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Interleukin (IL)‐5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL‐5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL‐5 in eosinophil‐associated diseases led to the development of anti‐IL‐5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil‐depletion alone may not account for all of the therapeutic effects of anti‐IL‐5 therapy and that IL‐5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL‐5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL‐5 biology relevant to disease pathogenesis beyond eosinophil‐associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL‐5 in type 2 inflammation. [ABSTRACT FROM AUTHOR]

Background: Expiratory flow limitation (EFL) can be detected using oscillometric reactance and is associated with a worse clinical presentation in chronic obstructive pulmonary disease (COPD). Reactance can show negative swings upon exhalation, which may develop at different rates between patients. We propose a new method to quantify the rate of EFL development; the EFL Development Index (ELDI). Methods: A retrospective analysis of data from 124 COPD patients was performed. Data included lung function tests, Impulse Oscillometry (IOS), St Georges Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) scale and COPD Assessment Test (CAT) score. Fifty four patients had repeat data after 6 months. Twenty two patients had data recorded after 5 days of treatment with long acting bronchodilator therapy. EDLI was calculated as the mean expiratory reactance divided by the minimum expiratory reactance. Results: The mean ELDI was used to categorise patients with rapid onset of EFL (> 0.63; n = 29) or gradual onset (≤ 0.63; n = 34). Those with rapid development had worse airflow obstruction, lower quality of life scores, and greater resting hyperinflation, compared to those with gradual development. In patients with EFL, ELDI correlated with symptoms scores, airflow obstruction, lung volumes and gas diffusion. Both EFL and ELDI were stable over 6 months. EFL and EDLI improved with bronchodilator treatment. Conclusions: COPD patients with rapid EFL development (determined by ELDI) had worse clinical characteristics than those with gradual EFL development. The rate of EFL development appears to be associated with clinical and physiological characteristics. Take home message: We propose a new method of quantifying the rate of EFL development (EFL Development Index; ELDI), and report that those with rapid EFL development upon exhalation have worse physiological and clinical characteristics. [ABSTRACT FROM AUTHOR]

Background and Purpose: Airway epithelial cells (AECs) regulate the activation of epithelial–mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure. Experimental Approach: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA‐sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma. Key Results: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)‐stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2‐mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling. Conclusion and Implications: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2‐mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients. [ABSTRACT FROM AUTHOR]

This study was performed to evaluate the impact on the upper airway and nasal cavity of a new minimally invasive surgical and miniscrew-assisted rapid palatal expansion (MISMARPE) technique for the treatment of adult patients with transverse maxillary deficiency, in comparison to surgically assisted rapid palatal expansion (SARPE). Computed tomography scans of 21 MISMARPE and 16 SARPE patients were obtained preoperatively (T0) and at the end of the activation period (T1) and analysed. Linear and volumetric measurements were performed in the dental, alveolar, nasal cavity, and oropharynx regions. Generalised estimating equations were used to consider the intervention time and surgery type, and their interaction. In both groups, measurements were increased at T1 (P < 0.001), except for oropharynx volume (P > 0.05). A greater expansion in nasal cavity floor and median palatal suture was shown for MISMARPE when compared to SARPE (P < 0.001), with the same degree of expander activation (P = 0.094). A trapezoidal (coronal plane) and 'V' shape (axial plane) expansion pattern, was observed after MISMARPE. Both surgical techniques were effective for maxillary expansion in adults. However, MISMARPE was performed without osteotomy of the pterygomaxillary suture, in an outpatient setting and with local anaesthesia. [ABSTRACT FROM AUTHOR]

Abstract Background Expiratory flow limitation (EFL) can be detected using oscillometric reactance and is associated with a worse clinical presentation in chronic obstructive pulmonary disease (COPD). Reactance can show negative swings upon exhalation, which may develop at different rates between patients. We propose a new method to quantify the rate of EFL development; the EFL Development Index (ELDI). Methods A retrospective analysis of data from 124 COPD patients was performed. Data included lung function tests, Impulse Oscillometry (IOS), St Georges Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) scale and COPD Assessment Test (CAT) score. Fifty four patients had repeat data after 6 months. Twenty two patients had data recorded after 5 days of treatment with long acting bronchodilator therapy. EDLI was calculated as the mean expiratory reactance divided by the minimum expiratory reactance. Results The mean ELDI was used to categorise patients with rapid onset of EFL (> 0.63; n = 29) or gradual onset (≤ 0.63; n = 34). Those with rapid development had worse airflow obstruction, lower quality of life scores, and greater resting hyperinflation, compared to those with gradual development. In patients with EFL, ELDI correlated with symptoms scores, airflow obstruction, lung volumes and gas diffusion. Both EFL and ELDI were stable over 6 months. EFL and EDLI improved with bronchodilator treatment. Conclusions COPD patients with rapid EFL development (determined by ELDI) had worse clinical characteristics than those with gradual EFL development. The rate of EFL development appears to be associated with clinical and physiological characteristics.

Asthma is a common and burdensome chronic inflammatory airway disease that affects both children and adults. One of the main concerns with asthma is the manifestation of irreversible tissue remodelling of the airways due to the chronic inflammatory environment that eventually disrupts the whole structure of the airways. Most people with troublesome asthma are treated with inhaled corticosteroids. However, the development of steroid resistance is a commonly encountered issue, necessitating other treatment options for these patients. Biological therapies are a promising therapeutic approach for people with steroid‐resistant asthma. Interleukin 5 is recently gaining a lot of attention as a biological target relevant to the tissue remodelling process. Since IL‐5‐neutralizing monoclonal antibodies (mepolizumab, reslizumab and benralizumab) are currently available for clinical use, this review aims to revisit the role of IL‐5 in asthma pathogenesis at large and airway remodelling in particular, in addition to exploring its role as a target for biological treatments. [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic inflammatory disorder arising from heterogenic geneenvironment interactions. Obesity is one of the risk factors for asthma. Evidence shows that several inflammatory markers are active in obese and overweight patients. There is growing evidence that obesity can affect the course and control of asthma. Aims and Objectives: The study was done to compare clinical characteristics, spirometry variables, and quality of life among obese and non-obese asthmatics. Materials and Methods: The study was a crosssectional comparative study conducted in a tertiary care hospital using a semi-structured pre-tested questionnaire. Detailed history and examination, quality of life using AQLQ score, and spirometry severity were assessed. Results: A total of 80 patients, 40 obese asthmatics and 40 non-obese asthmatics were included in the study. The study found that most subjects belonged to the age group of 31–40 years and body mass index of 30.89±1.94 among the obese group and 23.19±3.77 in non-obese, respectively. The majority had symptoms of breathlessness and wheezing in both groups. The mean forced expiratory volume in 1 s was similar in both groups. However, the mean forced vital capacity was lower in the obese group. The asthma control test (ACT) score was poorer in obese group as compared to nonobese group (7 in obese vs. 15 in non-obese). The dosage of inhaled steroids was higher in the obese group. Conclusion: The symptomatology was similar among the two groups. Restrictive abnormalities, higher asthma symptoms with lower ACT scores, and higher dosages of medications were seen in obese asthmatics as compared to non-obese patients.

Abstract Background Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial–mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. Methods We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson’s staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. Results Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. Conclusion We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD.

Background: Asthma is a chronic inflammatory disorder arising from heterogenic geneenvironment interactions. Obesity is one of the risk factors for asthma. Evidence shows that several inflammatory markers are active in obese and overweight patients. There is growing evidence that obesity can affect the course and control of asthma. Aims and Objectives: The study was done to compare clinical characteristics, spirometry variables, and quality of life among obese and non-obese asthmatics. Materials and Methods: The study was a crosssectional comparative study conducted in a tertiary care hospital using a semi-structured pre-tested questionnaire. Detailed history and examination, quality of life using AQLQ score, and spirometry severity were assessed. Results: A total of 80 patients, 40 obese asthmatics and 40 non-obese asthmatics were included in the study. The study found that most subjects belonged to the age group of 31-40 years and body mass index of 30.89±1.94 among the obese group and 23.19±3.77 in non-obese, respectively. The majority had symptoms of breathlessness and wheezing in both groups. The mean forced expiratory volume in 1 s was similar in both groups. However, the mean forced vital capacity was lower in the obese group. The asthma control test (ACT) score was poorer in obese group as compared to nonobese group (7 in obese vs. 15 in non-obese). The dosage of inhaled steroids was higher in the obese group. Conclusion: The symptomatology was similar among the two groups. Restrictive abnormalities, higher asthma symptoms with lower ACT scores, and higher dosages of medications were seen in obese asthmatics as compared to non-obese patients. [ABSTRACT FROM AUTHOR]

Background: Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial–mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. Methods: We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson's staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. Results: Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. Conclusion: We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD. [ABSTRACT FROM AUTHOR]

Abstract Background Small airway remodelling is a vital characteristic of chronic obstructive pulmonary disease (COPD), which is mainly caused by epithelial barrier dysfunction and epithelial-mesenchymal transition (EMT). Recent studies have indicated that histone deacetylase 6 (HDAC6) plays an important role in the dysregulation of epithelial function. In this study, we investigated the therapeutic effects and underlying mechanisms of an inhibitor with high selectivity for HDAC6 in COPD. Methods Cigarette smoke (CS) exposure was used to establish a CS-induced COPD mouse model. CAY10603 at doses of 2.5 and 10 mg/kg was injected intraperitoneally on alternate days. The protective effects of CAY10603 against CS-induced emphysema, epithelial barrier function and small airway remodeling were evaluated using hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, immunohistochemical staining, and western blot. The human lung bronchial epithelial cell line (HBE) was used to elucidate the underlying molecular mechanism of action of CAY10603. Results HDAC6 levels in the lung homogenates of CS-exposed mice were higher than that those in control mice. Compared to the CS group, the mean linear intercept (MLI) of the CAY10603 treatment group decreased and the mean alveolar number (MAN)increased. Collagen deposition was reduced in groups treated with CAY10603. The expression of α-SMA was markedly upregulated in the CS group, which was reversed by CAY10603 treatment. Conversely, E-cadherin expression in the CS group was further downregulated, which was reversed by CAY10603 treatment. CAY10603 affects the tight junction protein expression of ZO-1 and occludin. ZO-1 and occludin expression were markedly downregulated in the CS group. After CAY10603treatment, the protein expression level of ZO-1 and occludin increased significantly. In HBE cells, Cigarette smoke extract (CSE) increased HDAC6 levels. CAY10603 significantly attenuated the release of TGF-β1 induced by CSE. CAY10603 significantly increased the E-cadherin levels in TGF-β1 treated HBE cells, while concurrently attenuated α-SMA expression. This effect was achieved through the suppression of Smad2 and Smad3 phosphorylation. CAY10603 also inhibited TGF-β1 induced cell migration. Conclusions These findings suggested that CAY10603 inhibited CS induced small airway remodelling by regulating epithelial barrier dysfunction and reversing EMT via the TGF-β1/Smad2/3 signalling pathway.

Bronchial asthma is a heterogeneous disease characterised by chronic airway inflammation. A variety of immune cells such as eosinophils, mast cells, T lymphocytes, neutrophils and airway epithelial cells are involved in the airway inflammation and airway hyperresponsiveness in asthma pathogenesis, resulting in extensive and variable reversible expiratory airflow limitation. However, the precise molecular mechanisms underlying the allergic immune responses, particularly immunometabolism, remains unclear. Studies have detected enhanced oxidative stress, and abnormal metabolic progresses of glycolysis, fatty acid and amino acid in various immune cells, inducing dysregulation of innate and adaptive immune responses in asthma pathogenesis. Immunometabolism mechanisms contain multiple signalling pathways, providing novel therapy targets for asthma. This review summarises the current knowledge on immunometabolism reprogramming in asthma pathogenesis, as well as potential therapy strategies. [ABSTRACT FROM AUTHOR]

Abstract Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty‐four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine‐induced bronchoconstriction). However, for a well‐matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.

Abstract While asthma is considered an inflammatory-mediated airway epithelial and smooth muscle disorder, there is increasing evidence of airway capillary endothelial dysfunction associated with vascular remodelling and angiogenesis in some individuals with this condition. The inflammation is typically characterized as type-2 high (eosinophilic) vs type 2-low (neutrophilic and pauci-granulocytic); we hypothesized that the type-2 high group would be more likely to evidence endothelial dysfunction. As a biomarker of these processes, we hypothesized that nonsmokers with allergic asthma may have elevated plasma levels of endothelial microparticles (EMPs), membrane vesicles that are shed when endothelial cells undergo activation or apoptosis. Total and apoptotic circulating EMPs were measured by fluorescence-activated cell analysis in patients with allergic asthma (n = 29) and control subjects (n = 26), all nonsmokers. When the entire group of patients with asthma were compared to the control subjects, there were no differences in total circulating EMPs nor apoptotic EMPs. However, patients with asthma with elevated levels of IgE and eosinophils had higher levels of apoptotic EMPs, compared to patients with asthma with mildly increased IgE and eosinophil levels. This observation is relevant to precision therapies for asthma and highlights the importance of sub-phenotyping in the condition.

Airway remodelling is the main pathological mechanism of bronchiolitis obliterans (BO). Several studies have found that transforming growth factor-β (TGF-β) expression is increased in BO during airway remodelling, where it plays an important role in various biological processes by binding to its receptor complex to activate multiple signalling proteins and pathways. This review examines the role of TGF-β in airway remodelling in BO and its potential as a therapeutic target, highlighting the mechanisms of TGF-β activation and signalling, cellular targets of TGF-β actions, and research progress in TGF-β signalling and TGF-β-mediated processes. [ABSTRACT FROM AUTHOR]

Introduction: Asthma is one of the common chronic polygenic inflammatory diseases. Genome wide association studies have identified ADAM33 as an asthma candidate gene. The present study investigated possible association of rs2280090 (T1), rs2280091 (T2) and rs3918396 (S1) single nucleotide polymorphisms (SNPs) of ADAM33 with aeroallergen induced asthma in West Bengal population, India. In addition, in-silico analysis was performed to find out changes in protein function. Methods: Forced expiratory volume in 1 second (FEV1)/Forced vital capacity (FVC), peak expiratory flow rate (PEFR) were assessed using spirometry in 1039 participants. Allergic sensitivity of 619 spirometry positive asthma patients was assessed by skin prick test (SPT) against 22 aeroallergens. For genotyping of T1, T2, and S1 SNPs in 540 allergic asthma patient and 420 control subjects, polymerase chain reaction-based restriction fragment length polymorphism was performed. Total Immunoglobulin-E (IgE) level was measured in both patients and controls. ADAM333 haplotype blocks were constructed using Haploview software v.4.2. Structural model of transmembrane and cytoplasmic domains of ADAM33 was generated using RaptorX. Protein-protein interaction was analysed using the STRING server. Results: Highest number of patient sensitivity was observed towards Cocos nusifera (n = 215) and Dermatophagoides farinae (n = 229). Significant difference in sensitivity was observed between child and late adult (P = 0.03), child and early adult (P = 0.02), adolescent and late adult (P = 0.02) and adolescent and early adult (P = 0.01). Genotypic frequencies differed significantly between patients and controls (P

Background and Objective: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with worsening health outcomes and effective treatment of each episode is essential. In this study, we aimed to investigate if plasma levels of heparan sulphate (HS) are associated with the aetiology of AECOPD. Methods: COPD patients (N = 1189), GOLD grade II–IV, from a discovery cohort (N = 638) and from a validation cohort (N = 551), were included in the study. HS and heparanase (HSPE‐1) were measured longitudinally in plasma at stable state, at AECOPD and at 4 weeks follow‐up. Results: Plasma HS was higher in patients with COPD as compared with non‐COPD controls and was significantly increased at AECOPD as compared to stable state (p < 0.001) in the discovery and in the validation cohorts. Four distinct exacerbation groups were classified based on aetiology (no‐infection/bacterial‐infection/viral‐infection/bacterial and viral coinfection) in the validation cohort. The fold‐increase of HS from stable state to AECOPD was associated with the aetiology of exacerbation and was higher in cases with bacterial and viral coinfections. HSPE‐1 was also significantly increased at AECOPD, however, there was no association of HSPE‐1 levels with the aetiology of these events. The probability of having an infection at AECOPD was raised as HS levels increased from stable state to AECOPD. This probability was higher for bacterial infections than viral infections. Conclusion: The results of our study indicate that circulating levels of HS are increased at AECOPD and this increase may be associated with the aetiology of these events. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?The lung response to inhaled methacholine is reputed to be greater in male than in female mice. The underpinnings of this sex disparity are ill defined.What is the main finding and its importance?We demonstrated that male airways exhibit a greater content of airway smooth muscle than female airways. We also found that, although a more muscular airway tree in males might contribute to their greater responsiveness to inhaled methacholine than females, it might also curb the heterogeneity in small airway narrowing. Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty‐four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine‐induced bronchoconstriction). However, for a well‐matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity. [ABSTRACT FROM AUTHOR]

While asthma is considered an inflammatory-mediated airway epithelial and smooth muscle disorder, there is increasing evidence of airway capillary endothelial dysfunction associated with vascular remodelling and angiogenesis in some individuals with this condition. The inflammation is typically characterized as type-2 high (eosinophilic) vs type 2-low (neutrophilic and pauci-granulocytic); we hypothesized that the type-2 high group would be more likely to evidence endothelial dysfunction. As a biomarker of these processes, we hypothesized that nonsmokers with allergic asthma may have elevated plasma levels of endothelial microparticles (EMPs), membrane vesicles that are shed when endothelial cells undergo activation or apoptosis. Total and apoptotic circulating EMPs were measured by fluorescence-activated cell analysis in patients with allergic asthma (n = 29) and control subjects (n = 26), all nonsmokers. When the entire group of patients with asthma were compared to the control subjects, there were no differences in total circulating EMPs nor apoptotic EMPs. However, patients with asthma with elevated levels of IgE and eosinophils had higher levels of apoptotic EMPs, compared to patients with asthma with mildly increased IgE and eosinophil levels. This observation is relevant to precision therapies for asthma and highlights the importance of sub-phenotyping in the condition. [ABSTRACT FROM AUTHOR]

Fibrosis is an important phenomenon as it can occur early in the pathogenesis of asthma; it may be associated with disease severity and resistance to therapy. There is a strong evidence that infection caused by human rhinovirus (HRV) contributes to remodelling process, but there is lack of studies clearly explaining this pathway. Synthetic peroxisome proliferator‐activated receptor (PPAR) γ presents immunomodulatory and anti‐inflammatory features. In this study, we examined immunomodulatory properties of ciglitazone – PPAR‐γ agonist, in development and modulation of airway remodelling. Epithelial cells (NHBE) and two lines of fibroblasts (WI‐38, HFL1) were stimulated with ciglitazone and rhinovirus. The expression of genes related to airway remodelling process were analysed in the cells; moreover NF‐κB, c‐Myc and STAT3 were silenced in order to estimate potential pathways involved. Ciglitazone decreased mRNA expression of MMP‐9 and TGF‐β. It also modified the expression of α‐SMA and collagen after rhinovirus infection. Transcription factors knockdown altered the levels of expression. The results suggest possible anti‐fibrotic activity of PPAR‐γ agonist in human airway cells. Ciglitazone has been shown to be dependent on NF‐κB‐ and STAT3‐related pathways, thus, the PPAR‐γ agonist may have therapeutic potential for the treatment of airway remodelling in asthma. [ABSTRACT FROM AUTHOR]

Context Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with respiratory symptoms and narrowing of airways. Gyeji-tang (GJT) is a traditional Asian medicine that has been used to relieve early-stage cold symptoms, headache, and chills.Objective We examined the effect and potential molecular action mechanism of GJT in a mouse model of COPD induced by cigarette smoke (CS) plus lipopolysaccharide (LPS).Materials and methods COPD was induced in C57BL/6J mice via daily exposure to CS for 1 h for 8 weeks and intranasal administration of LPS on weeks 1, 3, 5, and 7. GJT (100 or 200 mg/kg) or roflumilast (5 mg/kg) was administrated daily for the final 4 weeks of COPD induction.Results Administration of GJT significantly suppressed the CS/LPS-induced increases in: the numbers of total cells and macrophages in bronchoalveolar lavage fluid; the expression levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-8; the activities (phosphorylation) of nuclear factor kappa B and signal transducer and activator of transcription 3; and the expression levels of the structural remodelling markers, transforming growth factor beta, matrix metallopeptidase (MMP)-7, and MMP-9.Discussion and conclusions These results demonstrate that GJT prevents the lung inflammation and airway remodelling induced by CS plus LPS exposure in mice, suggesting that GJT may have therapeutic potential for the treatment of COPD.

Asthma is a chronic inflammatory disease characterized by airway remodeling and lung inflammation. Collagen triple helix repeat containing 1 (CTHRC1), a glycoprotein, is involved in multiple pathological processes, including inflammation and fibrosis. However, the function of CTHRC1 in asthma remains unclear. In the present study, the mouse asthma model was successfully generated by sensitizing and challenging mice with ovalbumin (OVA). CTHRC1 expression at both RNA and protein levels was significantly upregulated in lung tissues of asthmatic mice. Asthmatic mice exhibited significant airway remodeling as evidenced by increased bronchial wall and smooth muscle cell layer thickness, goblet cell hyperplasia and collagen deposition, and epithelial-mesenchymal transition (EMT), but those characteristics were reversed by CTHRC1 silencing. The cell model with transforming growth factor-β1 (TGF-β1) induction in bronchial epithelial cells (BEAS-2B) was conducted to verify the effects of CTHRC1 on EMT, a classic mechanism that mediates airway remodeling. The results showed that TGF-β1 stimulation increased CTHRC1 expression, and CTHRC1 knockdown inhibited TGF-β1-induced EMT. OVA-treated mice also showed increased inflammatory cell infiltration and the production of OVA-specific immunoglobulin E (IgE), interleukin (IL)-4, IL-5, and IL-13, which were decreased by CTHRC1 downregulation. The effects of CTHRC1 on OVA-induced airway inflammation were further determined by treating BEAS-2B cells with IL-13, in which CTHRC1 knockdown reduced the IL-13-induced secretion of pro-inflammatory factors, including IL-4 and IL-5. In conclusion, these results indicate that CTHRC1 silencing attenuates asthmatic airway remodeling and inflammation in vivo and in vitro, suggesting that CTHRC1 may be a potential target for asthma treatment. [ABSTRACT FROM AUTHOR]

Background: Several studies have suggested that HIF-1α regulates eosinophil activity and induces epithelial inflammation via NF-κB activation in the pathophysiology of asthma. The purpose of this study was to examine the expression of the transcription factors HIF-1α and nuclear HIF in mononuclear cells obtained from peripheral blood samples of healthy pediatric patients, asthmatic patients, and asthmatic exacerbations, regardless of disease severity. Methods: HIF-1 levels were measured using immunocytochemistry in 133 patients aged 6 to 17 years in this crosssectional and comparative study. A microscope was used to examine glass slides, and positive cells were counted in four fields per slide using an image analyzer. Results: HIF-1α and nuclear HIF levels were significantly higher in asthma patients and even higher in patients experiencing asthma attacks (p<0.0001, 95% CI). There was no significant difference in the percentage of HIF-1α expression between groups with intermittent asthma and those with mild persistent asthma, nor between patients with asthma and those experiencing asthma exacerbations. Conclusions: When compared to healthy individuals, the expression of nuclear HIF and HIF-1α is increased in peripheral mononuclear cells in asthma patients and even more so in asthma exacerbations. This suggests that HIF-1α is important in the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]

Chitra Joseph, Amanda L Tatler Centre for Respiratory Research, National Institute for Health Research Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UKCorrespondence: Amanda L Tatler, Centre for Respiratory Research, National Institute for Health Research Biomedical Research Centre, School of Medicine, University of Nottingham, Hucknall Road, Nottingham, NG5 1PB, UK, Tel +44 11 5823 1683, Email Amanda.tatler@nottingham.ac.ukAbstract: Airway remodeling is a complex clinical feature of asthma that involves long-term disruption and modification of airway architecture, which contributes significantly to airway hyperresponsiveness (AHR) and lung function decline. It is characterized by thickening of the airway smooth muscle layer, deposition of a matrix below the airway epithelium, resulting in subepithelial fibrosis, changes within the airway epithelium, leading to disruption of the barrier, and excessive mucous production and angiogenesis within the airway wall. Airway remodeling contributes to stiffer and less compliant airways in asthma and leads to persistent, irreversible airflow obstruction. Current asthma treatments aim to reduce airway inflammation and exacerbations but none are targeted towards airway remodeling. Inhibiting the development of airway remodeling or reversing established remodeling has the potential to dramatically improve symptoms and disease burden in asthmatic patients. Integrins are a family of transmembrane heterodimeric proteins that serve as the primary receptors for extracellular matrix (ECM) components, mediating cell–cell and cell–ECM interactions to initiate intracellular signaling cascades. Cells present within the lungs, including structural and inflammatory cells, express a wide and varying range of integrin heterodimer combinations and permutations. Integrins are emerging as an important regulator of inflammation, repair, remodeling, and fibrosis in the lung, particularly in chronic lung diseases such as asthma. Here, we provide a comprehensive summary of the current state of knowledge on integrins in the asthmatic airway and how these integrins promote the remodeling process, and emphasize their potential involvement in airway disease.Keywords: asthma, airway remodeling, integrins, matrix, fibrosis, biomechanics

BackgroundAsthma is characterized by morphological modifications of the airways (inflammation and remodelling) and bronchial hyperresponsiveness. Mechanisms linking these two key features of asthma are still poorly understood. ADAM28 (a disintegrin and metalloproteinase 28) might play a role in asthma pathophysiology. ADAM28 exists as membrane-bound and soluble forms and is mainly expressed by lymphocytes and epithelial cells.MethodsADAM28-/- mice and ADAM28+/+ counterparts were sensitized and exposed to ovalbumin (OVA). Airway responsiveness was measured using the flexiVent® system. After sacrifice, bronchoalveolar lavage (BAL) was performed and lungs were collected for analysis of airway inflammation and remodelling.ResultsThe expression of the soluble form of ADAM28 was lower in the lungs of OVA-exposed mice (as compared to PBS-exposed mice) and progressively increased in correlation with the duration of allergen exposure. In lungs of ADAM28-/- mice exposed to allergens, the proportion of Th2 cells among CD4+ cells and the number of B cells were decreased. Bronchial responsiveness was lower in ADAM28-/- mice exposed to allergens and similar to the responsiveness of sham-challenged mice. Similarly, features of airway remodelling (collagen deposition, smooth muscle hyperplasia, mucous hyperplasia) were significantly less developed in OVA-exposed ADAM28-/- animals in sharp contrasts to ADAM28+/+. In addition, we report the first evidence of ADAM28 RNA expression by lung fibroblasts and we unveil a decreased capacity of lung fibroblasts extracted from OVA-exposed ADAM28-/- mice to proliferate as compared to those extracted from OVA-exposed ADAM28+/+ suggesting a direct contribution of this enzyme to the modulation of airway remodelling.ConclusionThese results suggest that ADAM28 might be a key contributor to the pathophysiology of asthma.

Chronic obstructive pulmonary diseases (COPD) is characterized by airflow limitation, chronic inflammation and airway remodeling (AR) in airways and lung parenchyma. AR, a lung response, involves mucus production, airflow issues, and structural changes. It is exacerbated by neurogenic inflammation from activated sensory nerves, highlighting the interplay between neuronal and immune regulation in COPD. Sirtuins play a crucial role in lung remodeling, with SIRT-2 being the least studied. Present study explores how SIRT-2 regulates neurogenic inflammation and fibrosis in experimental BALB/c mice with cigarette smoke-induced COPD. Mice from each group, except the control, were exposed to CS for 60 days and AK-7 (100ug/kg and 200ug/kg) was administered intranasally. The study evaluated lung injury and inflammation marked by increased Cortisol, ACTH, COX-2 and LDH in COPD group with its attenuation by SIRT-2 inhibition. Additionally, CS exposure exhibited neurogenic inflammation represented by activated TPRV1 and TRPM8, elevated neuromediators levels (dopamine, acetylcholine, substance P, serotonin) and their respective receptors which were mitigated by AK-7. CS exposure enhanced fibrosis by targeting the fibrotic cascade, enhancing MMP-9, total collagen, hydroxyproline, and upregulating αSMA, MUC5AC, TGF-β, PKA, GATA-3, FOXO3, and STAT-6. SIRT-2 inhibition effectively reversed all these factors suppressing fibrosis further supported by downregulated SIRT-2 expression and histopathological studies where collagen deposition and mucus production were also attenuated by AK-7. Molecular docking revealed strong binding affinity of certain protein such as COX-2, D5DR and 5HT with AK-7. Overall, targeting SIRT-2 to modulate neuro-immune interplay presents a promising therapeutic approach for addressing AR in COPD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background Bronchial asthma is a major health problem both globally and in developing countries like India. This heterogenous disease is characterised by chronic airway inflammation and hyperresponsiveness to various extrinsic and intrinsic stimuli. The innate and adaptive immune mechanisms play an important role in the pathogenesis of asthma. Vitamin D through its immunomodulatory function on innate and acquired immunity can affect asthma control and its exacerbation. In this study, serum levels of vitamin D in bronchial asthma patients were determined, and their correlation with asthma symptom control and exacerbation was studied. Materials and methods Serum vitamin D levels of patients diagnosed with bronchial asthma (based on their history and reversible obstruction in spirometry) who reported for follow-up at the Respiratory outpatient department of a tertiary care hospital in Western Maharashtra, India, were tested after obtaining informed consent. A questionnaire was given to assess their asthma control and exacerbations. Based on their symptom control over the past four weeks, they were categorized into well-controlled (WC), partially controlled (PC), and uncontrolled (UC) asthma groups. Results Serum vitamin D levels were determined for 70 patients diagnosed with asthma, of which 10 patients fell into the UC group, 28 into the PC group, and 32 into the WC group. Among the 10 patients in the WC group, vitamin D levels were deficient in six (60%) patients, insufficient in two (20%) patients, and normal in two (20%) patients. Among the 28 patients in the PC group, vitamin D levels were deficient in 19 (67%) patients, insufficient in seven (25%) patients, and normal in two (7.1%) patients. Among the 32 patients in the UC group, vitamin D levels were deficient in 17 (53.1%) patients, insufficient in 10 (31.2%) patients, and normal in five (15.6%) patients. Conclusions Although vitamin D deficiency was highly prevalent among Indian adult asthma patients, there was no statistically significant relationship between serum vitamin D levels and asthma control., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Ethical Committee, Armed Forces Medical College, Pune-40 issued approval IEC/04/2019 dated 18 Oct 2019. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Krishnan et al.)

Background and objective: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts. Methods: Transcriptomic profiles from U‐BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum. Results: Thirty‐six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment; immune‐related mechanisms; activation of CD4+ T cells, mast cells and IL18R1; and airway remodelling in SA. Conclusion: Our results identified differentially expressed pathways that highlight the role of CD4+ T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA. Transcriptome analysis from endobronchial biopsies and induced sputum from two independent cohorts of adults with severe asthma (SA) (U‐BIOPRED and Australian NOVocastrian Asthma cohort) demonstrated shared differentially expressed pathways previously linked to persistent unresolved inflammation and novel mechanisms of airway remodelling, which may represent potential novel mechanistic pathways involved in the pathogenesis of SA. See relatededitorial [ABSTRACT FROM AUTHOR]

Background: Airway remodeling is accepted to be a determining component within the natural history of asthma. Nebulized inhalation of Mycobacterium vaccae (M. vaccae) has a protective effect on asthmatic mice. However, little is known regarding the effect of M. vaccae on airway structural remodeling in asthmatic mice. The purpose of this study was to explore the effect and the underlying mechanism of M. vaccae aerosol inhalation on airway structural remodeling in an asthma mouse model. Methods: Chronic asthma mouse models were established by ovalbumin induction. The number of inflammatory cells in bronchoalveolar lavage fluid (BALF), pathological alterations in lung tissue, and levels of associated cytokines (IL-5, IL-13, TNF-α, and ovalbumin-specific immunoglobulin E [OVA-sIgE]) were all assessed after M. vaccae therapy. The relative expression of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), and Wnt1‐induced signaling protein 1 (WISP1) mRNA were detected. Western blotting and immunohistochemistry detected the expression of Wnt/β-catenin pathway-related proteins in lung tissue. Results:M. vaccae aerosol inhalation relieved airway inflammation, airway hyper-responsiveness, and airway remodeling. M. vaccae reduced the levels of IL-5, IL-13, TNF-α, and OVA-sIgE in and downregulated the expression of IL-1β, TNF-α, NF-κB, and WISP1 mRNA in the pulmonary. In addition, M. vaccae inhibited the expression of β-catenin, WISP1, and Wnt1 protein and upregulated the expression of glycogen synthase kinase-3beta (GSK-3β). Conclusion: Nebulized inhalation of M. vaccae can reduce airway remodeling during asthma. [ABSTRACT FROM AUTHOR]

Background: Airway smooth muscle remodelling in severe equine asthma includes both thickening of airway smooth muscle, resulting from hyperplasia and hypertrophy, and changes in contractility. However, airway smooth muscle changes have not been studied in milder forms of the disease. Objectives: To investigate bronchial smooth muscle remodelling in horses with mild and moderate asthma (MEA). Study design: Retrospective case‐control study. Methods: The endobronchial biopsies from 18 horses with MEA referred to the Equine Hospital of the Université de Montréal and from seven healthy age‐matched control horses were studied. The diagnosis was based on clinical signs and bronchoalveolar lavage fluid cytology. Airway smooth muscle cell proliferation was measured by quantifying the expression of the proliferating cell nuclear antigen (PCNA) using immunohistochemistry and histomorphometry. The expression of the (+)insert smooth muscle myosin heavy chain (SMMHC) isoform, an hypercontractile protein, was assessed by RT‐qPCR. Results: Expression of the (+)insert SMMHC isoform in airway smooth muscle was approximately 1.5 times greater in horses with MEA compared with controls (P =.02, mean difference 0.01). Although there were no differences between groups in the proliferation of airway smooth muscle cells (P =.4) or myocyte density (P =.3, mean difference −0.6), the percentage of proliferating myocytes was correlated to pulmonary neutrophilia in horses with neutrophilic inflammation (P =.01, r =.80) and to the expression of the (+)insert SMMHC isoform in asthmatic horses (P =.03, r =.66). Main limitations: Small cohorts of horses were studied, and conclusions are limited to the central airways. Conclusions: These results confirm the presence of bronchial smooth muscle remodelling in mild forms of equine asthma and pave the way for the development of biomarkers to measure asthma progression and response to therapy. [ABSTRACT FROM AUTHOR]

Background/Aims Current asthma therapies remain unsatisfactory for controlling airway remodelling in asthma. MicroRNA-21 is a key player in asthma pathogenesis, but the molecular mechanisms underlying its effects on airway remodelling are not completely understood. We investigated the effects of inhibition of microRNA-21 on allergic airway inflammation and remodelling. Methods Female BALB/c mice were divided into four groups: control, ovalbumin-sensitized and -challenged for 3 months, microRNA-negative control-treated ovalbumin-treated, and microRNA-21 inhibitor-treated ovalbumin-treated groups. Parameters related to airway remodelling, cytokine production, airway inflammation, and airway hyperresponsiveness were compared between groups. Human bronchial smooth muscle cells were used in a mechanism study. Results In this asthma model, ovalbumin-sensitized and -challenged mice exhibited allergic airway inflammation and airway remodelling. MicroRNA-21 inhibitor-treated mice had fewer inflammatory cells, lower TH2 cytokine production, and suppressed parameters related to remodelling such as goblet cell hyperplasia, collagen deposition, hydroxyproline content, and expression of smooth muscle actin. Inhibition of microRNA-21 decreased transforming growth factor β1 expression and induced Smad7 expression in lung tissue. In human bronchial smooth muscle cells stimulated with transforming growth factor β1, microRNA-21 inhibition upregulated Smad7 expression and decreased markers of airway remodelling. Conclusions Inhibition of microRNA-21 had both anti-inflammatory and anti-remodelling effects in this model of ovalbumin-induced chronic asthma. Our data suggest that the microRNA-21–transforming growth factor β1–Smad7 axis modulates the pathogenesis of ovalbumin-induced chronic asthma and in human bronchial smooth muscle cells. MicroRNA-21 inhibitors may be a novel therapeutic target in patients with allergic asthma, especially those with airway remodelling.

Obesity is a contributing factor to asthma severity; while it has long been understood that obesity is related to greater asthma burden, the mechanisms though which this occurs have not been fully elucidated. One common explanation is that obesity mechanically reduces lung volume through accumulation of adipose tissue external to the thoracic cavity. However, it has been recently demonstrated that there is substantial adipose tissue within the airway wall itself, and that the presence of adipose tissue within the airway wall is related to body mass index. This suggests the possibility of an additional mechanism by which obesity may worsen asthma, namely by altering the behaviour of the airways themselves. To this end, we modify Anafi & Wilson's classic model of the bistable terminal airway to incorporate adipose tissue within the airway wall in order to answer the question of how much adipose tissue would be required in order to drive substantive functional changes. This analysis suggests that adipose tissue within the airway wall on the order of 1%–2% of total airway cross-sectional area could be sufficient to drive meaningful changes, and further that these changes may interact with volume effects to magnify the overall burden. • Mathematical model demonstrates a mechanism by which obesity may contribute to asthma severity. • Adipose tissue is present in the airway wall in obese asthma. • Adipose tissue in the airway wall may alter the functional behaviour of the airway. • Such changes could contribute to the relationship between obesity and asthma. [ABSTRACT FROM AUTHOR]

Abstract Background Airway remodelling is the major pathological feature of chronic obstructive pulmonary disease (COPD), and leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective in controlling airway remodelling. In the present study, we investigated the potential role of artesunate in preventing and treating airway remodelling and the underlying molecular mechanisms in vitro and in vivo. Methods A COPD rat model was established by cigarette smoke (CS) exposure. After 12 weeks of artesunate treatment, pathological changes in the lung tissues of COPD rats were examined by ELISA and histochemical and immunohistochemical staining. A lung functional experiment was also carried out to elucidate the effects of artesunate. Human bronchial smooth muscle (HBSM) cells were used to clarify the underlying molecular mechanisms. Results Artesunate treatment inhibited CS-induced airway inflammation and oxidative stress in a dose-dependent manner and significantly reduced airway remodelling by inhibiting α-smooth muscle actin (α-SMA) and cyclin D1 expression. PPAR-γ was upregulated and TGF-β1/Smad2/3 signalling was inactivated by artesunate treatment in vivo and in vitro. Furthermore, PPAR-γ knockdown by siRNA transfection abolished artesunate-mediated inhibition of HBSM cell proliferation by activiting the TGF-β1/Smad2/3 signalling pathway and downregulating the expression of α-SMA and cyclin D1 in HBSM cells. Conclusions These findings suggest that artesunate could be used to treat airway remodelling by regulating PPAR-γ/TGF-β1/Smad signalling in the context of COPD.

Bronchial epithelial cells and fibroblasts play an essential role in airway remodelling, due to their protective and secretory functions. There are many studies proving that infection caused by human rhinovirus may contribute to the process of airway remodelling. The beneficial properties of curcumin, the basic ingredient of turmeric, have been proved in many studies. Therefore, the aim of this study was the evaluation of curcumin immunomodulatory properties in development of airway remodelling. Fibroblasts (WI‐38 and HFL1) and epithelial cells (NHBE) were incubated with curcumin. Additionally, remodelling conditions were induced with rhinovirus (HRV). Airway remodelling genes were determined by qPCR and immunoblotting. Moreover, NF‐κB, c‐Myc and STAT3 were silenced to analyse the pathways involved in airway remodelling. Curcumin reduced the expression of the genes analysed, especially MMP‐9, TGF‐β and collagen I. Moreover, curcumin inhibited the HRV‐induced expression of MMP‐9, TGF‐β, collagen I and LTC4S (p < 0.05). NF‐κB, c‐Myc and STAT3 changed their course of expression. Concluding, our study shows that curcumin significantly downregulated gene expression related to the remodelling process, which is dependent on NF‐κB and, partially, on c‐Myc and STAT3. The results suggest that the remodelling process may be limited and possibly prevented, however this issue requires further research. [ABSTRACT FROM AUTHOR]

Giovanna De Cunto, Eleonora Cavarra, Barbara Bartalesi, Monica Lucattelli, Giuseppe Lungarella Department of Molecular and Developmental Medicine, University of Siena, Siena, ItalyCorrespondence: Giuseppe Lungarella Email lungarella.giuseppe@gmail.comAbstract: Chronic obstructive pulmonary disease (COPD) is mainly associated with smoking habit. Inflammation is the major initiating process whereby neutrophils and monocytes are attracted into the lung microenvironment by external stimuli present in tobacco leaves and in cigarette smoke, which promote chemotaxis, adhesion, phagocytosis, release of superoxide anions and enzyme granule contents. A minority of smokers develops COPD and different molecular factors, which contribute to the onset of the disease, have been put forward. After many years of research, the pathogenesis of COPD is still an object of debate. In vivo models of cigarette smoke-induced COPD may help to unravel cellular and molecular mechanisms underlying the pathogenesis of COPD. The mouse represents the most favored animal choice with regard to the study of immune mechanisms due to its genetic and physiological similarities to humans, the availability of a large variability of inbred strains, the presence in the species of several genetic disorders analogous to those in man, and finally on the possibility to create models “made-to-measure” by genetic manipulation. The review outlines the different response of mouse strains to cigarette smoke used in COPD studies while retaining a strong focus on their relatability to human patients. These studies reveal the importance of innate immunity and cell surface receptors in the pathogenesis of pulmonary injury induced by cigarette smoking. They further advance the way in which we use wild type or genetically manipulated strains to improve our overall understanding of a multifaceted disease such as COPD. The structural and functional features, which have been found in the different strains of mice after chronic exposure to cigarette smoke, can be used in preclinical studies to develop effective new therapeutic agents for the different phenotypes in human COPD.Keywords: cigarette smoking, emphysema, airway remodelling, vascular remodelling, smoking cessation, persistent inflammation

SERPINE1 protein is one important member of the serine proteinase inhibitor E superfamily that plays a crucial role in the fibrinolytic system. It has been identified which is related to chronic inflammatory lung diseases like allergic asthma and lung fibrosis. Recently, researchers have focused on the impact of SERPINE1 and its genetic polymorphisms on inflammatory diseases of the upper respiratory tract. In this review, we conclude that SERPINE1 is widely involved in the pathological process of chronic rhinosinusitis and allergic rhinitis (AR) and may play a pivotal role in tissue remodelling in chronic rhinosinusitis without nasal polyps. It is also found that the 4G allele of SERPINE1 gene is associated with the risk of upper respiratory diseases. More studies are needed to further clarify how SERPINE1 influences chronic rhinosinusitis and AR, which would be conducive to improving the therapeutic efficacy of treatments for upper respiratory diseases. [ABSTRACT FROM AUTHOR]

Introduction: To compare pretreatment quantitative CT parameters between patients with well‐controlled and those with poorly controlled bronchial asthma after treatment. Methods: We retrospectively reviewed 785 patients with clinical diagnosis of bronchial asthma from January 2009 to April 2015. Of these, 43 patients underwent high‐resolution CT and pulmonary function tests at initial diagnosis. According to the Global Initiative for Asthma (GINA) 2015 guidelines, the patients were classified into two groups (well‐controlled (GINA1), n = 18; poorly controlled (GINA2 and GINA3), n = 25). Quantitative measurements for airways (total cross‐sectional area (TA), lumen area (LA), wall area (WA) and wall area percentage (WA%)), air trapping and emphysema were performed on initial pretreatment CT scans. We compared CT measurements for airways between well‐controlled and poorly controlled groups and also compared those between ever‐smokers and never‐smokers. The significant quantitative CT parameters were evaluated with multiple regression analysis. Results: The TA and the WA demonstrated significantly higher values in the poorly controlled than in the well‐controlled patient group (TA in RB1 and LB1, each P < 0.05; WA in RB1 and RB8, each P < 0.05). Quantitative parameters for air trapping and emphysema did not show significant differences between the two patient groups. On multiple regression analysis, the TA and the WA were statistically significant in comparison of two patient groups with an adjustment for age, sex, body mass index and smoking history (each P < 0.05). Significantly higher values of the WA and the WA% were revealed in the asthmatics with smoking history comparing to non‐smokers (P < 0.05). Conclusion: Most of the quantitative CT measurements did not correlate significantly with clinical outcomes in patients with bronchial asthma. And, further research that supplements the limitations of this study is needed to support and validate the association between CT parameters and therapeutic response. This can be justified by the fact that a trend of higher values in airway measurements on initial pretreatment HRCT scan in the poorly controlled than in the well‐controlled patient group. [ABSTRACT FROM AUTHOR]

Background and objective: Circulating fibrocytes act as precursors of myofibroblasts, contribute to airway remodelling in chronic asthma and migrate to injured tissues by expressing CXCR4 and CCR7. Anti‐IgE therapy improves severe allergic asthma (SAA) control and airway remodelling in T2‐high SAA. The effects of anti‐IgE therapy on fibrocyte activities were investigated in this study. Methods: The expression of CCR7, CXCR4, ST2 and α‐SMA (α‐smooth muscle actin) in both circulating and cultured fibrocytes from all patients with asthma was measured, and was repeated after omalizumab treatment in SAA. Fibrocytes recruitment, proliferation and transformation were also measured in response to anti‐IgE therapy. Results: Omalizumab effectively improved asthma control and pulmonary function in T2‐high SAA, associated with a decline in serum levels of IL‐33 and IL‐13. Omalizumab down‐regulates CXCR4 and CCR7 expression of fibrocytes, which could suppress fibrocyte recruitment into the lungs. Omalizumab also suppressed the increased number of fibrocytes and α‐SMA+ fibrocytes within the cultured non‐adherent non‐T (NANT) cells after 3–7 days of culture. The decrease in serum levels of IL‐33 by omalizumab contributed to the effectiveness in inhibiting fibrocyte recruitment, proliferation and myofibroblast transformation through IL‐33/ST2 axis. The elevated IL‐13 expression in SAA patients potentiated the effects of IL‐33 by increasing ST2 expression. Conclusion: Omalizumab reduced the number of circulating fibrocytes, cell and number of fibrocytes as well as α‐SMA+ fibrocytes after 3–7 days of culture in SAA patients. IL‐33 and IL‐13 may be implicated in the effectiveness of omalizumab in inhibiting fibrocyte activation contributing partly to the clinical benefits in reducing lamina propria and basement membrane thickening. [ABSTRACT FROM AUTHOR]

• Inhibition of airway remodeling helps prevent the lung deterioration from asthma. • This systematic review evaluated various traditional Chinese medicine interventions for asthma. • Traditional Chinese medicine, either alone or with conventional drugs, improved asthma outcomes. This systematic review aimed to evaluate the effectiveness and safety of traditional Chinese medicine (TCM) interventions for airway remodelling in patients with asthma. A systematic search was conducted of 8 international and Chinese databases and 2 clinical trial registries from the inception of the database to March 2022. The data were analysed for the outcomes of lung function, matrix metalloproteinases-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), and adverse events. The Cochrane "Risk of bias" tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods were used to assess the methodological quality and the certainty of the evidence. Descriptive analysis was employed to summarize the outcomes of TCM. The PROSPERO ID is CRD42022318617. This work was financially supported by the National Natural Science Foundation of China (No. 82,004,167). Twenty RCTs involving 1790 patients with asthma were included. The trials were at unclear or high risk of bias. The certainty of the evidence ranged from very low certainty to low certainty. The TCM used in each trial was different. Compared to those of conventional medicine, 9 trials showed greater effects of TCM alone or combined with conventional medicine on lung function, as indicated by the FEV 1 , FVC, and FEV 1 /FVC. Nine trials showed that TCM significantly reduced the expression of MMP-9 and TIMP-1. Five trials reported adverse events. TCM alone or in combination with conventional medicine alleviated airway remodelling symptoms in patients with asthma. However, additional high-quality randomized trials are still needed to confirm the beneficial effectiveness of TCM. [ABSTRACT FROM AUTHOR]

Introduction: The homeodomain transcription factor sine oculis homeobox homolog 1 (Six1) plays a crucial role in embryogenesis and is not expressed in normal adult tissue but is expressed in many pathological processes, including airway remodelling in asthma. The current study aimed to reveal the effects of Six1 in regulating the airway remodelling and its possible mechanism. Methods: A mouse model of ovalbumin-induced asthma-associated airway wall remodelling and a bronchial epithelial cell (16HBE) model of transforming growth factor β1 (TGFβ1)-induced epithelial-mesenchymal transition (EMT) were used to investigate the role of Six1. Then, 16HBE cells were transformed with Six1 expression vectors and treated with a TGFβ1 pathway inhibitor to determine the role of Six1 in EMT. The effect of Six1 and its possible mechanism were assessed by immunohistochemistry, RT-PCR, and Western blot. Results: Six1 expression was elevated in the lungs in an OVA mouse model of allergic asthma and in 16HBE cells treated with TGFβ1. Six1 overexpression promoted an EMT-like phenotype with a decreased protein expression of E-cadherin and increased protein expression of α-smooth muscle actin (α-SMA) as well as fibronectin in 16HBE cells; these effects appeared to promote TGFβ1 and phospho-Smad2 (pSmad2) production, which are the main products of the TGFβ1/Smad signalling pathway, which could be reduced by a TGFβ1 inhibitor. Conclusion: These data reveal that Six1 and TGFβ1 are potentially a part of an autocrine feedback loop that induces EMT, and these factors can be reduced by blocking the TGFβ1/Smad signalling pathway. As such, these factors may represent a promising novel therapeutic target for airway remodelling in asthma. [ABSTRACT FROM AUTHOR]

Calcium (Ca2+) signalling is well known to dictate cellular functioning and fate. In recent years, the accumulation of Ca2+ in the mitochondria has emerged as an important factor in Chronic Respiratory Diseases (CRD) such as Asthma and Chronic Obstructive Pulmonary Disease (COPD). Various reports underline an aberrant increase in the intracellular Ca2+, leading to mitochondrial ROS generation, and further activation of the apoptotic pathway in these diseases. Mitochondria contribute to Ca2+ buffering which in turn regulates mitochondrial metabolism and ATP production. Disruption of this Ca2+ balance leads to impaired cellular processes like apoptosis or necrosis and thus contributes to the pathophysiology of airway diseases. This review highlights the key role of cytoplasmic and mitochondrial Ca2+ signalling in regulating CRD, such as asthma and COPD. A better understanding of the dysregulation of mitochondrial Ca2+ homeostasis in these diseases could provide cues for the development of advanced therapeutic interventions in these diseases. [ABSTRACT FROM AUTHOR]

Background: Myofibroblast differentiation and extracellular matrix (ECM) deposition are observed in chronic obstructive pulmonary disease (COPD). However, the mechanisms of regulation of myofibroblast differentiation remain unclear. Materials and methods: We detected let‐7 levels in peripheral lung tissues, serum and primary bronchial epithelial cells of COPD patients and cigarette smoke (CS)‐exposed mice. IL‐6 mRNA was explored in lung tissues of COPD patients and CS‐exposed mice. IL‐6 protein was detected in cell supernatant from primary epithelial cells by ELISA. We confirmed the regulatory effect of let‐7 on IL‐6 by luciferase reporter assay. Western blotting assay was used to determine the expression of α‐SMA, E‐cadherin and collagen I. In vitro, cell study was performed to demonstrate the role of let‐7 in myofibroblast differentiation and ECM deposition. Results: Low expression of let‐7 was observed in COPD patients, CS‐exposed mice and CS extract (CSE)‐treated human bronchial epithelial (HBE) cells. Increased IL‐6 was found in COPD patients, CS‐exposed mice and CSE‐treated HBE cells. Let‐7 targets and silences IL‐6 protein coding genes through binding to 3' untranslated region (UTR) of IL‐6. Normal or CSE‐treated HBE cells were co‐cultured with human embryonic lung fibroblasts (MRC‐5 cells). Reduction of let‐7 in HBE cells caused myofibroblast differentiation and ECM deposition, while increase of let‐7 mimics decreased myofibroblast differentiation phenotype and ECM deposition. Conclusion: We demonstrate that CS reduced let‐7 expression in COPD and, further, identify let‐7 as a regulator of myofibroblast differentiation through the regulation of IL‐6, which has potential value for diagnosis and treatment of COPD. [ABSTRACT FROM AUTHOR]

The natural history of COPD is complex, and the disease is best understood as a syndrome resulting from numerous interacting factors throughout the life cycle with smoking being the strongest inciting feature. Unfortunately, diagnosis is often delayed with several longitudinal cohort studies shedding light on the long 'preclinical' period of COPD. It is now accepted that individuals presenting with different COPD phenotypes may experience varying natural history of their disease. This includes its inception, early stages and progression to established disease. Several scenarios regarding lung function course are possible, but it may conceptually be helpful to distinguish between individuals with normal maximally attained lung function in their early adulthood who thereafter experience faster than normal FEV1 decline, and those who may achieve a lower than normal maximally attained lung function. This may be the main mechanism behind COPD in the latter group, as the decline in FEV1 during their adult life may be normal or only slightly faster than normal. Regardless of the FEV1 trajectory, continuous smoking is strongly associated with disease progression, development of structural lung disease and poor prognosis. In developing countries, factors such as exposure to biomass and sequelae after tuberculosis may lead to a more airway‐centred COPD phenotype than seen in smokers. Mechanistically, COPD is characterized by a combination of structural and inflammatory changes. It is unlikely that all patients share the same individual or combined mechanisms given the heterogeneity of resultant phenotypes. Lung explants, bronchial biopsies and other tissue studies have revealed important features. At the small airway level, progression of COPD is clinically imperceptible, and the pathological course of the disease is poorly described. Asthmatic features can further add confusion. However, the small airway epithelium is likely to represent a key focus of the disease, combining impaired subepithelial crosstalk and structural/inflammatory changes. Insufficient resolution of inflammatory processes may facilitate these changes. Pathologically, epithelial metaplasia, inversion of the goblet to ciliated cell ratio, enlargement of the submucosal glands and neutrophil and CD8‐T‐cell infiltration can be detected. Evidence of type 2 inflammation is gaining interest in the light of new therapeutic agents. Alarmin biology is a promising area that may permit control of inflammation and partial reversal of structural changes in COPD. Here, we review the latest work describing the development and progression of COPD with a focus on lung function trajectories, exacerbations and survival. We also review mechanisms focusing on epithelial changes associated with COPD and lack of resolution characterizing the underlying inflammatory processes. [ABSTRACT FROM AUTHOR]

Background: Airway remodelling is the major pathological feature of chronic obstructive pulmonary disease (COPD), and leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective in controlling airway remodelling. In the present study, we investigated the potential role of artesunate in preventing and treating airway remodelling and the underlying molecular mechanisms in vitro and in vivo.Methods: A COPD rat model was established by cigarette smoke (CS) exposure. After 12 weeks of artesunate treatment, pathological changes in the lung tissues of COPD rats were examined by ELISA and histochemical and immunohistochemical staining. A lung functional experiment was also carried out to elucidate the effects of artesunate. Human bronchial smooth muscle (HBSM) cells were used to clarify the underlying molecular mechanisms.Results: Artesunate treatment inhibited CS-induced airway inflammation and oxidative stress in a dose-dependent manner and significantly reduced airway remodelling by inhibiting α-smooth muscle actin (α-SMA) and cyclin D1 expression. PPAR-γ was upregulated and TGF-β1/Smad2/3 signalling was inactivated by artesunate treatment in vivo and in vitro. Furthermore, PPAR-γ knockdown by siRNA transfection abolished artesunate-mediated inhibition of HBSM cell proliferation by activiting the TGF-β1/Smad2/3 signalling pathway and downregulating the expression of α-SMA and cyclin D1 in HBSM cells.Conclusions: These findings suggest that artesunate could be used to treat airway remodelling by regulating PPAR-γ/TGF-β1/Smad signalling in the context of COPD. [ABSTRACT FROM AUTHOR]

Objective: Cysteinyl leukotrienes (CysLTs), a group of inflammatory lipid mediators, are found elevated in obese-asthmatic patients. Leukotriene D4 (LTD4), a representative CysLT, is implicated in promoting lung inflammation and remodelling in allergic asthma, but its role in non-allergic asthma, especially in obese-asthmatic patients, is not known. Here, using primary human small airway epithelial cells (SAECs) we have investigated the mechanism of LTD4-induced inflammation and remodelling and assessed high proneness of obese mice to develop asthma upon challenge with allergen ovalbumin (OVA). Methods: Primary human small airway epithelial cells (SAECs) were stimulated with different concentrations of LTD4 for different time intervals and various inflammatory markers were measured through cytokine array, membrane-based ELISA and Western blotting. An air–liquid interface (ALI) model of SAECs was used to study the effects of LTD4-induced remodelling in SAECs using Western blotting, H&E staining and PAS staining. Further, OVA-based murine model was used to examine the propensity of high-fat diet (HFD)-fed obese mice to develop asthma symptoms by studying the infiltration of inflammatory cells (assessed by bronchioalveolar lavage (BAL) cytology) and airway remodelling (assessed by histopathology) upon allergen exposure. Results: The human primary small airway epithelial cells (SAECs) treated with LTD4 showed significant alterations in the levels of inflammatory markers such as GM-CSF, TNF-α, IL-1β, EGF and eotaxin in dose- and time-dependent manner. Further, LTD4 enhanced the activation of inflammasomes as evidenced by increased levels of NALP3, cleaved caspase-1 and IL-1β. LTD4 also enhanced inflammation by increasing the expression of COX-2 in SAECs. The airway remodelling markers Vimentin and Muc5AC were found elevated in ALI culture of SAECs when stimulated with LTD4, as it also increased TGF-β levels and activation of Smad2/3 phosphorylation in SAECs. Last, sensitization and challenge of HFD-fed obese mice with OVA showed increased infiltration of inflammatory cells in BAL and enhanced levels of remodeling phenotypes like loss of cilia, mucus cell metaplasia and collagen deposition in mice lung tissues. Conclusion: The results suggest that LTD4 could induce inflammatory response in human airway epithelial cell by activating NALP3 inflammasome. LTD4 could further promote airway epithelial cells' remodelling through TGF-β/smad2/3-mediated pathway. Our in vivo results suggested that obesity predisposed the OVA challenged mice to develop lung inflammation and remodelling akin to asthma-like phenotypes during obesity. [ABSTRACT FROM AUTHOR]