Fibrosis Airway Research Articles

Correlations between blood vessel distribution, lung function and structural change in idiopathic pulmonary fibrosis.

Correlations between the image analysis of CT scan, lung function and quality of life in patients with idiopathic pulmonary fibrosis (IPF) remain unclear. This study aimed to investigate the impacts of pulmonary blood-vessel distribution and the extent of fibrosis on the lung function and quality of life of patients with IPF. Patients were enrolled in an IPF registry and had completed pulmonary function tests, chest HRCT, St. George Respiratory Questionnaire (SGRQ) and echocardiography. Pulmonary blood-vessel distribution, specific image-derived airway volume (siVaw) and fibrosis extent (siVfib) were quantitatively calculated by functional respiratory imaging on HRCT. The study subjects were categorized into DLco <40% pred. (n = 40) and DLco ≥40% pred. (n = 19) groups. Patients with DLco <40% pred. had significantly higher scores of SGRQ, composite physiologic index (CPI), exercise oxygen desaturation (∆SpO2), siVaw, lower FVC% pred. and 6-minute walking distance% pred. The proportion of small blood vessels in the upper lobes (BV5PR-UL) was significantly correlated with CPI, DLco % Pred., FVC% pred., SGRQ and ∆SpO2. Only BV5PR-UL had a significant impact on all indices but not BV5PR in the lower lobes (BV5PR-LL). siVfib was significantly negatively correlated with BV5PR-UL, DLco% pred. and FVC% pred., as well as positively correlated with CPI, ∆SpO2 and siVaw. BV5PR-UL and siVfib had significant correlations with lung function and may become important indicators to assess the severity of IPF and the impact on quality of life.

Evaluating serum periostin and YKL-40 as biomarkers for airway remodeling and hyperresponsiveness in pediatric asthma

BackgroundPeriostin and human chitinase-3-like protein 1 (YKL-40) have been suggested to be involved in the development of airway fibrosis and remodeling. This study aimed to investigate the relationship between serum periostin levels and airway hyperresponsiveness (AHR) and between serum YKL-40 levels and AHR in children with asthma, comparing periostin as a marker for Th2 inflammation and atopy with YKL-40. MethodsThe study involved children aged 6–15 years, comprising 75 with asthma and 29 healthy controls. We measured serum periostin and YKL-40 levels and performed exercise bronchial provocation tests, methacholine challenge tests, spirometry, and FeNO measurements. ResultsCompared to the healthy controls, asthmatic children exhibited significantly elevated levels of periostin (86.7 [71.0–104.0] vs 68.3 [56.0–82.0] ng/mL; P = 0.006) and YKL-40 (29.0 [15.0–39.5] vs 27.7 [14.0–34.1] ng/mL; P = 0.034). The subgroup analysis revealed that periostin levels were significantly higher in the atopic asthma group than in the healthy controls (P = 0.003), but not in the non-atopic asthma group. YKL-40 levels were elevated in both the atopic and non-atopic asthma groups compared to healthy controls (P = 0.012 and P = 0.001, respectively). Serum periostin levels were significantly correlated with the postexerceise maximum percentage decrease in forced expiratory volume (FEV1), as well as with fractional exhaled nitric oxide (FeNO) and blood eosinophil counts, but showed no significant correlation with overall lung function. Conversely, serum YKL-40 levels were significantly linked to the Z score of FEV1 and AHR to methacholine but not with AHR to exercise or FeNO or blood eosinophil count. ConclusionsPeriostin is linked to atopic asthma and correlates with exercise-induced bronchoconstriction, FeNO, and eosinophil counts, highlighting its role in Th2 inflammation. YKL-40 is a general asthma marker, indicating airway remodeling. These findings suggest that targeting these markers can improve personalized treatment strategies for pediatric asthma.

PD-L1 Acts Independently of PD-1 as a Marker of Pathologic Fibroblasts in Laryngotracheal Stenosis.

Laryngotracheal stenosis (LTS) describes fibrotic airway obstruction that is life-threatening without treatment. Targeted therapies are needed as an adjunct to surgical management. We have previously observed the upregulation of immune checkpoint programmed cell death (PD)-1 and its ligand, PD-L1, in patients with LTS. This study aims to determine whether PD-1 and PD-L1 play a role in the pathophysiology of LTS. Basic science. Laboratory. Fibroblasts derived from the subglottic scar of 5 iSGS patients were cultured ex vivo with transforming growth factor β (TGFβ), PD-L1 agonist (PD-1), and PD-L1 blockade (anti-PD-L1). PD-L1, TGFβ receptor II (TGFβRII), and Collagen-1 expression were quantified by flow cytometry. A validated chemomechanical injury model of subglottic stenosis was applied in PD-1 knockout and wild-type (WT) mice, and subglottic thickening was assessed by histologic analysis. TGFβ significantly increased the expression of PD-L1 and Collagen-1 in human airway scar fibroblasts (P < .05). PD-1 knockout mice demonstrated no significant difference in subglottic airway fibrosis compared to WT mice. Ex vivo PD-L1 modulation had no impact on fibroblast Collagen-1 expression. PD-L1 high-intensity fibroblasts expressed greater Collagen-1 and TGFβRII compared to PD-L1 low-intensity fibroblasts. PD-1 knockout does not protect mice from the development of laryngotracheal fibrosis. However, its ligand, PD-L1 is highly expressed on pathologic fibroblasts unique to scar, characterized by high Collagen-1 and TGFβRII expression. PD-L1 is also upregulated in conjunction with Collagen-1 by TGFβ stimulation. PD-L1 may act independently of PD-1 to sensitize fibroblasts to TGFβ, suggesting direct targeting of PD-L1 may have therapeutic potential in LTS.

The Role of Aspergillus Antibody Detection in Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic lung disorder characterized by an exaggerated immune response to fungal allergens, particularly from Aspergillus fumigatus. ABPA leads to excessive mucus production and impaired mucociliary clearance. When A. fumigatus conidia are inhaled, they germinate, release exoproteases and other substances that further impede mucociliary clearance, and activate the immune response. The immune response is known by an exaggerated Th2 response to Aspergillus antigens, leading to production of IgE antibodies, eosinophilic infiltration of the lungs, and the formation of immune complexes. These immune complexes can deposit in the lung tissue, leading to airway inflammation, bronchiectasis, and fibrosis. This disease mainly occurs in individuals diagnosed with bronchial asthma and cystic fibrosis. Increased levels of A. fumigatus total IgE and specific IgE, IgG, and IgA antibodies, play a role in diagnosing patients with ABPA.

Inhibition of long non-coding RNA NEAT1 suppressed the epithelial mesenchymal transition through the miR-204-5p/Six1 axis in asthma.

Asthma, a prevalent chronic respiratory condition, is characterized by airway remodeling. Long non-coding RNA (lncRNA) NEAT1 has been demonstrated to participate in airway fibrosis. Furthermore, the miR-204-5p/Six1 axis significantly influences epithelial mesenchymal transition (EMT). However, the function of NEAT1/miR-204-5p/Six1 in asthmatic EMT remains unclear. This study intends to elucidate the function of NEAT1/miR-204-5p/Six1 axis in asthmatic EMT. TGF-β1 was used to induce the EMT model in BEAS-2B cells. Immunofluorescence and western blot were executed to verify the establishment of the EMT model. NEAT1, miR-204-5p, and Six1 expression levels were evaluated using RT-qPCR. The role of NEAT1 in EMT in vitro was explored by CCK8 assays and flow cytometry. The luciferase reporter assay was performed to validate the interaction between NEAT1 and miR-204-5p/Six1. NEAT1 expression was increased during EMT. Functional experiments showed that the knockdown of NEAT1 suppressed cell proliferation and promoted cell apoptosis in vitro. Furthermore, inhibition of NEAT1 decreased the expression of N-cadherin, vimentin, and α-SMA and increased the expression of E-cadherin. Mechanistically, NEAT1 was identified as a sponge for miR-204-5p, and Six1 was found to be a direct target of miR-204-5p. Down-regulation of NEAT1 reduced the Six1 expression via targeting miR-204-5p to inhibit the process of EMT in asthma. This study may provide new insight to reveal the underlying mechanisms of asthma.

3-Deazaneplanocin A (DZNep): A Drug That Deserves a Second Look.

The emerging data compiled during the past five years on 3-deazaneplanocin (DZNep) provide compelling evidence to reevaluate this drug as a better alternative over the specific catalytic inhibitors of histone methyl transferases (HTMs). The indirect mechanism of DZNep via inhibition of AdoHcy-ase, once considered a liability due to possible side effects, has now shown to be rather beneficial as additional pathways targeted by DZNep are important contributors to its superior anticancer properties. Furthermore, DZNep has demonstrated the ability to induce proteasomal degradation of its target and reduce toxicity in combination with well-established antitumor therapies in animal models. In addition, DZNep has shown important effects in suppressing fibrosis and inflammation in liver, kidney, peritoneum, and airways. Finally, inhibition of mRNA m6A methylation by DZNep suppresses the synthesis of the viral genome in SARS-Cov-2 infection and promises to have important therapeutic value when combined with its potent antiviral efficacy and anti-inflammatory effects.

Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection

Staphylococcus aureus is a pulmonary pathogen associated with substantial human morbidity and mortality. As vaccines targeting virulence determinants have failed to be protective in humans, other factors are likely involved in pathogenesis. Here we analysed transcriptomic responses of human clinical isolates of S. aureus from initial and chronic infections. We observed upregulated collagenase and proline transporter gene expression in chronic infection isolates. Metabolomics of bronchiolar lavage fluid and fibroblast infection, growth assays and analysis of bacterial mutant strains showed that airway fibroblasts produce collagen during S. aureus infection. Host-adapted bacteria upregulate collagenase, which degrades collagen and releases proline. S. aureus then imports proline, which fuels oxidative metabolism via the tricarboxylic acid cycle. Proline metabolism provides host-adapted S. aureus with a metabolic benefit enabling out-competition of non-adapted strains. These data suggest that clinical settings characterized by airway repair processes and fibrosis provide a milieu that promotes S. aureus adaptation and supports infection.

Long-term outcomes of surgical reconstruction for post-tuberculosis tracheobronchial stenosis: a 7-year follow-up in a tuberculosis-endemic region.

Surgical reconstruction is often necessary for severe tracheobronchial stenosis resulting from tuberculosis (TB). However, the long-term efficacy of this approach remains unclear. This study investigated the safety and long-term outcomes of surgery for severe post-TB tracheobronchial stenosis. We conducted a retrospective study of 48 patients with severe post-TB tracheobronchial stenosis who underwent surgical reconstruction between 2015 and 2018 in a TB-endemic region. Pre- and postoperative evaluations included Karnofsky performance status, modified Medical Research Council (mMRC) dyspnea scale, spirometry, chest computed tomography (CT) scan, and bronchoscopy. The primary outcome was intervention-requiring restenosis over the long term. The mean patient age was 30.6±9.9 years, with 91.7% females. Airway fibrosis was the predominant lesion (93.8%), affecting the bronchi (93.8%) and trachea (6.2%). All the patients underwent resection and anastomosis, and 56.2% required lobectomy. Postoperative complications occurred in 13 patients (27.1%), with prolonged air leaks being the most prevalent (12.5%). All complications resolved with conservative management. Significant improvements in performance status, dyspnea, and lung function were observed postoperatively and sustained for over 5 years. Within a median follow-up of 69 months, five cases of intervention-requiring restenosis occurred within the first year. The freedom from restenosis rate was 90% from 1 year onwards. Surgical reconstruction is safe and effective in treating severe post-TB tracheobronchial stenosis. Larger studies are required to validate these findings.

Lung microbiota participated in fibrous microplastics (MPs) aggravating OVA-induced asthma disease in mice

Environmental pollution is one of the risk factors for asthma. Currently, whether micro-plastics could aggravate asthma, is still unclear. In the air, fibrous MPs are the predominant shape. Since fibrous micro-plastics are reported to be detected in the lower respiratory tract and other body parts, the relationship of fibrous MP and asthma, as well as the potential mechanism is not well investigated. In this study, we produced fibrous MPs, whose lengths and widths were in accordance with the natural environment, and further, investigated the potential adverse effect of which on the asthma in a OVA (ovalbumin)-induced mice model, aiming at exploring the true life hazard of MP to the respiratory system. Following nasal exposure to fibrous MPs, the airway inflammation, mucus hypersecretion and fibrosis were aggravated in asthmatic mice. Fibrous MPs exposure also significantly increased the levels of total IgE, and, cardinal Th2 and Th1 pro-inflammatory cytokines participated in the etiopathogenesis of allergic airway inflammation. In addition, MP fibers exposure induced lung epithelial cells apoptosis, disruption of epithelial barrier integrity and activation of NLRP3 related signaling pathways. Moreover, fibrous MPs significantly altered the bacterial composition at the genus level. Compared to the control group, the relative abundance of Escherichia-Shigella and Uncultured were decreased to 4.47% and 0.15% in OVA group, while Blautia and Prevotella were elevated to 4.96% and 2.94%. For the OVA + MPs group, the relative abundance of Blautia and Uncultured were decreased to 2.27% and 0.006%, while Prevotella was increased to 3.05%. Our study highlights the detrimental effect of fibrous MPs on asthmatic population and facilitates an indication of the latent mechanisms of fibrous MPs induced airway pathology.

The adverse effects of vaping in young people

Vapes or e-cigarettes are battery operated devices that heat a liquid until it becomes a vapour, which is inhaled. Typically, e-liquids contain nicotine, different flavourings, and propylene glycol. Vaping devices are either disposable vapes or rechargeable. Vapes were initially developed as stop smoking aid but they have now become a recreational product popular among teenagers.Vaping has increased at an alarming rate among teenagers and young adults in Ireland. The European Schools Project for Alcohol and Other Drugs (ESPAD) survey 2019 showed that almost 4 in 10 Irish 16-year-olds had tried vaping and 15 % currently use them. More worrying is the dramatic rise in the use of disposable vapes in recent years. An Action on Smoking and Health (ASH) UK survey data revealed a 9-fold increase from 2021 to 2023 in their use (7.7 % to 69 %) among 11–17-year-old vapers.A combination of clever marketing by vaping companies, a strong social media presence, attractive flavours and easy accessibility has contributed to the increasing use of vapes by young people.Exposure of children and adolescents to nicotine in vaping solutions can lead to long-term negative impacts on brain development, as well as addiction. Many teenagers who vape experience poor concentration, anxiety, mood disorders and sleep disturbance. A paper from NEJM in 2022 reported a case series where chronic vaping resulted in small airway fibrosis of the airways. A systematic review conducted in 2021 concluded that teenager vapers were three to five times more likely to take up tobacco smoking when compared with non-vapers.Strong legislation is required to ban the sale of disposable vapes to teenagers along with controls on marketing online. Healthcare Professionals should ask and counsel their patients about vaping. Increased public awareness and education for Health care professionals on teenage vaping needs to be addressed.Vaping has become a global public health issue that must be addressed urgently.

Combination Therapy Blocking TNF Superfamily Members 14 and 15 Reverses Pulmonary Fibrosis

Abstract Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis in the clinic and there is an urgent unmet need to develop novel anti-fibrotic drugs capable of reversing disease. Our lab has identified two novel mediators of pulmonary fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Here, we show LIGHT and TL1A receptor are both significantly elevated in patient pulmonary fibrosis biopsies as compared to healthy control lungs. Using gain of function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another and that these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits TGFb-driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic and inflammatory signatures, including redundant, additive, and synergistic profibrotic activities. Importantly, using antagonistic reagents to neutralize both LIGHT and TL1A signaling in combination post-disease onset, we observe a significant decrease in collagen deposition and smooth muscle hypertrophy in a bleomycin model of pulmonary fibrosis as opposed to respective monotherapies. The implication of this work highlights a therapeutic need of concomitantly targeting LIGHT and TL1A to treat pulmonary fibrosis disorders in humans.

Spectrum of chronic lung allograft dysfunction pathology in human lung transplantation

BackgroundLong-term survival after lung transplantation (LTx) remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), with possible overlap. We aimed to detail and quantify pathological features of these CLAD sub-types. MethodsPeripheral and central paraffin-embedded explanted lung samples were obtained from 20 consecutive patients undergoing a second LTx for CLAD, from 3 lobes. Thirteen lung samples, collected from non-transplant lobectomies or donor lungs, were used as controls. Blinded semi-quantitative grading was performed to assess airway fibrotic changes, parenchymal and pleural fibrosis, as well as epithelial and vascular abnormalities. ResultsCLAD lung samples had higher scores for all airway- and lung-related parameters compared to controls. There was a notable overlap in pathological scores between BOS and RAS, with a wide range of scores in both conditions. Parenchymal and vascular fibrosis scores were significantly higher in RAS compared to BOS (p=0.003 for both). We observed a significant positive correlation between the degree of inflammation around each airway, the severity of epithelial changes and airway fibrosis. Immunofluorescence staining demonstrated a trend towards a lower frequency of club cells in CLAD, and a higher frequency of apoptotic club cells in BOS samples (p=0.01). ConclusionsCLAD is a spectrum of airway, parenchymal, and pleural fibrosis, as well as epithelial, vascular, and inflammatory pathological changes, where BOS and RAS overlap significantly. Our semi-quantitative grading score showed a generally high inter-reader reliability and may be useful for future CLAD pathological assessments.

Statement of Retraction: MicroRNA-335-5p alleviates inflammatory response, airway fibrosis, and autophagy in childhood asthma through targeted regulation of autophagy related 5

Statement of Retraction: MicroRNA-335-5p alleviates inflammatory response, airway fibrosis, and autophagy in childhood asthma through targeted regulation of autophagy related 5

Recombinant Slit2 attenuates tracheal fibroblast activation in benign central airway obstruction by inhibiting the TGF-β1/Smad3 signaling pathway

Airway fibrosis is among the pathological manifestations of benign central airway obstruction noted in the absence of effective treatments and requires new drug targets to be developed. Slit guidance ligand 2–roundabout guidance receptor 1 (Slit2–Robo1) is involved in fibrosis and organ development. However, its significance in airway fibrosis has not yet been reported. The study explored how the recombinant protein Slit2 functions in transforming growth factor-β1 (TGF-β1)-mediated airway fibrosis in vivo and in vitro. In this study, Slit2 expression initially increased in the tracheal granulation tissues of patients with tracheobronchial stenosis but decreased in the fibrotic tissue. In primary rat tracheal fibroblasts (RTFs), recombinant Slit2 inhibited the expression of extracellular matrices such as Timp1, α-SMA, and COL1A2, whereas recombinant TGF-β1 promoted the expression of Robo1, α-SMA, and COL1A2. Slit2 and TGF-β1 played a mutual inhibitory role in RTFs. Slit2 supplementation and Robo1 downregulation inhibited excessive extracellular matrix (ECM) deposition induced by TGF-β1 in RTFs via the TGF-β1/Smad3 pathway. Ultimately, exogenous Slit2 and Robo1 knockdown-mediated attenuation of airway fibrosis were validated in a trauma-induced rat airway obstruction model. These findings demonstrate that recombinant Slit2 alleviated pathologic tracheobronchial healing by attenuating excessive ECM deposition. Slit2–Robo1 is an attractive target for further exploring the mechanisms and treatment of benign central airway obstruction.

Allergic fungal airway diseases: analysis of data in asthma patient register

Introduction. Allergy to microscopic fungi (micromycetes), which can colonize the respiratory tract, is associated with an eosinophilic endotype of inflammation and severe disease course. Among the hallmarks of fungal allergy, experts identify fixed airways obstruction, bronchiectasis, and fibrosis. Currently, there has been proposed the term “allergic fungal airways disease” (AFAD), which combines various clinical phenotypes, which pathogenesis is based on IgE-mediated allergic reaction against fungal spores colonizing the respiratory tract. According to this approach, the AFAD group includes severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis (ABPA). A promising direction in AFAD treatment implies the use of genetically engineered biological drugs against T-2 inflammation. The aim of the study was to evaluate the prevalence ofAspergillusspp. sensitization and allergic bronchopulmonaryAspergillosis in patients with asthma.&#x0D; Materials and methods. A retrospective single-center registry study was conducted in the I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russian Federation. The study included 523 patients with asthma of varying severity. The level of total and specific blood serum IgE against aeroallergens, includingAspergillusspp., was analyzed by enzyme immunoassay. The diagnosis of asthma was established in accordance with the recommendations of the GINA working group and the Clinical recommendations of the Ministry of Health of the Russian Federation, fungal sensitization and ABPA — in accordance with the recommendations of the ISHAM working group.Results. During the examination of patients with asthma, sensitization toAspergillusspp. recorded in 16.6% cases, severe asthma with sensitization toAspergillusspp. — in 7.4%, ABPA — in 6.1%. In patients with allergic asthma, the prevalence of sensitization toAspergillusspp. was 22%, severe asthma with sensitization toAspergillusspp. — 10.1%, ABLA — 8.1%. Among patients with ABPA, females (64%) aged 40 years and older prevailed. The major clinical manifestations of ABPA were presented as cough (96%) and shortness of breath (76%), CT scan radiological changes were in a form of bronchiectasis (72%).&#x0D; Conclusion. A high prevalence of sensitization toAspergillusspp. in patients with asthma was found. It is necessary to includeAspergillusspp. into the list of tested allergens while examining patients with chronic lung diseases for timely detection of AFAD and prescription of proper anti-inflammatory or antimycotic therapy.

MiR-326-mediated overexpression of NFIB offsets TGF-β induced epithelial to mesenchymal transition and reverses lung fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a progressively fatal and incurable disease characterized by the loss of alveolar structures, increased epithelial-mesenchymal transition (EMT), and aberrant tissue repair. In this study, we investigated the role of Nuclear Factor I-B (NFIB), a transcription factor critical for lung development and maturation, in IPF. Using both human lung tissue samples from patients with IPF, and a mouse model of lung fibrosis induced by bleomycin, we showed that there was a significant reduction of NFIB both in the lungs of patients and mice with IPF. Furthermore, our in vitro experiments using cultured human lung cells demonstrated that the loss of NFIB was associated with the induction of EMT by transforming growth factor beta (TGF-β). Knockdown of NFIB promoted EMT, while overexpression of NFIB suppressed EMT and attenuated the severity of bleomycin-induced lung fibrosis in mice. Mechanistically, we identified post-translational regulation of NFIB by miR-326, a miRNA with anti-fibrotic effects that is diminished in IPF. Specifically, we showed that miR-326 stabilized and increased the expression of NFIB through its 3'UTR target sites for Human antigen R (HuR). Moreover, treatment of mice with either NFIB plasmid or miR-326 reversed airway collagen deposition and fibrosis. In conclusion, our study emphasizes the critical role of NFIB in lung development and maturation, and its reduction in IPF leading to EMT and loss of alveolar structures. Our study highlights the potential of miR-326 as a therapeutic intervention for IPF. The schema shows the role of NFIB in maintaining the normal epithelial cell characteristics in the lungs and how its reduction leads to a shift towards mesenchymal cell-like features and pulmonary fibrosis. A In normal lungs, NFIB is expressed abundantly in the epithelial cells, which helpsin maintaining their shape, cell polarity and adhesion molecules. However, when the lungs are exposed to factors that induce pulmonary fibrosis, such as bleomycin, or TGF-β, the epithelial cells undergo epithelial to mesenchymal transition (EMT), which leads to a decrease in NFIB. B The mesenchymal cells that arise from EMT appear as spindle-shaped with loss of cell junctions, increased cell migration, loss of polarity and expression of markers associated with mesenchymal cells/fibroblasts. C We designed a therapeutic approach that involves exogenous administration of NFIB in the form of overexpression plasmid or microRNA-326. This therapeutic approach decreases the mesenchymal cell phenotype and restores the epithelial cell phenotype, thus preventing the development or progression of pulmonary fibrosis.

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.

Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade

BackgroundSevere asthmatics can present with eosinophilic type 2 (T2), neutrophilic or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common beta (βc) receptor signals for three cytokines GM-CSF, IL-5 and IL-3, that collectively mediate T2 and neutrophilic inflammation. ObjectivesTo determine the pathogenesis of βc receptor mediated inflammation and remodeling in severe asthma, and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease. Methodsβc gene expression was analysed in bronchial biopsies from mild/moderate and severe asthmatics. House dust mite extract (HDM) and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analysed by RNA-sequencing. The monoclonal antibody CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling. Resultsβc gene expression was increased in severe asthmatics. CSL311 potently reduced lung neutrophils, eosinophils and interstitial macrophages, and improved airway pathology and lung function in the acute steroid resistant HDM model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalised the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. Conclusionsβc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

Angiotensin-(1–7) suppresses airway inflammation and airway remodeling via inhibiting ATG5 in allergic asthma

BackgroundAngiotensin (Ang)-(1–7) can reduce airway inflammation and airway remodeling in allergic asthma. Autophagy-related 5 (ATG5) has attracted wide attentions in asthma. However, the effects of Ang-(1–7) on ATG5-mediated autophagy in allergic asthma are unclear.MethodsIn this study, human bronchial epithelial cell (BEAS-2B) and human bronchial smooth muscle cell (HBSMC) were treated with different dose of Ang-(1–7) to observe changes of cell viability. Changes of ATG5 protein expression were measured in 10 ng/mL of interleukin (IL)-13-treated cells. Transfection of ATG5 small interference RNA (siRNA) or ATG5 cDNA in cells was used to analyze the effects of ATG5 on secretion of cytokines in the IL-13-treated cells. The effects of Ang-(1–7) were compared to the effects of ATG5 siRNA transfection or ATG5 cDNA transfection in the IL-13-treated cells. In wild-type (WT) mice and ATG5 knockout (ATG5−/−) mice, ovalbumin (OVA)-induced airway inflammation, fibrosis and autophagy were observed. In the OVA-induced WT mice, Ang-(1–7) treatment was performed to observe its effects on airway inflammation, fibrosis and autophagy.ResultsThe results showed that ATG5 protein level was decreased with Ang-(1–7) dose administration in the IL-13-treated BEAS-2B and IL13-treated HBSMC. Ang-(1–7) played similar results to ATG5 siRNA that it suppressed the secretion of IL-25 and IL-13 in the IL-13-treated BEAS-2B cells, and inhibited the expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (α-SMA) protein in the IL-13-treated HBSMC cells. ATG5 cDNA treatment significantly increased the secretion of IL-25 and IL-13 and expression of TGF-β1 and α-SMA protein in IL-13-treated cells. Ang-(1–7) treatment suppressed the effects of ATG5 cDNA in the IL-13-treated cells. In OVA-induced WT mice, Ang-(1–7) treatment suppressed airway inflammation, remodeling and autophagy. ATG5 knockout also suppressed the airway inflammation, remodeling and autophagy.ConclusionsAng-(1–7) treatment suppressed airway inflammation and remodeling in allergic asthma through inhibiting ATG5, providing an underlying mechanism of Ang-(1–7) for allergic asthma treatment.

Effects of chitinase-1 inhibitor in obesity-induced and -aggravated asthma in a murine model

AimsDespite recent investigations on the role of chitinase in asthma, its role in obesity-induced asthma has not been evaluated. Therefore, we investigated the roles of chitin, chitinase-1, and a chitinase-1 inhibitor (compound X, CPX) in a murine model. Main methodsWe assigned C57BL/6 mice to the ovalbumin (OVA) model or obesity model group. In the OVA model, mice received intraperitoneal OVA twice within a 2-week interval and intranasal OVA for 3 consecutive days. Additionally, chitin was intranasally administered for 3 consecutive days, and CPX was intraperitoneally injected three times over 5 days. In the obesity model, a high-fat diet (HFD) was maintained for 13 weeks, and CPX was intraperitoneally injected eight times over 4 weeks. Key findingsIn the OVA model, chitin aggravated OVA-induced airway hyper-responsiveness (AHR), increased bronchoalveolar lavage fluid (BALF) cell proliferation, increased fibrosis, and increased the levels of various inflammatory cytokines (including chitinase-1, TGF-β, TNF-α, IL-1 β, IL-6, IL-4, and IL-13). CPX treatment significantly ameliorated these effects. In the obesity model, HFD significantly increased AHR, BALF cell proliferation, fibrosis, and the levels of various inflammatory cytokines. Particularly, compared to the control group, the mRNA expression of chitinase, chitinase-like molecules, and other molecules associated with inflammation and the immune system was significantly upregulated in the HFD and HFD/OVA groups. Immunofluorescence analysis also showed increased chitinase-1 expression in these groups. CPX significantly ameliorated all these effects in this model. SignificanceThis study showed that CPX can be an effective therapeutic agent in asthma, especially, obesity-induced and -aggravated asthma to protect against the progression to airway remodeling and fibrosis.