antioxidative, and antitumor properties. However, the detailed regulatory role and associated regulatory mechanism in the progression of asthma remain elusive. In this work, it was demonstrated that the extensive infiltration of bronchial inflammatory cells and the thickening of airway wall were observed in ovalbumin (OVA)-induced mice, but these impacts were reversed by JB (10 mg/kg) treatment, indicating that JB relieved the provocative symptoms in OVA-induced asthma mice. In addition, JB can control OVA-triggered lung function and pulmonary resistance. Moreover, JB attenuated OVA-evoked inflammation by lowering the levels of interleukin (IL)-4, IL-5, and IL-13. Besides, the activated nuclear factor kappa B (NF-κB) and transforming growth factor-beta-mothers against decapentaplegic homolog 3 (TGFß/smad3) pathways in OVA-induced mice are rescued by JB treatment. In conclusion, it was disclosed that JB reduced allergic airway inflammation and airway remodeling in asthmatic mice by modulating the NF-κB and TGFß/smad3 pathways. This work could offer new opinions on JB for lessening progression of asthma.
Subject(s)
Airway Remodeling , Asthma , Disease Models, Animal , Diterpenes , Mice, Inbred BALB C , NF-kappa B , Ovalbumin , Animals , Asthma/drug therapy , Asthma/immunology , Airway Remodeling/drug effects , Mice , Diterpenes/pharmacology , Diterpenes/administration & dosage , Diterpenes/therapeutic use , Ovalbumin/immunology , NF-kappa B/metabolism , Female , Transforming Growth Factor beta/metabolism , Cytokines/metabolism , Smad3 Protein/metabolism , Signal Transduction/drug effects , Humans , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Asthmatic Agents/pharmacology , Anti-Asthmatic Agents/therapeutic use , Euphorbia/chemistryABSTRACT
Asthma is a chronic immunological disease related to oxidative stress and chronic inflammation; both processes promote airway remodeling with collagen deposition and matrix thickening, causing pulmonary damage and lost function. This study investigates the immunomodulation of C-phycocyanin (CPC), a natural blue pigment purified from cyanobacteria, as a potential alternative treatment to prevent the remodeling process against asthma. We conducted experiments using ovalbumin (OVA) to induce asthma in Sprague Dawley rats. Animals were divided into five groups: (1) sham + vehicle, (2) sham + CPC, (3) asthma + vehicle, (4) asthma + CPC, and (5) asthma + methylprednisolone (MP). Our findings reveal that asthma promotes hypoxemia, leukocytosis, and pulmonary myeloperoxidase (MPO) activity by increasing lipid peroxidation, reactive oxygen and nitrogen species, inflammation associated with Th2 response, and airway remodeling in the lungs. CPC and MP treatment partially prevented these physiological processes with similar action on the biomarkers evaluated. In conclusion, CPC treatment enhanced the antioxidant defense system, thereby preventing oxidative stress and reducing airway inflammation by regulating pro-inflammatory and anti-inflammatory cytokines, consequently avoiding asthma-induced airway remodeling.
Subject(s)
Airway Remodeling , Asthma , Disease Models, Animal , Ovalbumin , Oxidative Stress , Phycocyanin , Rats, Sprague-Dawley , Animals , Phycocyanin/pharmacology , Phycocyanin/therapeutic use , Asthma/drug therapy , Asthma/metabolism , Asthma/chemically induced , Oxidative Stress/drug effects , Ovalbumin/adverse effects , Rats , Airway Remodeling/drug effects , Inflammation/metabolism , Inflammation/drug therapy , Male , Lung/drug effects , Lung/pathology , Lung/metabolism , Cytokines/metabolismABSTRACT
Crosstalk between T cells and airway smooth muscle (ASM) may play a role in modulating asthmatic airway inflammation and remodelling. Infiltrating T cells have been observed within the ASM bundles of asthmatics, and a wide range of direct and indirect interactions between T cells and ASM have been demonstrated using various in vitro and in vivo model systems. Contact-dependent mechanisms such as ligation and activation of cellular adhesion and costimulatory molecules, as well as the formation of lymphocyte-derived membrane conduits, facilitate the adhesion, bidirectional communication and transfer of materials between T and ASM cells. T cell-derived cytokines, particularly of the Th1, Th2 and Th17 subsets, modulate the secretome, proliferation and contractility of ASM cells. This review summarizes the mechanisms governing T cell-ASM crosstalk in the context of asthma. Understanding the underlying mechanistic basis is important for directing future research and developing therapeutic interventions targeted towards this complex interaction.
ABSTRACT
Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-ß1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-ß1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-ß1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-ß1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-ß1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.
Subject(s)
Airway Remodeling , Asthma , Forkhead Transcription Factors , Glycolysis , Sirtuin 2 , Asthma/metabolism , Asthma/pathology , Animals , Sirtuin 2/metabolism , Sirtuin 2/genetics , Mice , Airway Remodeling/physiology , Humans , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Epithelial-Mesenchymal Transition , Mice, Inbred BALB C , Female , Transforming Growth Factor beta1/metabolism , Lung/metabolism , Lung/pathology , Cell LineABSTRACT
BACKGROUND: Asthma's complexity, marked by airway inflammation and remodeling, is influenced by hypoxic conditions. This study focuses on the role of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) and P53 ubiquitination in asthma exacerbation. METHODS: High-throughput sequencing and bioinformatics were used to identify genes associated with asthma progression, with an emphasis on GO and KEGG pathway analyses. An asthma mouse model was developed, and airway smooth muscle cells (ASMCs) were isolated to create an in vitro hypoxia model. Cell viability, proliferation, migration, and apoptosis were assessed, along with ELISA and Hematoxylin and Eosin (H&E) staining. RESULTS: A notable increase in HIF-1α was observed in both in vivo and in vitro asthma models. HIF-1α upregulation enhanced ASMCs' viability, proliferation, and migration, while reducing apoptosis, primarily via the promotion of P53 ubiquitination through MDM2. In vivo studies showed increased inflammatory cell infiltration and airway structural changes, which were mitigated by the inhibitor IDF-11,774. CONCLUSION: The study highlights the critical role of the HIF-1α-MDM2-P53 axis in asthma, suggesting its potential as a target for therapeutic interventions. The findings indicate that modulating this pathway could offer new avenues for treating the complex respiratory disorder of asthma.
Subject(s)
Asthma , Hypoxia-Inducible Factor 1, alpha Subunit , Myocytes, Smooth Muscle , Tumor Suppressor Protein p53 , Asthma/metabolism , Asthma/pathology , Asthma/genetics , Animals , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Mice , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Cells, Cultured , Mice, Inbred BALB C , Apoptosis/physiology , Cell Proliferation/physiology , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins c-mdm2/genetics , Hypoxia/metabolism , Hypoxia/pathology , Disease Models, Animal , Cell Hypoxia/physiology , Female , Humans , Cell Movement/physiology , UbiquitinationABSTRACT
OBJECTIVES: To explore the effects of iris xanthin on airway inflammation, airway remodeling, and the high mobility group box 1 protein (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in asthmatic young mice. METHODS: Sixty male BALB/c young mice were randomly assigned into six groups: a blank group, a model group, a dexamethasone group, and low, medium, and high dose groups of iris xanthin, with ten mice per group. Asthma models were induced through intraperitoneal injections of a sensitizing agent [ovalbumin (OVA) 20 µg + aluminum hydroxide gel 2 mg], followed by 4% OVA aerosol inhalation. Lung function was measured using a pulmonary function tester to determine lung volume (LV), resting ventilation per minute (VE), and airway reactivity (Penh value). Hematoxylin-eosin (HE) staining was employed to examine and analyze airway remodeling. The contents of interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid were quantified using ELISA. Real-time fluorescence quantitative polymerase chain reaction and Western blot analysis were used to assess the expression of HMGB1/TLR4/NF-κB pathway-related mRNA and proteins in lung tissues. RESULTS: Compared to the model group, the dexamethasone and iris xanthin-treated groups (low, medium, and high doses) exhibited significant increases in LV and VE (P<0.05), with incremental dose-dependent increases observed in the iris xanthin groups. Additionally, Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, and NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were all reduced (P<0.05) in a dose-dependent manner. When compared to the dexamethasone group, the low and medium dose iris xanthin groups showed decreases in LV and VE (P<0.05), whereas Penh values, IL-1ß, IL-6, TNF-α, and airway remodeling indicators, along with mRNA levels of HMGB1, TLR4, NF-κB p65 and protein levels of HMGB1, TLR4, and p-NF-κB p65, were increased (P<0.05). No significant differences were noted in these indices between the high dose iris xanthin group and the dexamethasone group (P>0.05). CONCLUSIONS: Iris xanthin can effectively alleviates airway inflammation and inhibits airway remodeling in asthmatic young mice, possibly through the suppression of the HMGB1/TLR4/NF-κB pathway.
Subject(s)
Airway Remodeling , Asthma , HMGB1 Protein , Mice, Inbred BALB C , NF-kappa B , Signal Transduction , Toll-Like Receptor 4 , Animals , Airway Remodeling/drug effects , Asthma/drug therapy , Asthma/metabolism , Male , Mice , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , HMGB1 Protein/genetics , HMGB1 Protein/metabolism , NF-kappa B/metabolism , Signal Transduction/drug effectsABSTRACT
Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.
Subject(s)
Allergens , Asthma , Humans , Asthma/metabolism , Asthma/immunology , Asthma/pathology , Allergens/immunology , Animals , Airway RemodelingABSTRACT
BACKGROUND: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma. METHODS: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways. RESULTS: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-ß1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced. CONCLUSION: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically.
Subject(s)
Airway Remodeling , Asthma , Bronchoalveolar Lavage Fluid , Disease Models, Animal , Drugs, Chinese Herbal , Mice, Inbred BALB C , NF-kappa B , Ovalbumin , Signal Transduction , Toll-Like Receptor 4 , Animals , Asthma/drug therapy , Asthma/chemically induced , Toll-Like Receptor 4/metabolism , Airway Remodeling/drug effects , Signal Transduction/drug effects , NF-kappa B/metabolism , Drugs, Chinese Herbal/pharmacology , Mice , Immunoglobulin E/blood , Lung/drug effects , Lung/pathology , Lung/metabolism , Female , Inflammation/drug therapy , Eosinophils/drug effects , Eosinophils/metabolism , Anti-Asthmatic Agents/pharmacology , Cytokines/metabolismABSTRACT
BACKGROUND: Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, ß-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB). METHODS: Human ASM cells were pre-treated with ß-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of ß-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration. RESULTS: ß-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, ß-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2. CONCLUSIONS: In conclusion, the inhibition of RhoA activation and ROS production by ß-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling.
ABSTRACT
BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
Subject(s)
Airway Remodeling , Amino Acid Oxidoreductases , Asthma , Ovalbumin , Proto-Oncogene Proteins c-akt , Signal Transduction , Animals , Amino Acid Oxidoreductases/metabolism , Amino Acid Oxidoreductases/genetics , Amino Acid Oxidoreductases/biosynthesis , Ovalbumin/toxicity , Airway Remodeling/physiology , Proto-Oncogene Proteins c-akt/metabolism , Mice , Humans , Asthma/pathology , Asthma/metabolism , Asthma/enzymology , Asthma/genetics , Signal Transduction/physiology , Female , Mice, Inbred BALB C , Male , Epithelial-Mesenchymal Transition/physiologyABSTRACT
Background: Small airway dysfunction (SAD) and airway inflammation are vital in asthma exacerbations. Type 2 inflammation (T2), mediated by cytokines from T helper 2 cell (Th2) such as interleukin (IL)-4, IL-5, and IL-13, is a potential mechanism underlying SAD. Research on small airway function in asthma is limited. We aimed to explore the correlation between small airway function and respiratory symptoms and comorbidity in T2 and non-T2 asthma. Methods: Derived from the National Health and Nutrition Examination Survey (NHANES), our study encompassed 2,420 asthma patients aged 6 - 79 years, including pulmonary function (PF) data such as forced expiratory flow between 25% and 75% of forced vital capacity (FEF25-75), forced expiratory volume in 1 second (FEV1), forced expiratory volume in 3 seconds (FEV3), forced expiratory volume in 6 seconds (FEV6), and forced vital capacity (FVC). To evaluate the small airway function, we calculated z-scores for FEF25-75, FEF25-75/FVC, FEV1/FEV6, and FEV3/FEV6. Logistic regression determined the adjusted odds ratios (aORs) for symptoms and comorbidity. Results: FEF25-75, FEV1/FEV6, and FEV3/FEV6 correlated with asthmatic symptoms. FEF25-75 had the strongest association with wheezing or whistling attacks. An increase of 1 standard deviations (SD) in FEF25-75 reduced recurrent wheezing (aOR: 0.70; 95% confidence intervals (95% CIs): 0.65 - 0.76) and severe attacks (aOR: 0.67; 95% CI: 0.62 - 0.94). These indices were also linked to dry cough and hay fever, particularly FEV3/FEV6 reducing hay fever risk (aOR: 0.70; 95% CI: 0.55 - 0.91) in non-T2 asthma. FEF25-75/FVC related to persistent (aOR: 0.78; 95% CI: 0.72 - 0.84) and severe attacks (aOR: 1.14; 95% CI: 1.08 - 1.22) in non-T2 groups. Lower indices combined with T2 exposure raised severe attack risk. Conclusions: In this nationwide study, small airway function correlated with symptom onset, especially in T2 asthma. Small airway injury differed between T2 and non-T2 asthma. Prospective research is needed to establish reference values.