Bronchial Remodeling Research Articles

Oxidative Stress and Antioxidants in Pediatric Asthma's Evolution and Management.

Within the pediatric population, bronchial asthma is one of the most prevalent chronic respiratory system diseases. The number of exacerbations, severity, and duration of symptoms all have a significant impact on children's life quality. In the last decades, the prevention and management strategies of this pathology have focused on maintaining or even increasing the pulmonary function to maximum levels in early childhood, as it has been demonstrated that functional deficits at this level occurring before school age cause pathological manifestations later, in adulthood. The epithelium of the airways and implicitly that of the lung is the first barrier against the lesions caused by pro-oxidative factors. Both oxidative and antioxidative factors can be of endogenous origin (produced by the body) or exogenous (from the environment or diet). Good functioning of antioxidant defense mechanisms from the molecular level to the tissue level, and a balance between pro-oxidative factors and anti- oxidative factors, influence the occurrence of compensatory mechanisms at the level of the respiratory epithelium, causing the delay of local responses to the stress induced by chronic inflammation (bronchial remodeling, thickening of airway smooth muscles, bronchoconstriction, bronchial hyper-reactivity). These mechanisms underlie the pathophysiological changes in asthma. Numerous studies carried out among the pediatric population inclusively have demonstrated the effectiveness of antioxidants in the prophylaxis, slowing down and preventing the progression of this pathology. This review complements the scientific articles, aiming at emphasizing the complexity of oxidative physio-pathological pathways and their importance in the occurrence, development, and therapeutic response in asthma, providing a good understanding of the relationship between oxidative and antioxidative factors, and being a source of future therapeutic strategies.

Pulmonary adaptation to repeated poly(I:C) exposure is impaired in asthmatic mice: an observational study

BackgroundWhile asthma exacerbations remain a major challenge in patient management, few animal models exist to explore the underlying mechanisms. Here, we established an animal model of asthma that can be used to study pathophysiological mechanisms and therapeutic strategies on asthma exacerbation.MethodsFemale BALB/c mice were sensitized and exposed to PBS or Dermatophagoides pteronyssinus (DerP) extract for 11 weeks. Asthmatic phenotype was assessed through lung inflammation, bronchial hyperresponsiveness and bronchial smooth muscle remodeling. Asthmatic and control mice were exposed once or three times to poly(I:C) to simulate virus-induced inflammation.ResultsFourteen days after exposure to DerP, asthmatic mice showed resolution of inflammation with sustained bronchial hyperresponsiveness and bronchial smooth muscle remodeling compared to control. At this stage, when mice were subjected to a single exposure to poly(I:C), control and asthmatic mice were characterized by a significant increase in neutrophilic inflammation and bronchial hyperresponsiveness. When mice were repeatedly exposed to poly(I:C), control mice showed a significant decrease in neutrophilic inflammation and bronchial hyperresponsiveness, while asthmatic mice experienced worsening of these outcomes.ConclusionsThis observational study report an asthmatic mouse model that can undergo exacerbation after repeated exposure to poly(I:C). Our findings on pulmonary adaptation in control mice may also pave the way for further research into the mechanism of adaptation that may be impaired in asthma and raise the question of whether asthma exacerbation may be a loss of adaptation.

Increased TGFβ1, VEGF and IFN-γ in the Sputum of Severe Asthma Patients With Bronchiectasis

BackgroundBronchiectasis is one of the most common comorbidities in severe asthma. However, the mechanisms by which asthma promotes the development and progress of this condition are not well defined. This study aimed to analyze the inflammatory phenotypes and quantify the expression of proinflammatory and remodeling cytokines in asthma patients with and without bronchiectasis. MethodsThe study sample comprised individuals with severe asthma and bronchiectasis (group AB, n=55) and a control population of individuals with severe asthma without bronchiectasis (group AC, n=45). Induced sputum samples were obtained and cell types determined by differential cell count. Proinflammatory and bronchial remodeling cytokines (IL-8, neutrophilic elastase, TGFβ1, VEGF, IFN-γ, TNF-α, and GM-CSF) were analyzed by immunoassay in sputum supernatant. ResultsNeutrophilic inflammation was the primary phenotype in both asthma groups. Higher levels of TGFβ1, VEGF and IFN-γ were observed in asthma patients with bronchiectasis (group AB) than in controls (group AC) (15 vs 24pg/ml, p=0.014; 183 vs 272pg/ml, p=0.048; 0.85 vs 19pg/ml, p<0.001, respectively). Granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were significantly lower in the AB group than in the AC group (1.2 vs 4.4pg/ml, p<0.001). IL-8, neutrophil elastase and TNF-α did not present significant differences between the groups. ConclusionsRaised levels of TGFβ1 and VEGF cytokines may indicate airway remodeling activation in asthma patients with bronchiectasis. The type of inflammation in asthma patients did not differ according to the presence or absence of bronchiectasis.

The Role of Galectins in Asthma Pathophysiology: A Comprehensive Review.

Galectins are a group of β-galactoside-binding proteins with several roles in immune response, cellular adhesion, and inflammation development. Current evidence suggest that these proteins could play a crucial role in many respiratory diseases such as pulmonary fibrosis, lung cancer, and respiratory infections. From this standpoint, an increasing body of evidence have recognized galectins as potential biomarkers involved in several aspects of asthma pathophysiology. Among them, galectin-3 (Gal-3), galectin-9 (Gal-9), and galectin-10 (Gal-10) are the most extensively studied in human and animal asthma models. These galectins can affect T helper 2 (Th2) and non-Th2 inflammation, mucus production, airway responsiveness, and bronchial remodeling. Nevertheless, while higher Gal-3 and Gal-9 concentrations are associated with a stronger degree of Th-2 phlogosis, Gal-10, which forms Charcot-Leyden Crystals (CLCs), correlates with sputum eosinophilic count, interleukin-5 (IL-5) production, and immunoglobulin E (IgE) secretion. Finally, several galectins have shown potential in clinical response monitoring after inhaled corticosteroids (ICS) and biologic therapies, confirming their potential role as reliable biomarkers in patients with asthma.

Problems in diagnosing pre-COPD (case report)

Cigarette smoke is a key risk factor for developing COPD (GOLD, 2024). One of the factors responsible for tissue damage and bronchial remodeling in the early stages of the disease is patients’ hypersensitivity to nicotine and components of cigarette smoke. Because of early life adversity combined with environmental and genetic interactions, pulmonary function measures alone may not be appropriate for the early recognition and diagnosis of COPD. It seems necessary to identify biomarkers of the risk of developing pre-COPD to identify the early stage of the disease. In the article we describe the clinical case of patient M., 21 years old, a smoker with a history of respiratory symptoms, who has signs of chronic obstructive pathology with the formation of bronchial hypersensitivity and persistent obstruction that does not reach the threshold for COPD, which reflects a common clinical problem. Сertainly, the formation of the concept of pre-COPD and the development of clinical and instrumental diagnostic criteria are necessary. Previously, we developed and tested a prick-prick test method with nicotine. We propose to use skin testing with a nicotine solution as one of the diagnostic biomarkers to identify hypersensitivity at the first stage of tissue damage.

Low levels of microRNA-21 in neutrophil-derived exosomes may contribute to airway smooth muscle hyperproliferation in horses with severe asthma.

Neutrophilic inflammation is associated with the degree of airway obstruction in severe equine asthma (SEA), but the contribution of these leukocytes to bronchial remodeling remains ill defined. Neutrophils could cause structural alterations of the airways by the release of exosomes, a type of cell-derived nanoparticles that can modify the biology of local and distant cells. Neutrophil-derived exosomes have been shown to increase airway smooth muscle (ASM) cell proliferation in humans and horses. Therefore, this study aimed to identify neutrophil exosomal microRNAs (miRs) implicated in the regulation of ASM biology in SEA. 6 horses with SEA and 6 healthy controls. The expression of selected miRs in exosomes from peripheral neutrophils was studied by quantitative PCR. The effects of miR-21 transfection in ASM cells were evaluated by gene expression analysis and proliferation studies. The miR-21 was downregulated in neutrophil exosomes from SEA horses, and it attenuated the proliferation of ASM cells stimulated with lipopolysaccharide. The lower level of miR-21 in neutrophil-derived exosomes could contribute to ASM hyperproliferation, which could, in turn, promote the thickening of the bronchial wall in SEA.

The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process.

Bronchial asthma is a heterogeneous disease characterized by persistent respiratory system inflammation, airway hyperreactivity, and airflow obstruction. Airway remodeling, defined as changes in airway wall structure such as extensive epithelial damage, airway smooth muscle hypertrophy, collagen deposition, and subepithelial fibrosis, is a key feature of asthma. Lung fibrosis is a common occurrence in the pathogenesis of fatal and long-term asthma, and it is associated with disease severity and resistance to therapy. It can thus be regarded as an irreversible consequence of asthma-induced airway inflammation and remodeling. Asthma heterogeneity presents several diagnostic challenges, particularly in distinguishing between chronic asthma and other pulmonary diseases characterized by disruption of normal lung architecture and functions, such as chronic obstructive pulmonary disease. The search for instruments that can predict the development of irreversible structural changes in the lungs, such as chronic components of airway remodeling and fibrosis, is particularly difficult. To overcome these challenges, significant efforts are being directed toward the discovery and investigation of molecular characteristics and biomarkers capable of distinguishing between different types of asthma as well as between asthma and other pulmonary disorders with similar structural characteristics. The main features of bronchial asthma etiology, pathogenesis, and morphological characteristics as well as asthma-associated airway remodeling and lung fibrosis as successive stages of one process will be discussed in this review. The most common murine models and biomarkers of asthma progression and post-asthmatic fibrosis will also be covered. The molecular mechanisms and key cellular players of the asthmatic process described and systematized in this review are intended to help in the search for new molecular markers and promising therapeutic targets for asthma prediction and therapy.

Central Bronchial Deformity in Pulmonary Sarcoidosis: A Finding Suggestive of an Upper Lobe Fibrotic Phenotype on Chest Images

Bronchial and lung parenchymal structural remodeling may occur due to disease progression in patients with pulmonary sarcoidosis; however, its mechanisms remain unclear. Central bronchial deformity (CBD) associated with shrinkage in the upper lobe (SUL) is often observed in such patients. This study aimed to examine the association between CBD and structural remodeling to identify features indicating disease severity on chest images. This retrospective cohort study included 72 patients with pulmonary sarcoidosis, excluding patients with only bilateral hilar lymphadenopathy. The participants were divided into with and without CBD groups to examine the association between CBD and other structural remodeling, including SUL, cyst and/or low attenuation area-like emphysema (Cyst/LAA), pleural/sub-pleural thickening (PT), and traction bronchiectasis (TrBE), in the upper lobe on chest images. The association of CBD phenotype with respiratory dysfunction was also examined. CBD was highly associated with SUL (81.4% vs. 8.9%), Cyst/LAA (44.4% vs. 6.7%), and PT (59.2% vs. 3.7%). The respective odds ratios in the univariable and multivariable analyses were as follows: SUL, 45.1 and 39.9; Cyst/LAA, 11.2 and 14.2; and PT, 64.0 and 68.7. TrBE was frequently associated with CBD (22.25% vs. 4.4%); the odds ratio was 6.14 in the univariable analysis. Furthermore, participants with CBD exhibited lower %FVC and %DLCO. CBD is significantly associated with lung remodeling (SUL, Cyst/LAA, TrBE, and PT) and respiratory dysfunction. CBD may be a crucial clinical phenotype to identify upper lobe fibrotic changes.

Bronchial Remodeling Following Airway Stenting in Pediatric Patients With Tracheobronchial and Congenital Heart Disease.

Treatment of tracheobronchial disease in medically complex infants with congenital heart disease (CHD) is often challenging. When conservative management or surgery fails or is contraindicated, airway stenting can allow for advancement of care or weaning of respiratory support. We identified 8 cases of airway stenting with balloon-expandable coronary bare-metal stents performed at our institution between February 2019 and September 2022 to relieve conservative treatment-refractory tracheobronchial disease in pediatric patients with CHD. All patients underwent rigid microlaryngoscopy, bronchoscopy, and flexible bronchoscopy as well as computed tomography angiography. Eight patients underwent technically uncomplicated placement of balloon-expandable coronary bare-metal stents in the trachea or bronchus. Immediate improvement in respiratory parameters was noted following stent placement. Six patients were able to wean mechanical ventilation following stent placement, with a median of 2.5 days of mechanical ventilation following the procedure (range, 0-219). All stents were subsequently endoscopically removed at a median of 6.8 months (range, 0.4-16.3 months). In 6 patients, bronchoscopy after stent removal demonstrated a rounder configuration of the airway consistent with bronchial remodeling. In pediatric patients with tracheobronchial and CHD, airway stenting with balloon-expandable bare-metal coronary stents relieved respiratory symptoms with minimal complications and resulted in bronchial remodeling after stent removal.

Loke zupa decoction attenuates bronchial EMT-mediated airway remodelling in chronic asthma through the PI3K-Akt/HIF-1α signaling pathway

Context Loke zupa decoction (Lok) is a well-established classic Chinese folk remedy for asthma. Objective We sought to investigate the effect and mechanism of Lok on asthma airway remodelling and provide novel insights for the prevention and treatment of asthma. Materials and methods For in vitro experiments, BEAS-2B cells were assigned into six groups: Control, TGF-β1 (10 μM), TGF-β1 + Lok-20, TGF-β1 + Lok-40, TGF-β1 + Lok-80 μg/mL and TGF-β1 + SB431542 (5 μM). CCK8 and wound healing assays were performed. For in vivo experiments, 60 female BALB/c mice were randomly divided into 5 groups: Control, model, Lok-4.55, Lok-9.1, and DEX group. Lok was administrated by gavage during the challenge stage for 8 consecutive weeks (4.55 and 9.1 g/kg/day). We investigated airway inflammation and airway remodelling in the lungs and verified the activation status of EMT-related markers and the PI3K-Akt/HIF-1α signalling pathway. Results In vitro, Lok efficiently inhibited TGF-β1-induced BEAS-2B cell proliferation ability (cell viability 165% vs. 105%) and migration (migration areas 85% vs. 35%) without affecting their normal growth (IC50 274.2 µg/mL at 48 h). In vivo, Lok effectively protected mice from asthma, as evidenced by decreased histological damage and level of cytokines in BALF (IL-4, IL-13 and TGF-β1) by 17%–77%. Mechanistic research revealed that Lok reduced the levels of EMT-related molecules and significantly downregulated the PI3K-Akt/HIF-1α signalling pathway. Discussion and conclusions Our findings provide novel insights into the protective effect of Lok on asthma and the underlying mechanisms, providing a theoretical basis and potential treatment possibilities for this patient population.

Higher Prevalence and Severity of Eosinophilic Otitis Media in Patients with Asthma-COPD Overlap Compared with Asthma Alone

Introduction: Eosinophilic otitis media (EOM) is well-known to frequently co-exist with adult-onset asthma. Both diseases are similar type 2 inflammation and are considered to have a “one airway, one disease” relationship. Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO), characterized by airway obstruction caused by airway wall thickening (AWT), is a severe condition with a higher incidence of mortality compared to asthma alone or COPD alone. Based on the “one airway, one disease” concept, we hypothesized that the inflammatory pathophysiology of EOM differs depending on its comorbidity with ACO or with asthma alone. Methods: A total of 77 chronic rhinosinusitis (CRS) patients with asthma were enrolled in this study. The subjects were divided into 2 groups: a group with comorbid asthma alone (asthma group; 46 patients), and a group with comorbid ACO (ACO group; 31 patients). The 2 groups were compared and assessed with regard to various factors, including the patients’ clinical characteristics, prevalence rate of EOM, EOM severity, EOMs relationships with smoking and AWT, and the eosinophil and neutrophil cell counts in the middle ear effusion (MEE). Results: The ACO group included significantly more males (p < 0.05), was significantly older (p < 0.05), and showed significantly lower lung function values (FEV1 [L], FEV1 [%pred]) (p < 0.01) compared with the asthma group. The ACO group also had a significant history of smoking as shown by the Brinkman index (p < 0.01) and greater AWT as assessed by high-resolution computed tomography (p < 0.05). The EOM prevalence rate was significantly higher in the ACO group (p < 0.05), especially with increased ACO severity (p < 0.05). The EOM severity was also significantly higher in the ACO group (p < 0.05) and also correlated with the ACO severity (p < 0.05). The pretreatment ear clinical characteristics score and the average air conduction hearing level were significantly higher in the ACO group (p < 0.05). The eosinophil percentage in the MEE/otorrhea was significantly lower in the ACO group (25.3%) than in the asthma group (54.7%) (p < 0.05). Conversely, the neutrophil percentage was significantly higher in the ACO group (75.7% vs. 41.9%) (p < 0.05). Conclusions: Our findings suggest that, in CRS patients with asthma, comorbidity with ACO may be a clinical factor leading to increased EOM prevalence and severity, as well as a higher neutrophil infiltration percentage in the middle ear. Cessation of smoking and early therapeutic intervention for ACO may mitigate progression of bronchial remodeling (i.e., reduce AWT) and help reduce the prevalence and severity of EOM.

Bronchial Fibroblasts from Asthmatic Patients Display Impaired Responsiveness to Direct Current Electric Fields (dcEFs).

Accumulating evidence suggests that an important role is played by electric signals in modifying cell behaviour during developmental, regenerative and pathological processes. However, their role in asthma has not yet been addressed. Bronchial fibroblasts have recently been identified having important roles in asthma development. Therefore, we adapted an experimental approach based on the lineages of human bronchial fibroblasts (HBF) derived from non-asthmatic (NA) donors and asthmatic (AS) patients to elucidate whether their reactivity to direct current electric fields (dcEF) could participate in the asthmatic process. The efficient responsiveness of NA HBF to an electric field in the range of 2-4 V/cm was illustrated based on the perpendicular orientation of long axes of the cells to the field lines and their directional movement towards the anode. These responses were related to the activity of TGF-β signalling, as the electrotaxis and re-orientation of NA HBF polarity was impaired by the inhibitors of canonical and non-canonical TGF-β-dependent pathways. A similar tendency towards perpendicular cell-dcEF orientation was observed for AS HBF. However, their motility remained insensitive to the electric field applied at 2-4 V/cm. Collectively, these observations demonstrate the sensitivity of NA HBF to dcEF, as well as the inter-relations between this parameter and the canonical and non-canonical TGF-β pathways, and the differences between the electrotactic responses of NA and AS HBF point to the possible role of their dcEFs in desensitisation in the asthmatic process. This process may impair the physiologic behaviour of AS HBF functions, including cell motility, ECM deposition, and contractility, thus promoting bronchial wall remodelling, which is a characteristic of bronchial asthma.

Use of fractional exhaled nitric oxide as a potential predictor of bronchodilator response.

Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV1): positive (BD+) and negative (BD-). Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count (BD+, P = .03; BD-, P = .04) and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127 (95% confidence interval,-0.269 to -0.486) and 0.696 (95% confidence interval, 0.246-0.899; P = .007), respectively. Measuring FENO levels may be useful for identifying patients with BD+.

Mast Cell Tryptase Promotes Airway Remodeling by Inducing Anti-Apoptotic and Cell Growth Properties in Human Alveolar and Bronchial Epithelial Cells

Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth–death regulation.

The Role of Vitamins in the Pathogenesis of Asthma.

Vitamins play a crucial role in the proper functioning of organisms. Disturbances of their levels, seen as deficiency or excess, enhance the development of various diseases, including those of the cardiovascular, immune, or respiratory systems. The present paper aims to summarize the role of vitamins in one of the most common diseases of the respiratory system, asthma. This narrative review describes the influence of vitamins on asthma and its main symptoms such as bronchial hyperreactivity, airway inflammation, oxidative stress, and airway remodeling, as well as the correlation between vitamin intake and levels and the risk of asthma in both pre- and postnatal life.

YKL-40 as a possible marker of neutrophilic asthma.

Asthma is a heterogeneous chronic disorder of the airways, with inflammation and bronchial hyperresponsiveness as its major underlying phenomena. Asthmatics vary in terms of inflammation pattern, concomitant pathologies, and factors aggravating the course of the disease. As a result, there is a need for sensitive and specific biomarkers that could facilitate diagnosing asthma as well as phenotyping in everyday practice. Chitinases and chitinase-like proteins (CLPs) seem promising in this field. Chitinases are evolutionarily conserved hydrolases that degrade chitin. In contrast, CLPs bind chitin but do not have degrading activity. Mammalian chitinases and CLPs are produced by neutrophils, monocytes, and macrophages in response to parasitic or fungal infections. Recently, several questions have been raised about their role in chronic airway inflammation. Several studies demonstrated that overexpression of CLP YKL-40 was associated with asthma. Moreover, it correlated with exacerbation rate, therapy resistance, poor control of symptoms, and, inversely, with FEV1. YKL-40 facilitated allergen sensitization and IgE production. Its concentration was elevated in bronchoalveolar lavage fluid after an allergen challenge. It was also found to promote the proliferation of bronchial smooth muscle cells and correlate with subepithelial membrane thickness. Thus, it may be involved in bronchial remodeling. Associations between YKL-40 and particular asthma phenotypes remain unclear. Some studies showed that YKL-40 correlates with blood eosinophilia and FeNO, suggesting a role in T2-high inflammation. Quite the opposite, cluster analyses revealed the highest upregulation in severe neutrophilic asthma and obesity-associated asthma. The main limitation in the practical application of YKL-40 as a biomarker is its low specificity. High serum levels of YKL-40 were also found in COPD and several malignancies, in addition to infectious and autoimmune diseases. To conclude, the level of YKL-40 correlates with asthma and some clinical features in the whole asthmatic population. The highest levels are found in neutrophilic and obesity-related phenotypes. However, due to its low specificity, the practical application of YKL-40 remains uncertain but could be useful in phenotyping, especially when combined with other biomarkers.

Клінічні особливості персистування бронхіальної астми в дітей за альтернативного вмісту маркерів ремоделінгу в дихальних шляхах

The research of bronchial remodeling and the role of angiogenesis processes in it are currently relevant for the study of the phenotypic features of the course of bronchial asthma in children and require further study in order to develop preventive and therapeutic measures. Purpose - to optimize treatment and prevention measures for persistent bronchial asthma (pBA) in children, to determine the clinical and anamnestic features of its phenotype, taking into account the accumulation of mediators of neoangiogenesis (фактора росту ендотелію судин - VEGF, матрична металопротеїназа-9 - MMP-9) in the respiratory tract as markers of bronchial remodeling. Materials and methods. A comprehensive examination of 116 children with pBA aged from 6 to 17 years (average age 11.6±0.29 years) and disease duration of 4.9±0.38 years was conducted. Three clinical groups were formed: the Group 1 was formed by 37 children with pBA with VEGF &gt;80.0 ng/ml and MMP-9 &gt;5.2 ng/ml in the sputum supernatant; the Group 2 included 41 children with an excess of one of these markers; and the control group consisted of 38 patients with values of these biomarkers below the median (VEGF&lt;80.0 ng/ml and MMP-9 &lt;5.2 ng/ml). The main clinical characteristics of the observation groups were comparable. Results. The article shows that uncontrolled pBA (sum of points &gt;20) during the 4-year follow-up occurred most often in children of еру Group 1 and the Group 2, and indications of insufficient control of asthma indicated a probable risk of developing structural changes in the bronchi: OR - 2.23 (95% CI: 1.2-4.1), RR - 1.5 (95% CI: 1.0-2.2) and RR - 22%. The severe course of pBA was also associated with the risk of bronchial remodeling with the accumulation of angiogenesis mediators in their lumen as follows: OR - 2.2 (95% CI: 1.1-4.52), RR - 1.42 (95% CI: 1.0-2.5) and AR - 19%. Accumulation of remodeling markers in airways in patients with asthma in the Group 1 and the Group 2 is associated with a predominantly eosinophilic phenotype of the disease. At the same time, patients with a low content of markers of bronchial remodeling in sputum (control group) have better chances of achieving complete control over the symptoms of pBA compared to children with a high content (total absolute risk - 19.0%, total relative risk - 45.1%, the minimum number of patients who need to be treated to obtain a positive result - 2.2) and average (total absolute risk - 10.2%, total relative risk - 30.6%, the minimum number of patients who need to be treated to obtain a positive result - 3.2) content of angiogenesis factors in sputum. Conclusions. In patients with pBA, the accumulation of markers of bronchial remodeling in the lumen of the airways was associated with a severe uncontrolled course of asthma and worse chances of achieving disease control. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

The extract from Hyssopus cuspidatus Boriss. Prevents bronchial airway remodeling by inhibiting mouse bronchial wall thickening and hASMC proliferation and migration

Ethnopharmacological relevanceBronchial asthma, a non-communicable chronic respiratory disease, affects people of all ages. An important pathological feature of bronchial asthma is airway remodeling. Hyssopus cuspidatus Boriss. has been used to treat bronchial asthma for over 100 years in Uygur medicine. The ethanol extract of Hyssopus cuspidatus Boriss.(JAX2) can improve airway inflammation in asthma. However, the anti-asthmatic airway-remodeling effect of JAX2 is unclear. Aim of the studyThe current study investigated the anti-airway remodeling effect of JAX2 and elucidated its mechanism of action. Materials and methodsThe present study established an ovalbumin-induced mouse model of asthma and platelet-derived growth factor-BB-induced human airway smooth muscle cells (hASMCs) proliferation model, with dexamethasone (DEX) and feining tablets (FNP) designated as positive control drugs. Pathological changes in lung tissues were observed using hematoxylin and eosin staining. Interleukin (IL)-5, IL-10, IL-13, and IL-33 levels in the bronchoalveolar lavage fluid (BALF) and serum of mice were determined using enzyme-linked immunosorbent assay (ELISA). Changes in the expression and distribution of TGF-β1, p-ERK1/2, Smad2/3, and p-Smad3 in lung tissues were determined using immunohistochemistry. Western blotting (WB) was used to determine the protein levels of p-ERK1/2 in lung tissues and cells. MTS assay was used to determine the effects of JAX2 on cell proliferation. IL-5, IL-10, IL-13, MMP-2, and MMP-9 levels in the cell supernatant were determined using ELISA. HASMCs migration was observed using the scratch and transwell methods. The effect of JAX2 on the hASMCs cycle was determined using flow cytometry. ResultsJAX2 significantly improved the pathological status of lung tissues in asthmatic mice. It could also significantly reduce IL-5, IL-13, and IL-33 levels in the BALF and serum of asthmatic mice in a dose-dependent manner and significantly increase IL-10 levels. TGF-β1, p-ERK1/2, Smad2/3, and p-Smad3 expression in lung tissues were decreased in a dose-dependent manner. The protein level of p-ERK1/2 in lung tissues was also reduced. JAX2 could significantly inhibit the proliferation and migration of PDGF-BB-induced hASMCs. IL-5, IL-13, MMP-9, and MMP-2 levels decreased significantly, and IL-10 levels increased significantly in a dose-dependent manner in the cell supernatant. JAX2 could block hASMCs in the G0/G1 phase, thereby inhibiting cell proliferation. p-ERK1/2 protein levels were found to decrease in a dose-dependent manner. ConclusionsJAX2 significantly inhibits airway remodeling in asthma. Its mechanism of action may be inhibiting the proliferation and migration of hASMCs, releasing inflammatory factors and metalloproteinases, activating the ERK1/2 signal pathway, and promoting the secretion of anti-inflammatory factors.

Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma.

Senescent cells can drive age-related tissue dysfunction partially via a senescence-associated secretory phenotype (SASP) involving proinflammatory and profibrotic factors. Cellular senescence has been associated with a structural and functional decline during normal lung aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Asthma in the elderly (AIE) represents a major healthcare burden. AIE is associated with bronchial airway hyperresponsiveness and remodeling, which involves increased cell proliferation and higher rates of fibrosis, and resistant to standard therapy. Airway smooth muscle (ASM) cells play a major role in asthma such as remodeling via modulation of inflammation and the extracellular matrix (ECM) environment. Whether senescent ASM cells accumulate in AIE and contribute to airway structural or functional changes is unknown. Lung tissues from elderly persons with asthma showed greater airway fibrosis compared with age-matched elderly persons with nonasthma and young age controls. Lung tissue or isolated ASM cells from elderly persons with asthma showed increased expression of multiple senescent markers including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP components. Senescence and SASP components were also increased with aging per se. These data highlight the presence of cellular senescence in AIE that may contribute to airway remodeling.