Airway Remodeling Research Articles

Research progress of Chinese herbal medicines and classic prescriptions in the treatment of COPD based on the TCM theory and medicinal characteristics

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex pathogenesis, which causes the lack of precise and personalized prevention, control, and treatment approaches in clinical practice. Traditional Chinese medicine (TCM) with multiple components acting on multiple targets plays a role in the prevention and treatment of COPD. After evaluating the treatment of cough, dyspnea, and lung distension based on syndrome differentiation in TCM, we summarized the commonly used TCM preparations for treating COPD. These preparations are mainly composed of medicines for clearing interior heat and releasing exterior, tonifying, activating blood and resolving stasis, resolving phlegm, relieving cough and breathlessness, and regulating Qi movement. Because all of them contain a variety of active ingredients such as flavonoids, terpenoids, and phenols, we analyzed the mechanisms of the classic prescriptions alone or in combination with other medicines or therapeutic methods. These mechanisms involve counteracting inflammation, oxidative stress, and fibrosis, inhibiting apoptosis, alleviating airway remodeling, and enhancing immunity. Meantime, we summarized the existing problems in the treatment of COPD by TCM. This review provides a scientific basis for the research and treatment of COPD in the future.

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines.

Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma. Ultra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers. Phytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels. Taken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.

Heat-killed Akkermansia muciniphila ameliorates allergic airway inflammation in mice.

Allergic asthma (AA) is a common inflammatory airway disease characterized by increased airway hyper-responsiveness (AHR), inflammation, and remodeling. Akkermansia muciniphila is a strictly anaerobic bacterium residing in the gut and is a promising next-generation probiotic to improve metabolic inflammatory syndrome. A recent study suggested the beneficial effect of live A. muciniphila on allergic airway inflammation (AAI) in mice. However, whether the heat-killed form can improve AAI requires further investigation. Mice sensitized and challenged with house dust mites (HDM) develop AA hallmarks including inflammatory cell infiltration, goblet cell hyperplasia, and subepithelial collagen deposition in the lungs. These phenomena were reversed by oral administration of the heat-killed A. muciniphila strain EB-AMDK19 (AMDK19-HK) isolated from the feces of healthy Koreans. Furthermore, AMDK19-HK diminished the HDM-induced AHR to inhaled methacholine, lung mast cell accumulation, and serum HDM-specific IgE levels. It also led to the overall suppression of IL-4, IL-13, and eotaxin production in bronchoalveolar lavage fluids, and Il4, Il5, Il13, and Ccl17 gene expression in lung tissues. Moreover, AMDK19-HK suppressed Th2-associated cytokine production in the splenocytes of HDM-sensitized mice in vitro. Additionally, a combination of 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis in cecal samples revealed that AMDK19-HK modulated the relative abundance of circulating SCFA-associated gut genera, including a positive correlation with Lachnospiraceae_ NK4A136_group and a negative correlation with Lachnoclostridium and significantly increased cecal SCFA concentrations. Finally, AMDK19-HK improved intestinal mucosal barrier function. These results suggest that the oral administration of AMDK19-HK ameliorates HDM-induced AAI in mice by suppressing Th2-mediated immune responses and could have a protective effect against AA development.

The Possible Roles of IL-4/IL-13 in the Development of Eosinophil-Predominant Severe Asthma.

Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.

Estrogen Metabolites Modulate Airway Hyperreactivity in a Murine Model of Asthma

Objective: Airway hyperreactivity (AHR) and remodeling are the key contributors to airway changes in asthma resulting in airway narrowing and resistance to airflow. Sex-steroid signaling, especially estrogen’s differential role in asthma undoubtedly questions its prime involvement in regulating airway structure and function in context to asthma. Evidence from cardiovascular (CV) and reproductive systems suggests that estrogen metabolites particularly 2-hydroxyestradiol (2HE) and 16α-hydroxyestradiol (16αHE2) influence a multitude of cellular functions. Accordingly, the aim of this study is to determine how estrogen metabolites regulate AHR and remodeling using a mouse model of asthma. Methods: WT C57BL/6J (male and female) mice were procured from Jackson Laboratory. Experimental animals were administered with PBS, 2-HE (2 mg/kg), 16αHE2 (2 mg/kg) with/without MA intranasally on alternate days for 28 days. On day 29, mice were anesthetized and subjected to SCIREQ flexiVent to measure Lung mechanics like airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and lung tissue samples processed for histology using hematoxylin and eosin (H&E) staining and Sirius-red and fast-green (SRFG). Results: MA-challenged group increased airway Rrs and reduced Crs in response to methacholine (MCh) in both male and female mice with profound effects in female mice. Animals exposed to MA and administered with 16αHE2 showed significant increase the Rrs while 2-HE downregulated the MA effect. The exacerbated effect of 16αHE2 on Rrs was significantly higher in MA-challenged female mice compared to male mice. Histology study including H&E and SRFG stained lung sections show increased ASM mass in 16αHE2 exposed mixed MA challenged mice. Whereas 2HE reversed MA induced effect. DLC in BAL showed increased neutrophils and eosinophils in MA challenged mice, this was attenuated by 2HE. Conclusion: This study highlights the distinct role of estrogen metabolites in regulating airway hyperresponsiveness and remodeling in the context of asthma. Thus, providing possible therapeutic potential for observed sex differences in asthma. Acknowledgment: Supported by NIH grant R01-HL146705 (Sathish). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pectolinarigenin ameliorated airway inflammation and airway remodeling to exhibit antitussive effect.

Cough is a common symptom of several respiratory diseases. However, frequent coughing from acute to chronic often causes great pain to patients. It may turn into cough variant asthma, which seriously affects people's quality of life. For cough treatment, it is dominated by over-the-counter antitussive drugs, such as asmeton, but most currently available antitussive drugs have serious side effects. Thus, there is a great need for the development of new drugs with potent cough suppressant. BALB/c mice were used to construct mice model with cough to investigate the pharmacological effects of pectolinarigenin (PEC). Hematoxylin-eosin and Masson staining were used to assess lung injury and airway remodeling, and ELISA was used to assess the level of inflammatory factor release. In addition, inflammatory cell counts were measured to assess airway inflammation. Airway hyperresponsiveness assay was used to assess respiratory resistance in mice. Finally, we used Western blotting to explore the potential mechanisms of PEC. We found that PEC could alleviate lung tissue injury and reduce the release of inflammatory factors, inhibit of cough frequency and airway wall collagen deposition in mice model with cough. Meanwhile, PEC inhibited the Ras/ERK/c-Fos pathway to exhibit antitussive effect. Therefore, PEC may be a potential drug for cough suppression.

Effect of down-regulating TRPV1 on airway remodeling in COPD rats based on NF-κB/TGF-β1/Smads pathway analysis.

Effect of down-regulating TRPV1 on airway remodeling in COPD rats based on NF-κB/TGF-β1/Smads pathway analysis.

Neutralization of CX3CL1 Attenuates TGF-β-Induced Fibroblast Differentiation Through NF-κB Activation and Mitochondrial Dysfunction in Airway Fibrosis.

Severe asthma, characterized by inflammation and airway remodeling, involves fibroblast differentiation into myofibroblasts expressing α-SMA. This process leads to the production of fibronectin and connective tissue growth factor (CTGF), driven by factors such as transforming growth factor (TGF)-β. Furthermore, the persistent presence of myofibroblasts is associated with resistance to apoptosis and mitochondrial dysfunction. The chemokine (C-X3-C motif) ligand 1 (CX3CL1) plays a role in tissue fibrosis. However, it is currently unknown whether neutralization of CX3CL1 decreases TGF-β-induced fibroblast differentiation and mitochondrial dysfunction in normal human lung fibroblasts (NHLFs). CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1), CX3CL1 was analyzed by immunofluorescence (IF) or immunohistochemical (IHC) staining of ovalbumin-challenged mice. CX3CL1 release was detected by ELISA. TGF-β-induced CTGF, fibronectin, and α-SMA expression were evaluated in NHLFs following neutralization of CX3CL1 (TP213) treatment for the indicated times by Western blotting or IF staining. Mitochondrion function was detected by a JC-1 assay and seahorse assay. Cell apoptosis was observed by a terminal uridine nick-end labeling (TUNEL) assay. An increase in CX3CL1 expression was observed in lung tissues from mice with ovalbumin-induced asthma by IF staining. CX3CR1 was increased in the subepithelial layer of the airway by IHC staining. Moreover, CX3CR1 small interfering (si)RNA downregulated TGF-β-induced CTGF and fibronectin expression in NHLFs. CX3CL1 induced CTGF and fibronectin expression in NHLFs. TGF-β-induced CX3CL1 secretion from NHLFs. Furthermore, TP213 decreased TGF-β-induced CTGF, fibronectin, and α-SMA expression in NHLFs. Mitochondrion-related differentially expressed genes (DEGs) were examined after CX3CL1 neutralization in TGF-β-treated NHLFs. TP213 alleviated TGF-β-induced mitochondrial dysfunction and apoptosis resistance in NHLFs. CX3CL1 induced p65, IκBα, and IKKα phosphorylation in a time-dependent manner. Furthermore, CX3CL1-induced fibronectin expression and JC-1 monomer were decreased by p65 siRNA. TP213 reduced TGF-β-induced p65 and α-SMA expression in NHLFs. These findings suggest that neutralizing CX3CL1 attenuates lung fibroblast activation and mitochondrial dysfunction. Understanding the impacts of CX3CL1 neutralization on fibroblast mitochondrial function could contribute to the development of therapeutic strategies for managing airway remodeling in severe asthma.

Quanzhen Yiqi decoction attenuates inflammation in mice with smoking-induced COPD by activating the Nrf2/HO-1 pathway and inhibiting the NLRP3 inflammasome.

Quanzhen Yiqi decoction (QZYQ) is a traditional Chinese medicine for treating chronic obstructive pulmonary disease. Mice were exposed to cigarette smoke (CS) 6 days/week (40 cigarettes/day) for 24 weeks and then intragastrically administered QZYQ (4.72, 9.45, or 18.89g/kg) or dexamethasone (DEX, 0.6mg/kg) for 6 weeks. We examined the lung function and collected bronchoalveolar lavage fluid for inflammatory cell and cytokine quantification. The pathological lung changes, ROS and oxidative biomarkers were measured. We used immunohistochemistry and western blotting to evaluate the levels of Nrf2/HO-1, NLRP3/ASC/Caspase1/IL-1β/IL-18. The CS group showed significant increases in the forced vital capacity, lung resistance, and chord compliance and a lower FEV50/FVC compared with the control, and QZYQ improved these changes. In addition, QZYQ effectively reduced emphysema, immune cell infiltration, and airway remodeling. QZYQ stimulated HO-1 expression and reduced oxidative stress through the Nrf2 pathway. QZYQ inhibited the production of NLRP3/ASC/Caspase-1 to inhibit IL-1β and IL-18. Our study suggested that QZYQ can improve the function and histology of the lungs and reduce inflammatory cell recruitment. QZYQ inhibits ROS production and NLRP3 inflammasome activation by upregulating Nrf2 to reduce lung injury. The anti-inflammatory effects of QZYQ are similar to those of DEX.

Differences in Airway Remodeling and Emphysematous Lesions between Rats Exposed to Smoke from New-Type and Conventional Tobacco Varieties.

Genes from Perilla frutescens and Ocimum basilicum were introduced into N. tabacum L. var. HHY via distant hybridization, and the new-type tobacco varieties "Zisu" and "Luole" were developed, with noticeable differences in chemical composition. Smoking is the leading cause of chronic obstructive pulmonary disease (COPD), and its pathogenesis is complex. In the present study, 48 male Sprague-Dawley (SD) rats were randomly divided into four groups, namely, the control, "HHY", "Zisu" and "Luole", and then exposed to fresh air/cigarette smoke (CS) for 30 days and 60 days. The COPD model was constructed, and their health hazards were compared and evaluated. CS from different tobacco varieties influenced rats in varying degrees at the tissue, cell and molecular levels. The rats in the "HHY" group showed obvious symptoms, such as cough and dyspnea, which were less severe in the "Zisu" and "Luole" groups. Pathological and morphological analyses, including scores, MLI, MAN, WAt/Pbm and WAm/Pbm, showed that "Zisu" and "Luole" caused less damage to the airways and lung parenchyma than "HHY". Significant increases in the numbers of total leukocytes and neutrophils in the BALF were found in "HHY" compared to those in "Zisu" and "Luole". Moreover, they caused less oxidative stress and apoptosis in lung tissues, as reflected by indicators such as ROS, MDA, T-AOC, GSH, the apoptotic index and the ratio of Bcl-2 to Bax. "Zisu" and "Luole" even altered the ratios of MMP-9/TIMP-1 and IFN-γ/IL-4 in lung tissues to a lesser degree. These differences between CS-exposed rats may be closely related to the altered expression of Nrf2, p38 MAPK and p-p38 MAPK. Changes in chemical composition via introducing genes from some medicinal plants may be an attractive strategy for tobacco harm reduction.

Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling

Asthma is a heterogeneous disease characterized by chronic airway inflammation, reversible airflow limitation, and airway remodeling. Eosinophil peroxidase (EPX) is the most abundant secondary granule protein unique to activated eosinophils. In this study, we aimed to illustrate the effect of EPX on the epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Our research found that both EPX and ADAM33 were negatively correlated with FEV1/FVC and FEV1%pred, and positively correlated with IL-5 levels. Asthma patients had relatively higher levels of ADAM33 and EPX compared to the healthy control group. The expression of TSLP, TGF-β1 and ADAM33 in the EPX intervention group was significantly higher. Moreover, EPX could promote the proliferation, migration and EMT of BEAS-2B cells, and the effect of EPX on various factors was significantly improved by the PI3K inhibitor LY294002. The findings from this study could potentially offer a novel therapeutic target for addressing airway remodeling in bronchial asthma, particularly focusing on EMT.

The role and mechanism of macrophage autophagy in the experimental model of chronic obstructive pulmonary disease.

Macrophages play an important role in chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) impairs autophagy in alveolar macrophages from COPD patients, and autophagic impairment leads to reduced clearance of protein aggregates, dysfunctional mitochondria, and defective bacterial delivery to lysosomes. However, the exact function of lung macrophage autophagy in the pathogenesis of CS-induced COPD remains largely unknown. Western blot detected the expression of autophagy-related proteins induced by CSE. The model of COPD mice was established by CS exposure combined with CSE intraperitoneal injection. Double immunofluorescence was used to measure the CD206+LC3B+ cells. The morphological changes and effects on lung function were observed. Masson staining detected the changes in collagen fibers in lung tissue. The expression levels of E-cadherinb and N-cadherinb were detected by immunohistochemistry. Western blot detected the expression of ATP6V1E1 in lung tissue. At 24 hours of exposure to CSE, the expression levels of LC3B (microtubule-associated protein 1A/1B-light chain 3B) and P62 (nucleoporin 62) were highest at 1% CSE and AGT5 (nucleoporin 62) at 2.5% CSE; at 48 hours, the expression levels of LC3B, P62 and AGT5 were highest at 2.5% CSE, and as the intervention time increased.CD206+LC3B+ cells were significantly higher in the COPD group. Enhanced macrophage autophagy may promote emphysema formation and aggravate lung function damage. The expression of E-cadherinb in lung tissue of the COPD group was decreased, and N-cadherinb expression was increased; the expression of E-cadherinb was increased, and N-cadherinb expression was decreased in ATG5myeΔ COPD mice. The expression of ATP6V1E1 in the lung tissue was increased in the COPD group; ATP6V1E1 expression was decreased in the lung tissues of ATG5myeΔ COPD mice. CSE enhanced macrophage autophagy, leads to increased lung function impairment and collagenous fiber in lung tissue, as well as promotes epithelial-mesenchymal transition, and eventually leads to small airway remodeling, which may be achieved through the ATG5/ATP6V1E1 pathway.

Revisiting airway epithelial dysfunction and mechanisms in chronic obstructive pulmonary disease: Role of mitochondrial damage.

Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). Mitochondrial damage has been identified as one of the mechanisms of airway abnormalities in COPD, which is closely related to airway inflammation and airflow limitation. In this review, we evaluate updated evidence for airway epithelial mitochondrial damage in COPD and focus on the role of mitochondrial damage in airway epithelial dysfunction. In addition, the possible mechanism of airway epithelial dysfunction mediated by mitochondrial damage is discussed in detail, and recent strategies related to airway epithelial-targeted mitochondrial therapy are summarized. Results have shown that dysregulation of mitochondrial quality and oxidative stress may lead to airway epithelial dysfunction in COPD. This may result from mitochondrial damage as a central organelle mediating abnormalities in cellular metabolism. Mitochondrial damage mediates pro-cellular senescence effects due to mitochondrial reactive oxygen species, which effectively exacerbate different types of programmed cell death, participate in lipid metabolism abnormalities, and ultimately promote airway epithelial dysfunction and trigger COPD airway abnormalities. These can be prevented by targeting mitochondrial damage factors and mitochondrial transfer. Thus, because mitochondrial damage is involved in COPD progression as a central factor of homeostatic imbalance in airway epithelial cells, it may be a novel target for therapeutic intervention to restore airway epithelial integrity and function in COPD.

Cellular and molecular mechanisms involved in the protective effects of Aerva Lanata Linn.on airways remodeling in experimental model of bronchial asthma in rats

Bronchial asthma is a chronic inflammatory respiratory disease characterized by bronchoconstriction and hyperresponsiveness of the bronchial airways. The treatment for bronchial asthma is mainly aimed at relieving symptoms by bronchodilators and controlling asthmatic attacks with anti-inflammatory agents. These therapeutic strategies are associated with several adverse drug effects and high cost that may negatively affect the compliance to therapy. Chronic asthma also results in structural remodeling of the airways which enhances the incidence of refractory asthma and increases morbidity/mortality. It is therefore important to explore adjuncts from alternative forms of therapy to compliment/supplement the conventional treatment. The study assessed the effects of Aerva Lanata Linn., a medicinal plant used in the traditional systems of medicine, on airway remodeling in an experimental model of asthma in rats. Wistar rats were immunized on day 0 with ovalbumin and Al(OH)3 and challenged with aerosolized ovalbumin from day 15 to 22. The rats were treated orally with various doses of standardized aqueous extract of whole plant of Aerva Lanata Linn. or prednisolone (10 mg/kg) for 22 days. After 24 hrs of last challenge, blood, bronchoalveolar lavage (BAL) fluid and lung tissue were collected and assayed for markers of structural remodeling viz, (a) cytokine levels (TGF-β and IL-13); (b) hydroxyproline content, and (c) histopathology. The results showed that Aerva Lanata Linn. markedly reduced the levels of TGF-β, IL-13 in both blood and BAL fluid and hydroxyproline content in lung homogenates. Histopathological examination of lung tissue confirmed the modulatory effects of Aerva Lanata Linn. on airway remodeling as evidenced by reductions in goblet cell hyperplasia, inflammatory cells infiltration and sub epithelial fibrosis, as compared to that in the experimental (disease control) group. The results showed that Aerva Lanata Linn. Attenuated the histopathological changes and biochemical markers of airway remodeling by altering the levels of IL-13 and TGFβ, and the study suggested that it could be beneficial in cases of chronic bronchial asthma.

A Quick Method to Assess Airway Distensibility in Mice

Airway distensibility is defined as the ease whereby airways are dilating in response to inflating lung pressure. If measured swiftly and accurately, airway distensibility would be a useful readout to parse the various elements contributing to airway wall stiffening, such as smooth muscle contraction, surface tension, and airway remodeling. The goal of the present study was to develop a method for measuring airway distensibility in mice. Lungs of BALB/c and C57BL/6 mice from either sex were subjected to stepwise changes in pressure. At each pressure step, an oscillometric perturbation was used to measure the impedance spectrum, on which the constant-phase model was fitted to deduce a surrogate for airway caliber called Newtonian conductance (GN). The change in GN over the change in pressure was subsequently used as an index of airway distensibility. An additional group of mice was infused with methacholine to confirm that smooth muscle contraction changes airway distensibility. GN increased with increasing steps in pressure, suggesting that the extent to which this occurs can be used as an index of airway distensibility. Airway distensibility was greater in BALB/c than C57BL/6 mice, and its variation by sex was mouse strain dependent, being greater in female than male in BALB/c mice with an inverse trend in C57BL/6 mice. Airway distensibility was also decreased by methacholine. This novel method swiftly measures airway distensibility in mice. Airway distensibility was also shown to vary with sex and mouse strain and to be sensitive to the contraction of smooth muscle.

Stiffness Mediated-Mechanosensation of Airway Smooth Muscle Cells on Linear Stiffness Gradient Hydrogels.

In obstructive airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), the extracellular matrix (ECM) protein amount and composition of the airway smooth muscle (ASM) is often remodelled, likely altering tissue stiffness. The underlying mechanism of how human ASM cell (hASMC) mechanosenses the aberrant microenvironment is not well understood. Physiological stiffnesses of the ASM were measured by uniaxial compression tester using porcine ASM layers under 0, 5 and 10% longitudinal stretch above in situ length. Linear stiffness gradient hydrogels (230 kPa range) were fabricated and functionalized with ECM proteins, collagen I (ColI), fibronectin (Fn) and laminin (Ln), to recapitulate the above-measured range of stiffnesses. Overall, hASMC mechanosensation exhibited a clear correlation with the underlying hydrogel stiffness. Cell size, nuclear size and contractile marker alpha-smooth muscle actin (αSMA) expression showed a strong correlation to substrate stiffness. Mechanosensation, assessed by Lamin-A intensity and nuc/cyto YAP, exhibited stiffness-mediated behaviour only on ColI and Fn-coated hydrogels. Inhibition studies using blebbistatin or Y27632 attenuated most mechanotransduction-derived cell morphological responses, αSMA and Lamin-A expression and nuc/cyto YAP (blebbistatin only). This study highlights the interplay and complexities between stiffness and ECM protein type on hASMC mechanosensation, relevant to airway remodelling in obstructive airway diseases.

Exploring Related Progress in Asthma Treatment Based on The Pathogenesis of Asthma

Asthma is a disease widely distributed in the world, and mainly produced by allergens stimulating the respiratory tract. At present, the treatment of this disease is mainly the combination of glucocorticoids and other drugs such as β-receptor agonists, vitamin D, montelukast sodium and so on. Bronchial asthma in children can lead to airway remodeling and other symptoms, but the specific pathogenic factors are not clear. This article reviews the recent studies on the pathogenesis, pathogenesis and treatment of asthma. It was found that the occurrence of asthma could be effectively controlled by keeping away from allergens and using vitamin D and other drugs combined with glucocorticoids. The causes of asthma are extremely complex, not only involving external factors but also involving its own factors, such as nervous, endocrine and immune systems. This paper analyzes the factors involved in asthma in a single way, and future research needs to focus more on the analysis from a comprehensive perspective. Vitamin D has the prospect of becoming an effective treatment for asthma in the future.

ALKBH5 Modulates Asthma Progression by Downregulating N6-methyladenosine Methylation.

Asthma is a chronic respiratory disease that is characterized by airway inflammation, excessive mucus production, and airway remodeling. Prevention and treatment for asthma is an urgent issue in clinical studies. In recent years, N6-methyladenosine methylation (m6A) has emerged as a promising regulatory approach involved in multiple diseases. ALKBH5 (alkB homolog 5) is a demethylase widely studied in disease pathologies. This work aimed to explore the regulatory mechanisms underlying the ALKBH5-regulated asthma. We established an interleukin-13 (IL-13)-stimulated cell model to mimic the in vitro inflammatory environment of asthma. ALKBH5 knockdown in bronchial epithelial cells was performed using siRNAs, and the knockdown efficacy was analyzed by quantitative PCR (qPCR). Cell viability and proliferation were measured by cell counting kit 8 (CCK-8) and colony formation assay. The ferroptosis was assessed by measuring the total iron, Fe2+, lipid reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. The enrichment of N6-methyladenosine methylation (m6A) modification was detected by the MeRIP assay. Knockdown of ALKBH5 significantly elevated the survival and colony formation ability of bronchial epithelial cells in the IL-13 induction model. The levels of total iron, Fe2+, lipid ROS, and MDA were remarkedly elevated, and the SOD level was reduced in IL-13-induced bronchial epithelial cells, and depletion of ALKBH5 reversed these effects. Knockdown of ALKBH5 elevated the enrichment of m6A modification and expression of glutathione peroxidase 4 (GPX4). Knockdown of GPX4 abolished the pro-proliferation and anti-ferroptosis effects of siALKBH5. Knockdown of ALKBH5 improved the proliferation of bronchial epithelial cells and alleviated cell ferroptosis.

8-Iso-prostaglandin F2α as a biomarker of type 2 low airway inflammation and remodeling in adult asthma

BackgroundAlthough 8-iso-prostaglandin F2a has been proposed as a potential biomarker for oxidative stress in airway diseases, its specific role in asthma remains poorly understood. ObjectiveTo evaluate the diagnostic potential of 8-iso-prostaglandin F2a in assessing airway inflammation, airway remodeling, airway hyperresponsiveness, and oxidative stress in asthma. MethodsBlood and urine concentrations of 8-iso-prostaglandin F2a were quantified using liquid chromatography–tandem mass spectrometry in 128 adults with asthma who had maintained antiasthma medications. Their correlations with clinical data, sputum cell counts, lung function parameters, and serum markers of epithelial/neutrophil activity and airway remodeling were then analyzed. ResultsThe urinary 8-iso-prostaglandin F2a concentrations were significantly higher in patients with noneosinophilic asthma than in those with eosinophilic asthma (P < .05). The area under the curve was 0.678, indicating moderate diagnostic accuracy for noneosinophilic asthma. There were significant correlations with neutrophilic inflammation markers and airway remodeling markers (all P < .05). Negative correlations were observed with forced expiratory volume in 1 second (%), forced expiratory volume in 1 second/forced vital capacity, forced expiratory flow at 25% to 75% of forced vital capacity, and serum club cell protein 16 levels (all P < .05). High 8-iso-prostaglandin F2a concentrations were also noted in obese and smoking subgroups (all P < .05). However, the serum 8-iso-prostaglandin F2a concentrations were not correlated with these asthma-related parameters. ConclusionUrinary 8-iso-prostaglandin F2a concentrations are a potential biomarker for phenotyping severe asthma, particularly noneosinophilic asthma, offering oxidative stress-induced epithelial inflammation/remodeling as an additional target in asthma management.

β-glucan mitigates ovalbumin-induced airway inflammation by preventing oxidative stress and CD8+ T cell infiltration

BackgroundBronchial asthma is a severe respiratory condition characterized by airway inflammation, remodeling, and oxidative stress. β-Glucan (BG) is a polysaccharide found in fungal cell walls with powerful immunomodulatory properties. This study examined and clarified the mechanisms behind BG's ameliorativeactivitiesin an allergic asthma animal model. MethodBG was extracted from Chaga mushroom and characterized using FT-IR, UV–visible, zeta potential, and 1H NMR analysis. The mice were divided into five groups, including control, untreated asthmatic, dexamethasone (Dexa)-treated (1 mg/kg), and BG (30 and 100 mg/kg)-treated groups. ResultsBG treatment reduced nasal scratching behavior, airway-infiltrating inflammatory cells, and serum levels of IgE significantly. Additionally, BG attenuated oxidative stress biomarkers by lowering malonaldehyde (MDA) concentrations and increasing the levels of reduced glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT). Immunohistochemical and flow cytometric analyses have confirmed the suppressive effect of BG on the percentage of airway-infiltrating cytotoxic CD8+ T cells. ConclusionThe findings revealed the role of CD8+ T cells in the pathogenesis of asthma and the role of BG as a potential therapeutic agent for asthma management through the suppression of airway inflammation and oxidative stress.