Airway Remolding Research Articles

Promising Therapeutic Functions of Bone Marrow Mesenchymal Stem Cells Derived-Exosome in Asthma.

Asthma is a chronic inflammatory disturbance of the airways in which many cells and cellular elements are involved. Wheezing, breathlessness, chest tightness, and coughing, especially at night or in the early morning, are typical symptoms of asthma. At present, inhaled corticosteroid (ICS) and long-acting β-agonists (LABAs) are standard treatments for regular management. Oral corticosteroids (OCSs) were recommended for controlling asthma exacerbation but only for a short-term treatment because of the side effects on organs. Biologic therapies have achieved exciting and notable effects in clinical treatment but are not applicable for all phenotypes of asthma. At present, some new approaches are under exploration to lessen side effects and improve curative effects. Studies have revealed that bone marrow mesenchymal stem cells (BMMSCs) hold various curative effects in asthma and may benefit in the long term with high safety. Extracellular vesicles (EVs) enriched in body fluid were characterized as subcomponents of extracellular vesicles and delivered carriers combined with genetic messages in vivo. The therapeutic potential of exosomes has become a research hotspot in many diseases. BMMSC-derived exosomes were considered as the dominant part of BMMSCs in cell-to-cell communications and playing curative effects. Points also hold that BMMSC-Exo could interfere with airway inflammation and airway remolding in asthma via modulating the immune response, regulating gene expression, adjusting the phenotype of macrophage, etc. However, BMMSC-Exo still lacked more clinical trials for evaluating the effects on asthma, and the technology of extraction and purification still needs to be improved for wide use. This review aims to draw the relationship among asthma, BMMSC, and exosome, which may provide innovate ideas for treatment of asthma, and arouse attention about the curative potential of BMMSC-Exo.

Interleukin‑27 ameliorates allergic asthma by alleviating the lung Th2 inflammatory environment.

Interleukin (IL)-27 can inhibit the differentiation of Th2 cells and plays a role in the development of asthma. However, whether the therapeutic administration of IL-27 in a mouse model of asthma can inhibit allergic responses remains a matter of debate. Additionally, the mechanisms through which IL-27 ameliorates inflammatory responses in asthma are not yet fully understood. Thus, the aim of the present study was to examine the effects of IL-27 on asthma using a mouse model and to elucidate the underlying mechanisms. For this purpose, mice received an intranasal administration of IL-27 and the total and differential cell counts, levels of cytokines and type 1 regulatory T (Tr1) cells in the lungs were detected. The protein and mRNA levels of signal transducer and activator of transcription (STAT)1 and STAT3 were analyzed and airway remodeling was assessed. The results indicated that IL-27 did not ameliorate airway inflammation, airway hyperresponsiveness, and airway remolding when administrated therapeutically. Preventatively, the administration of IL-27 decreased the concentrations of Th2 cytokines and increased the number of Tr1 cells. The protein and mRNA levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrate that the prophylactic administration of IL-27 ameliorates asthma by alleviating the lung Th2 inflammatory environment through the restoration of both the STAT1 and STAT3 pathways. IL-27 may thus prove to be useful as a novel agent for the prevention of asthma.

Glycyrrhizic acid restrains airway inflammation and remodeling in asthma via the TGF-β1/Smad signaling pathway.

The anti-inflammatory effects of glycyrrhizic acid (GA) against asthma have previously been reported; however, the underlying molecular mechanism of GA in asthma has not yet been elucidated. Thus, the present study aimed to determine the function and potential molecular mechanism of GA for modulating the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway in asthma-associated airway inflammation and remodeling. In order to study the mechanism of GA on airway inflammation and airway remodeling in asthmatic mice, a mouse model of chronic asthma was constructed. A total of 50 female mice were randomly assigned into five groups (10 mice/group), as follows: Blank group, asthma group, GA group, dexamethasone group and GA + TGF-β1 group. Hematoxylin and eosin, and Masson staining were performed to assess the airway inflammation and remodeling in mice with ovalbumin (OVA)-induced asthma. The serum levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in mice were assessed via the enzyme-linked immunosorbent assay. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the levels of TGF-β1 and Smads in lung tissues of each group of mice. The results demonstrated that GA and dexamethasone treatment mitigated airway inflammation, inflammatory cell infiltration and airway remolding, with a concomitant decrease in the expression levels of IL-4, IL-5, IL-13 and IL-17, in mice with OVA-induced asthma. In addition, the levels of TGF-β1 and Smad2 notably decreased, while Smad7 expression increased in the GA and dexamethasone groups compared with the asthma group. Furthermore, histopathological morphometry exhibited significantly elevated inflammatory cell infiltration, airway wall and smooth muscle, collagen secretion and inflammatory cytokines in the serum of mice in the GA + TGF-β1 group compared with the GA group. Taken together, the results of the present study suggest that GA ameliorates airway inflammation and remodeling via the TGF-β1/Smad signaling pathway in mice with asthma.

Erratum to "Tetrandrine Ameliorates Airway Remodeling of Chronic Asthma by Interfering TGF-β1/Nrf-2/HO-1 Signaling Pathway-Mediated Oxidative Stress".

[This corrects the article DOI: 10.1155/2019/7930396.].

Tetrandrine Ameliorates Airway Remodeling of Chronic Asthma by Interfering TGF-β1/Nrf-2/HO-1 Signaling Pathway-Mediated Oxidative Stress.

Background Imbalanced oxidative stress and antioxidant defense are involved in airway remodeling in asthma. It has been demonstrated that Tetrandrine has a potent role in antioxidant defense in rheumatoid arthritis and hypertension. However, the correlation between Tetrandrine and oxidative stress in asthma is utterly blurry. This study aimed to investigate the role of Tetrandrine on oxidative stress-mediated airway remolding. Materials and Methods Chronic asthma was established by ovalbumin (OVA) administration in male Wistar rats. Histopathology was determined by HE staining. Immunofluorescence was employed to detect the expression of α-SMA and Nrf-2. Level of oxidative stress and matrix metalloproteinases were examined by ELISA kits. Cell viability and cell cycle of primary airway smooth muscle cells (ASMCs) were evaluated by CCK8 and flow cytometry, respectively. Signal molecules were detected using western blot. Results Tetrandrine effectively impairs OVA-induced airway inflammatory and airway remodeling by inhibiting the expression of CysLT1 and CysLTR1. The increase of oxidative stress and subsequent enhancement of MMP9 and TGF-β1 expression were rescued by the administration of Tetrandrine in the rat model of asthma. In in vitro experiments, Tetrandrine markedly suppressed TGF-β1-evoked cell viability and cell cycle promotion of ASMCs in a dose-dependent manner. Furthermore, Tetrandrine promoted Nrf-2 nuclear transcription and activated its downstream HO-1 in vivo and in vitro. Conclusion Tetrandrine attenuates airway inflammatory and airway remodeling in rat model of asthma and TGF-β1-induced cell proliferation of ASMCs by regulating oxidative stress in primary ASMCs, suggesting that Tetrandrine possibly is an effective candidate therapy for asthma.

Curcumin Attenuates Airway Inflammation and Airway Remolding by Inhibiting NF-κB Signaling and COX-2 in Cigarette Smoke-Induced COPD Mice.

The purpose of this study is to evaluate the therapeutic effects of curcumin on airway inflammation using LPS and cigarette smoke (LC)-induced COPD murine models and LPS-stimulated human bronchial epithelial (BEAS-2B) cells. In this research, COPD murine models were established after challenged with LPS for 2days and exposed to cigarette smoke for 35days. Treatment with curcumin for 10days distinctly alleviated airway inflammation and airway remolding in LC-induced COPD mice according to the lung H&E histopathological examination. The number of neutrophils and lymphocytes in broncho alveolar lavage fluid (BALF) was significantly decreased in curcumin+LC-treated group compared with the LC-induced mice. Additionally, curcumin inhibited BEAS-2B cells proliferation, which suggested the preventive effect of curcumin on progressive airway remolding and inflammatory response mediated by bronchial epithelial cells. Further investigation demonstrated an underlying molecular mechanism for the therapeutic effects of curcumin may rely on the inhibition of the degradation of IκBα and COX-2 expression in curcumin+LC-treated COPD mice and LPS-stimulated BEAS-2B cells. Overall, curcumin alleviates the airway inflammation and airway remolding, which is closely related to inhibit the BEAS-2B cells proliferation and suppress the activation of NF-κB and COX-2 expression. These findings indicate that curcumin may be a potential agent for the therapy of COPD.

Study on the Short-Time Remolding of Upper Airway After Uvulopalatopharyngoplasty.

To verify the short-time remolding of upper airway in patients diagnosed with obstructive sleep disordered breathing after Uvulopalatopharyngoplasty (UPPP). Twenty-one male adult patients aged 27 to 52 years followed up ranged from preoperation to 6 months after the operation. Lateral cephalometric radiographs (conventional and when pronouncing "i") were obtained 2 weeks preoperatively, 3 days postoperatively, and 1, 2, 3, 6 months after the surgery. The anterolateral diameters of different levels of upper airway and parameters of hyoid position of the patients were then measured. SAS 8.02 was used to analyze the differences by time. The study illustrated that the UPPP major affected the velopharyngeal and glossopharyngeal areas: parameters wane (P <0.05). On the other hand, UPPP leaded to the decline and retreat of hyoid. Most of the parameters remained metabolic. The nasopharynx kept statical (P >0.05) while the velopharyngeal parameters were increasing (P <0.05). The glossopharyngeal parameters increased in the first month after UPPP (P <0.05), while hypopharyngeal parameters underwent decline since 2 months after UPPP (P <0.05). The hyoid obtained decline and retreat (P <0.05) overall, while it endured a short-time climb in the first month after UPPP (P <0.05). Short-time upper airway remolding after UPPP existed.

The application of low dose CT scan and quantitative analysis in airway remodeling and air trapping of asthma

Objective To explore airway remodeling and air trapping in asthmatic patients with low dose CT scanning and quantitative analysis. Methods 52 stable asthmatic patients in which 29 were severe and 23 were slight, and 20 healthy control cases were underwent low dose dual phase CT scanning. The LA/BSA, WA/BSA, TA/BSA, WA% and Pi10WA were analyzed as airway remolding indexes. The MLD of expiratory, VI-850 (% ) of expiratory, MLD E/I, VI-850E-I (% ) and VI-850/-950E-I (% ) were analyzed as air-trapping indexes. One-Way ANOVA or H Kruskal-Wallis was used to analyze the above indicators. Results Airway remodeling indexes and LA/BSA were (9.6 ± 2.6), (11.0 ± 3.4) and (12.6 ± 3.0)mm2/m2 in severe asthmatics group, non-severe asthmatics group and healthy control group respectively, and there was significant difference between the three groups (F=5.60, P=0.006). WA% of each group was (65.1±2.5)%, (63.3±4.4)% and (62.0±3.0)%, and there was significant difference between the three groups (F=5.53, P= 0.006). The Pi10WA was (18.4±2.6), (17.7±3.1) and (16.4±1.4) mm2 respectively with significant difference between the three groups (F=3.59, P=0.033). Air-trapping indexes, MLD of expiratory of each group was -(771±59), -(724±43) and -(676±60) HU respectively with significant difference (F=5.60, P=0.006). VI-850(%) of expiratory of each group was 30.79(30.45)%, 13.53(12.09)% and 2.85(6.87)% respectively with significant difference (H=17.20, P<0.001). Conclusions Low dose of CT scan and quantitative analysis can provide an objective and quantitative information for patients with airway disease of asthma, and both WA% and Pi10WA were objective indexes. The severe asthmatic patients were associated with obvious airway remodeling and air trapping compared with non-severe asthmatic patients. Key words: Asthma; Airway remodeling; Air trapping; Tomography, X-ray computed

Oxidized graphene-aggravated allergic asthma is antagonized by antioxidant vitamin E in Balb/c mice.

Nanomaterials have been widely used in a number of applications; however, these nanomaterials may potentially be risky for human health, particularly for the respiratory system. In this study, we used a mouse asthma model to study whether graphene oxide (GO), a promising carbonaceous nanomaterial with unique physicochemical properties, aggravates allergic asthma via the oxidative stress pathway. Mice were sensitized with ovalbumin (OVA) to trigger immune reactions, while vitamin E (Ve) was administered as an antioxidant. Our results showed that GO aggravated OVA-induced allergic asthma in mice, as suggested by increased reactive oxygen species (ROS), elevated total immunoglobulin E (IgE), upregulated Th2 response, and the aggravation of allergic asthma symptoms, such as airway remolding, collagen deposition with mucus hypersecretion, and airway hyperresponsiveness (AHR). The administration of Ve dramatically attenuated all of the above effects. In conclusion, Ve showed anti-allergic properties in antagonizing the exacerbation of allergic asthma induced by GO, providing a new possibility for the treatment of allergic asthma.

Therapeutic effects of resveratrol in a mouse model of HDM-induced allergic asthma.

Asthma is an inflammatory disease of the lungs characterized by airway remolding. In this study, we examined whether resveratrol exerts protective effects on allergic asthma in a murine model. To investigate the effects of resveratrol on allergic airway inflammation in house dust mite (HDM)-induced mouse asthma and explore its mechanism, a chronic asthma mouse model was established by intranasally administering extracts of HDM (25μg of protein in 10μl of saline) for 5days/week for up to 7 consecutive weeks. Resveratrol (50mg/kg body weight), dexamethasone (1mg/kg body weight) or a vehicle was administered orally 1h before antigen challenges for up to 2weeks. Compared with the HDM-induced mice, the level of TNF-α of the BALF in the resveratrol+HDM-treated mice had obviously decreased. Histological examination of the lung tissue revealed that the resveratrol treatments attenuated the fibrotic response and airway inflammation. In addition, resveratrol inhibited the expression of the Syk protein and degranulation in mast cells. The presented findings collectively suggest that resveratrol has a therapeutic effect on mouse allergic asthma, and its mechanism of action might be related to reducing the production of the Syk protein.

Effect of Pingchuanguben Decoction on interleukin-17 of bronchial alveolar lavage fluid and airway inflammation in mice with asthma

Objective To study the effect of Pingchuanguben Decoction on IL-17 level of bronchial alveolar lavage fluid (BALF) and airway remolding in mice with asthma. Methods Forty healthy female Kunming mice were randomly divided into 4 groups (10 rats in each group): normal control group, asthma group, Pingchuanguben Decoction group and Budesonide group.The asthmatic models were established by ovalbumin (OVA); the normal control group was treated with phosphate buffer solution (PBS liquid) by celiac injection, during this period Pingchuanguben Decoction was administered to the mice in Pingchuanguben Decoction group each day.In stimulation stage, the normal control group was atomization inhalated PBS liquid, and the rest of the 3 groups were given aerosolized OVA instead.Bude-sonide atomization was administered to mice in Budesonide group before stimulation.The levels of IL-17 in BALF were measured with enzyme-linked immunosorbent assay (ELISA), and the levels of matrix metalloproteinase-9 (MMP-9) and the tissue inhibitor of metalloproteinase-1(TIMP-1) in lung tissues were tested with immunohistochemical analysis. Results 1.The levels of IL-17 in BALF in Pingchuanguben Decoction group and Budesonide group were significantly lower than those in asthma group (all P 0.05). Conclusions Pingchuanguben Decoction may restrain airway inflammation and remolding, which can replace Budesonide to a certain extent. Key words: Asthma; Interleukin-17; Matrix metalloproteinase-9; Pingchuanguben Decoction; Budesonide suspension; Mouse

Adverse Effect of Nano-Silicon Dioxide on Lung Function of Rats with or without Ovalbumin Immunization

BackgroundThe great advances of nanomaterials have brought out broad important applications, but their possible nanotoxicity and risks have not been fully understood. It is confirmed that exposure of environmental particulate matter (PM), especially ultrafine PM, are responsible for many lung function impairment and exacerbation of pre-existing lung diseases. However, the adverse effect of nanoparticles on allergic asthma is seldom investigated and the mechanism remains undefined. For the first time, this work investigates the relationship between allergic asthma and nanosized silicon dioxide (nano-SiO2).Methodology/Principal FindingsOvalbumin (OVA)-treated and saline-treated control rats were daily intratracheally administered 0.1 ml of 0, 40 and 80 µg/ml nano-SiO2 solutions, respectively for 30 days. Increased nano-SiO2 exposure results in adverse changes on inspiratory and expiratory resistance (Ri and Re), but shows insignificant effect on rat lung dynamic compliance (Cldyn). Lung histological observation reveals obvious airway remodeling in 80 µg/ml nano-SiO2-introduced saline and OVA groups, but the latter is worse. Additionally, increased nano-SiO2 exposure also leads to more severe inflammation. With increasing nano-SiO2 exposure, IL-4 in lung homogenate increases and IFN-γ shows a reverse but insignificant change. Moreover, at a same nano-SiO2 exposure concentration, OVA-treated rats exhibit higher (significant) IL-4 and lower (not significant) IFN-γ compared with the saline-treated rats. The percentages of eosinophil display an unexpected result, in which higher exposure results lower eosinophil percentages.Conclusions/SignificanceThis was a preliminary study which for the first time involved the effect of nano-SiO2 to OVA induced rat asthma model. The results suggested that intratracheal administration of nano-SiO2 could lead to the airway hyperresponsiveness (AHR) and the airway remolding with or without OVA immunization. This occurrence may be due to the Th1/Th2 cytokine imbalance accelerated by the nano-SiO2 through increasing the tissue IL-4 production.

Adjuvant effect of di-(2-ethylhexyl) phthalate on asthma-like pathological changes in ovalbumin-immunised rats

Pollution of phthalates, including di-(2-ethylhexyl)phthalate (DEHP), is widespread because of their use in plastics and other daily consumer products. Epidemiological studies have shown that the largest source of general population exposure to DEHP is on dietary. Studies have suggested an association between exposure to phthalate plasticisers, and increased prevalence of asthma. To investigate the adjuvant effect of DEHP on asthmatic pathological changes in ovalbumin-immunised rat model. Wistar rats were randomly divided into five groups (eight rats of each group): (1) saline; (2) ovalbumin (OVA); (3) OVA+DEHP 0.7mg·kg−1·d−1; (4) OVA+DEHP 70 mg·kg−1·d−1; and (5) DEHP 70 mg·kg−1·d−1. DEHP treatment groups which were administered to 0.7 mg and 70 mg DEHP/kg/d by gastric gavage for 30d before and during the process of OVA immunisation or saline treatment. The in vivo pulmonary function analysis, bronchoalveolar lavage (BAL) fluid collection and section histological observation were conducted. DEHP exposure could significantly increase airway hyperresponsiveness, airway remolding, and eosinophil infiltration in the OVA-immunised rats. But the DEHP exposure alone group does not show significant airway structural change and inflammatory cell infiltration, compared with control group. DEHP administered by gastric gavage play an adjuvant effect on respiratory systems in ovalbumin-immunised rat model.

Correlation of reticular basement membrane thickness and airway wall remolding in asthma patients

To investigate the correlation between the reticular basement membrane thickness and the airway wall remolding in asthma patients. Lung tissues were obtained from 5 patients who died from asthma, 3 males and 2 females, aged 45 +/- 16 (fatal asthma group), 5 asthmatics who died of diseases unrelated to asthma, 3 males and 2 females, aged 47 +/- 13, (non-fatal asthma group), and 5 dead patients without asthma, 3 males and 2 females, aged 24 +/- 14 (control group) to select 41, 38, and 43 transverse sections of tracheae respectively. The samples of tracheae were divided into cartilaginous and membranous airways by light microscopy (x100). The thickness of reticular basement membrane and the dimensions of the airway wall, including the smooth muscle area, submucosal gland area, inner and outer wall areas, and lumen area were measured. The correlations of reticular basement membrane thickness with the airway changes were analyzed. The reticular basement membrane was significantly thicker in both cartilaginous and membranous airways in the fatal and non-fatal asthma groups than in the control group (all P < 0.05). The submucosal gland area of the fatal asthma group was significantly larger than those of the non-fatal asthma group and control group (both P < 0.05). The inner wall area of the cartilaginous airway of the fatal asthma group was significantly larger than that of the non-fatal asthma group (P < 0.05); however, the inner wall area of the membranous airway of the fatal asthma group was not significantly different from that of the non-fatal asthma group. The outer wall areas of cartilaginous and membranous airways of the fatal asthma group were both significantly larger than those of the other 2 groups (all P < 0.05). There was no significant difference in the lumen areas of cartilaginous and membranous airways between the fatal and non-fatal asthma groups. The reticular basement membrane thickness was correlated with the smooth muscle area (P < 0.05), submucosal gland area (P < 0.05), and inner wall area (P < 0.01) of the corresponding bronchi in regard to the cartilaginous airway; and was correlated with the smooth muscle area (P < 0.05) and inner wall area (P < 0.01) of the corresponding bronchi in regard to the membranous airway, but was not correlated with the airway size, lumen area, and outer wall area in regard to the 2 kinds of airways. The reticular basement membrane thickness of central airway reflects the airway remolding of the central airway and the changes of smooth muscle and inner wall of the peripheral airway. It is worthwhile to do end bronchial biopsy to measure the reticular basement membrane thickness so as to assess the pathology of the airway and to conduct long-term follow-up among the asthma patients.