Effects of Qingfei Shenshi Decoction on the expressions of MMP-2, MMP-9 and TIMP-1 in lung tissue of bronchial asthma mice / 国际中医中药杂志

Objective:To investigate the effects of Qingfei Shenshi Decoction on the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 and tissue inhibitor of metalloproteinase timps-1 (TIMP-1) in lung tissue of asthma mice.Methods:Totally 50 male BALB/C mice were divided into 5 groups: normal group, model group, dexamethasone group, Qingfei Shenshi Decoction low- and high-dosage groups (10 mice /group) according to random number table method. Asthma model mice were prepared by ovalbumin (OVA) challenge method. After successful modeling, the dexamethasone group was given dexamethasone for gavage at the rate of 1.56 mg/kg, while Qingfei Shenshi Decoction groups were given high and low doses of Qingfei Shenshi Decoction for gavage at the rate of 14.235 g/kg and 28.470 g/kg, respectively. Normal group and model group were given 0.9% sodium chloride solution by gavage. At the end of gavage administration for 4 weeks, the airway reactivity (Penh value) in each group was detected; HE staining was used to observe the pathological changes of lung tissue; the contents of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor -α (TNF-α) in alveolar lavage fluid were determined by enzyme Linked immunosorbent assay (ELISA); the expressions of MMP-2, MMP-9 and TIMP-1 in lung tissue were detected by Western-blot.Results:Compared with model group, the damage of airway wall and alveolar wall of lung tissue in Qingfei Shenshi Decoction groups was significantly reduced. Compared with model group, the Penh value, IL-6, IL-1β and TNF-α levels in Qingfei Shenshi Decoction low- and high-dosage groups decreased ( P<0.05), and the expressions of MMP-9, MMP-2 and TIMP-1 in lung tissue decreased ( P<0.05), with a certain dose dependence. Conclusion:Qingfei Shenshi Decoction can effectively alleviate airway inflammation, reduce airway hyperresponsiveness, improve lung function and inhibit airway remodeling in asthmatic mice. Its mechanism may be related to down-regulating the expressions of MMP-2, MMP-9 and TIMP-1.

Effect mechanism of acupuncture for anti-asthmatic airway remodeling based on TGF-β1 / Smad3 signaling pathway / 中国针灸

OBJECTIVE@#To observe the effect of acupuncture at "Feishu" (BL 13) + "Dingchuan" (EX-B 1) and "Kongzui" (LU 6) + "Yuji" (LU 10) for the airway remodeling in asthma rats based on the transforming growth factor-β1 (TGF-β1)/ Smad family member 3 (Smad3) signaling pathway; and explore the efficacy difference between the two acupoint combinations.@*METHODS@#Forty SPF male SD rats, aged 4 weeks, were randomly divided into a blank group (n = 10) and a modeling group (n = 30). The ovalbumin (OVA) sensitization method was used to establish asthma model in the modeling group. After successful model preparation, the rats of the modeling group were randomized into a model group, an acupuncture at "Feishu" (BL 13) + "Dingchuan" (EX-B 1) (AAF) group, and acupuncture at "Kongzui" (LU 6)+"Yuji" (LU 10) (AAK) group, with 10 rats in each one. Starting from day 15 of the experiment, 5 min after motivating, acupuncture was applied to "Feishu" (BL 13) + "Dingchuan" (EX-B 1) and "Kongzui" (LU 6)+"Yuji" (LU 10) in the AAF group and the AAK group respectively. The intervention was delivered for 30 min each time, once daily, lasting 3 weeks consecutively. Using lung function detector, the airway resistance (RL) and dynamic compliance (Cdyn) of the lungs were detected. The histomorphology of lung tissues was detected with HE staining and Masson staining, and the mRNA and protein expression of TGF-β1 and Smad3 in lung tissues was detected with the real-time PCR and Western blot methods.@*RESULTS@#Compared with the blank group, RL was increased and Cdyn was decreased in the rats of the model group (P<0.01); and RL was reduced and Cdyn was increased in the AAF group and the AAK group when compared with those in the model group (P<0.01, P<0.05). The rats of the model group had bronchial lumen stenosis, inflammatory cell infiltration, collagen fibre hyperplasia and thickened smooth muscle in the lung tissues when compared with those in the blank group; and in comparison with the model group, all of the above morphological changes were attenuated in the AAF group and the AAK group. Besides, these morphological changes of the lung tissues were more alleviated in the AAF group when compared with those in the AAK group. In comparison with the blank group, the mRNA and protein expression of TGF-β1 and Smad3 of the lung tissues was increased in the model group (P<0.01), and it was reduced in the AAF group and the AAK group when compared with that in the model group (P<0.05, P<0.01). The mRNA expression of TGF-β1 and Smad3 was lower in the AAF group when compared with that in the AAK group (P<0.05).@*CONCLUSION@#Acupuncture at either "Feishu" (BL 13)+"Dingchuan" (EX-B 1) or "Kongzui" (LU 6)+"Yuji" (LU 10) reduces the airway remodeling in the rats with asthma, which may be related to the down-regulation of mRNA and protein expression of TGF-β1 and Smad3. The better efficacy is obtained with acupuncture at "Feishu" (BL 13)+"Dingchuan" (EX-B 1).

Research progress on effect and mechanism of diesel exhaust particles on asthma / 环境与职业医学

As a source of traffic-related air pollution, diesel particulate matter (DPM) associate with a variety of lung-related diseases, but there is no systematic review of the relationship between DPM and the development and progression of asthma. This article reviewed the relationship between DPM and asthma, the effect and mechanism of DPM on airway inflammation and remodeling in asthma, and illustrated that DPM exposure may participate in airway inflammation and remodeling through oxidative stress, immune regulation and regulation of lung and intestinal microecology, so as to promote the development and progression of asthma.

Effects of nebulization with high-dose budesonide combined with ipratropium bromide on airway remodeling and mucus secretion in patients with AECOPD / 中国基层医药

Objective:To investigate the effects of nebulization with high-dose budesonide (BUD) combined with ipratropium bromide (IB) on airway remodeling and mucus secretion in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).Methods:Ninety patients with AECOPD who received treatment in Wenling Hospital of Traditional Chinese Medicine between January 2020 and June 2021 were included in this study. They were assigned to the conventional-dose group ( n = 45, odd number) and high-dose group ( n = 45, even number) according to the number of admission. In the conventional-dose group, nebulization with IB (0.5 mg administered within 20 minutes, three times daily) and BUD (2 mg administered within 20 minutes, twice daily) was performed. In the high-dose group, nebulization with IB (0.5 mg administered within 20 minutes, three times daily) and BUD (4 mg administered within 20 minutes, twice daily) was performed. After nebulization, a mouthwash was required in each group. After 7 days of treatment, clinical efficacy was compared between the two groups. Before and 7 days after treatment, airway remodeling level (matrix metalloproteinase-9 and interleukin-8), airway mucus secretion (mucin-5ac and neutrophil elastase) and the incidence of adverse reactions were compared between the two groups. Results:Total response rate in the high-dose group was significantly higher than that in the conventional-dose group [95.56% (43/45) vs. 82.22% (37/45), χ2 = 4.05, P < 0.05]. After 7 days of treatment, serum matrix metalloproteinase-9 and interleukin-8 levels in the high-dose group were (416.96 ± 30.96) μg/L and (6.33 ± 1.03) μg/L, respectively, which were significantly lower than those in the conventional-dose group [(452.25 ± 32.16) μg/L, (7.85 ± 1.24) μg/L, t = 5.30, 6.32, both P < 0.001)]. After 7 days of treatment, serum mucin-5ac and neutrophil elastase levels in the high-dose group were (1.33 ± 0.21) μg/L and (4.06 ± 1.03) μg/L, respectively, which were significantly lower than those in the conventional-dose group [(1.58 ± 0.23) μg/L, (5.11 ± 1.14) μg/L, t = 5.38, 4.58, both P < 0.001]. There was no significant difference in incidence of adverse reactions between high-dose and conventional-dose groups [8.89% (4/45) vs. 4.44% (2/45), χ2 = 0.71, P > 0.05). Conclusion:Nebulization with high-dose BUD combined with IB for treatment of AECOPD can improve airway remodeling, reduce airway mucus hypersecretion and has definite therapeutic effects. Findings from this study are of great innovation and science.

Pharmacological blockade of protease-Activated Receptor 2 improves airway remodeling and lung inflammation in experimental allergic asthma

Abstract Protease-activated receptors (PARs) are metabotropic G-protein-coupled receptors that are activated via proteolytic cleavage of a specific sequence of amino acids in their N-terminal region. PAR2 has been implicated in mediating allergic airway inflammation. This study aims to study the effect of PAR2 antagonist ENMD1068in lung inflammation and airway remodeling in experimental asthma. Allergic lung inflammation was induced in sensitized BALB/c mice through intranasal instillations of ovalbumin (OVA), and mice were pretreated with ENMD1068 1 hour before each OVA challenge. Bronchoalveolar lavage fluid (BALF) was collected, and the lungs were removed at different time intervals after OVA challenge to analyze inflammation, airway remodeling and airway hyperresponsiveness. Ovalbumin promoted leukocyte infiltration into BALF in a PAR2-dependent manner. ENMD1068 impaired eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity in the lung parenchyma into BALF and reduced the loss of dynamic pulmonary compliance, lung resistance in response to methacholine, mucus production, collagen deposition and chemokine (C-C motif) ligand 5 expression compared to those in OVA-challenged mice. We propose that proteases released after an allergen challenge may be crucial to the development of allergic asthma in mice, and PAR2 blockade may be useful as a new pharmacological approach for the treatment of airway allergic diseases.

Management of Airway Remodeling in a Mouse Model of Allergic Airways Inflammation Using Extracellular Vesicles from Human Bone Marrow-Derived Mesenchymal Stromal Cells

Abstract: Asthma is a chronic respiratory disease affecting 300 million people worldwide. It results in several structural changes in the airways, which are minimally accessible in clinical practice. Cell therapy using mesenchymal stromal cells (MSCs) is a promising strategy for treating asthma due to the paracrine activity of MSCs, which influences tissue regeneration and modulates the immune response. Studies using extracellular vesicles (EV) released by MSCs have demonstrated their regenerative properties in animal models. The aim of this study was to evaluate the potential of EVs isolated from human bone marrow MSCs (hBM-MSCs) to control lung tissue remodeling in ovalbumin-induced allergic asthma in Balb/c mice. We isolated hBM-MSCs from a single donor, expanded and characterized them, and then isolated EVs. Asthma was induced in 43 male Balb/c mice, divided into four groups: control, asthmatic (AS), asthmatic plus systemic EVs (EV-S), and asthmatic plus intratracheal EVs (EV-IT). Upon completion of asthma induction, animals were treated with EVs either locally (EV-IT) or intravenously (EV-S). Seven days after, we performed bronchoalveolar lavage (BAL) and the total nuclear cells were counted. The animals were euthanized, and the lungs were collected for histopathological analysis of the airways. The EV-S group showed improvement in only the total BAL cell count compared with the AS group, while the EV-IT group showed significant improvement in almost all evaluated criteria. Therefore, we demonstrate that the local application of EVs derived from hBM-MSCs may be a potential treatment in controlling asthma.

Angiotensin-converting enzyme 2 particapates in ozone-induced lung inflammation and airway remodeling in mice / 南方医科大学学报

OBJECTIVE@#To investigate the roles of angiotensin-converting enzyme 2 (ACE2) in ozone-induced pulmonary inflammation and airway remodeling in mice.@*METHODS@#Sixteen wild-type (WT) C57BL/6J mice and 16 ACE2 knock-out (KO) mice were exposed to either filtered air or ozone (0.8 ppm) for 3 h per day for 5 consecutive days. Masson's staining and HE staining were used to observe lung pathologies. Bronchoalveolar lavage fluid (BALF) was collected and the total cell count was determined. The total proteins and cytokines in BALF were determined by BCA and ELISA method. The transcription levels of airway remodeling-related indicators in the lung tissues were detected using real-time quantitative PCR. The airway resistance of the mice was measured using a small animal ventilator with methacholine stimulation.@*RESULTS@#Following ozoneexposure ACE2 KO mice had significantly higher lung pathological scores than WT mice (P < 0.05). Masson staining results showed that compared with ozone-exposed WT mice, ozone-exposed ACE2 KO mice presented with significantly larger area of collagen deposition in the bronchi [(19.62±3.16)% vs (6.49±1.34)%, P < 0.05] and alveoli [(21.63±3.78)% vs (4.44±0.99)%, P < 0.05]. The total cell count and total protein contents in the BALF were both higher in ozone-exposed ACE2 KO mice than in WT mice, but these differences were not statistically significant (P > 0.05). The concentrations of IL-6, IL-1β, TNF-α, CXCL1/KC and MCP-1 in the BALF were all higher in ozone-exposed ACE2 KO mice than in ozone-exposed WT mice, but only the difference in IL-1β was statistically significant (P < 0.05). The transcription levels of MMP-9, MMP-13, TIMP 4, COL1A1, and TGF-β in the lung tissues were all significantly higher in ozone-exposed ACE2 KO mice (P < 0.01). No significant difference was found in airway resistance between ozone-exposed ACE KO mice and WT mice after challenge with 0, 10, 25, or 100 mg/mL of methacholine.@*CONCLUSION@#ACE2 participates in ozone-induced lung inflammation and airway remodeling in mice.

Correlation Between microRNA and Bronchial Asthma and Regulatory Mechanism of Chinese Medicine： A Review / 中国实验方剂学杂志

Bronchial asthma is a common heterogeneous chronic inflammatory disorder of airways characterized by airway hyperreactivity， mucus hypersecretion， and airflow obstruction. The incidence of asthma has been on the rise worldwide， and about 45.7 million adults in China suffer from asthma. Asthma is considered a costly disease， resulting in a significant economic and social burden. microRNAs （miRNAs） are long noncoding RNAs that regulate gene expression. They play a role in asthma through their activity in multiple immune and non-immune cell subsets. They impact multiple facets of critical cell function including cell survival， proliferation， and differentiation， which in turn induce the occurrence of airway spasm， mucus hypersecretion， and asthma symptoms. Traditional Chinese medicine has a long history in the treatment of asthma. Over the past a few decades， a growing number of herbs have proven effective in treating asthma in clinical trials or asthma inflammation in animal models. Chinese medicine has the features of multiple components and multiple targets. Evidence suggests that Chinese medicine and components of Chinese medicine can regulate immune homeostasis， improve airway inflammation and airway remodeling by modulating microRNA expression for asthma treatment. However， there is a lack of systematic and detailed reviews on the regulation of asthma-related microRNA expression by Chinese medicine. The article aims to review the correlation between microRNAs and asthma in animal experiments and clinical trials in recent years， as well as the mechanism of microRNA regulation by Chinese medicine in the treatment of asthma， with the intention of providing a reference for basic research and clinical application.

Molecular mechanism of airway epithelial cells involved in airway remodeling through epithelial mesenchymal transition in asthma / 国际儿科学杂志

Airway remodeling is one of the main pathological features of bronchial asthma.Airway remodeling may lead to increased airway hyperresponsiveness and pulmonary function decline in asthmatic patients.Some studies suggest that airway epithelial cells may play an important role in the development of airway remodeling in asthma, and they can differentiate into mesenchymal cells through epithelial-mesenchymal transition.This article reviews the signaling pathways involved in epithelial-mesenchymal transition, such as TGF-β 1 signaling pathways, Wnt/β-catanin signaling pathway and sonic hedgehog signaling pathway, to further elucidate the molecular mechanisms in airway remodeling in asthma.It provides a new perspective for the study of the pathogenesis of asthma and the development of new, effective and safe targeted therapy.

Progress of Experimental Research on Effect of Traditional Chinese Medicine on Proteins Associated Asthmatic Airway Remodeling / 中国实验方剂学杂志

Airway remodeling is an important pathological basis of asthma， and also the main reason for the difficulty in asthma therapy. By referring to the experimental reports on the treatment of airway remodeling in asthma with traditional Chinese medicine （TCM） in recent years， the authors comprehensively analyzed the effect of TCM on proteins related to airway remodeling in asthma， and it was found that TCM could regulate the signal pathway related proteins （such as transforming growth factor-β1/Smads， extracellular signal-regulated kinase and Wnt/β-catenin）， structural proteins （such as α-smooth muscle actin， collagen， osteopontin and fibrin） and gene regulatory proteins （such as matrix metalloproteinase-9， vascular endothelial growth factor， B lymphoma cell-2 related X protein）， and participate in the regulation of airway remodeling signaling pathway， tissue structure homeostasis and gene expression， so as to inhibit airway remodeling in asthma. In conclusion， TCM can improve the pathological morphology of airway remodeling and delay the progress of airway remodeling by controlling the corresponding proteins. At present， however， a lot of studies are limited to single Chinese herbal or TCM extract in animal experiments， and there is a lack of clinical research. It is suggested to establish a systematic and multi-level study on the mechanism of TCM for treating airway remodeling in asthma based on the theory of TCM， so as to provide a better reference for clinical practice.

Nasal lavage cytology and mucosal histopathological alterations in patients with rhinitis / Citologia do lavado nasal e alterações histopatológicas na mucosa nasal de pacientescom rinite

Abstract Introduction The extent of epithelial lesion in allergic and non-allergic rhinitis and its association with inflammatory changes in nasal lavage has not been clarified. Objective To verify the association between the inflammatory cells in the nasal lavage, epithelial lesion extent and basement membrane thickness, in the nasal mucosa of patients with rhinitis; to determine the cutoff point of the percentage of eosinophils in the nasal lavage associated with the atopic patients. Methods Patients with rhinitis and indication for septoplasty and (or) turbinectomy for turbinate hypertrophy were selected, and were submitted to allergy skin tests, nasal lavage with measurement of albumin and interleukin-8 levels, total and differential counting of cells, and mucosal histopathological analysis to determine the extent of epithelial lesion, and degree of basement membrane thickening. Results Fifty-six patients with a median age of 24.5 years and a diagnosis of allergic rhinitis (n = 36) and non-allergic rhinitis (n = 20) were studied. In atopic subjects, allergy skin tests were positive for Dermatophagoides pteronyssinus in 35 (97.0%) and Lolium perenne in 18 (50.0%). Atopic subjects showed a higher clinical score index of rhinitis compared to non-atopic ones. The total count of cells, neutrophils, and levels of albumin and IL-8 were not different in the nasal lavage of atopic and non-atopic subjects. The cutoff point for eosinophil count in nasal fluid for the distinction between allergic rhinitis and non-allergic rhinitis was 4%. Some degree of epithelial lesion was more frequent in allergic rhinitis (94%) than in non-allergic rhinitis (65%) patients. In the presence of basement membrane thickness, as a marker of remodeling, there was no difference in the nasal lavage of patients with allergic rhinitis and non-allergic rhinitis. Conclusion In this series, 4% was the cutoff point for the number of eosinophils in the nasal lavage, for atopy differentiation. Upper airway remodeling accessed by basement membrane thickness showed similar inflammatory cell infiltrate in the nasal lavage, regardless of the presence of atopy.

Resumo Introdução A extensão da lesão epitelial na rinite alérgica e não alérgica e sua associação com alterações inflamatórias no lavado nasal ainda não estão esclarecidas. Objetivo Verificar a relação entre o processo inflamatório no lavado nasal, extensão da lesão epitelial e espessamento da membrana basal na mucosa nasal de pacientes com rinite; determinar o ponto de corte do percentual de eosinófilos no lavado nasal associado à presença de atopia. Método Foram selecionados pacientes com rinite e indicação de septoplastia e (ou) turbinectomia por hipertrofia de conchas nasais, os quais foram submetidos aos testes cutâneos alérgicos, lavado nasal com determinação das concentrações de albumina, interleucina-8 (IL-8), contagem total e diferencial de células, análise da extensão da lesão epitelial, e grau de espessamento da membrana basal por meio de histopatologia da mucosa. Resultado Foram estudados 56 pacientes, mediana de 24,5 anos com diagnóstico de rinite alérgica (n = 36) e rinite não alérgica (n = 20). Nos atópicos os testes cutâneos alérgicos foram positivos para D. pteronyssinus em 35 (97,0%) e L. perenne em 18 (50,0%). Atópicos apresentaram maior índice de escore clínico para rinite em comparação a não atópicos. A contagem total de células, neutrófilos e níveis de albumina e IL-8 não foi diferente entre o lavado nasal de atópicos e não atópicos. O ponto de corte da contagem de eosinófilos no fluido nasal para a distinção de rinite alérgica e rinite não alérgica foi de 4%. Algum grau de lesão epitelial foi mais frequente em pacientes com rinite alérgica (94%) do que em pacientes com rinite não alérgica (65%). Na presença de espessamento da membrana basal, como marcador de remodelamento, não houve diferença no lavado nasal entre pacientes com rinite alérgica e não alérgica. Conclusão Nesta casuística, 4% foi o ponto de corte do número de eosinófilos no lavado nasal, para diferenciação de atopia. Remodelamento da via aérea superior pelo espessamento da membrana basal revelou infiltrado semelhante de células inflamatórias no lavado nasal, independentemente da presença de atopia.

Effect of Dialectical Therapy of Bufeitang Combined with Shengesan and Fujiu Application on COPD at Stable Period and Lung-kidney Qi Deficiency Syndrome / 中国实验方剂学杂志

Objective::To observe the clinical efficacy of dialectical therapy of Bufeitang combined with Shengesan and Fujiu application on chronic obstructive pulmonary disease (COPD) and lung-kidney Qi deficiency syndrome, and its effect on inflammatory damage and airway remodeling. Method::One hundred and thirty-four patients were randomly divided into control group (66 cases) and observation group (68 cases) by random number table. Patients in control group got spiriva by powder inhaler, 1 grain/time, 1 time/day, and salmeterol xinafoate and fluticasone propionate powder for inhalation for spray as appropriate, 1 suction/time, 1-2 times/days, for a continued 12 months. In addition to the therapy of control group, patients in observation group were also given Fujiu application at two-tailed acupoints of Feiyu, Piyu and Shenyu for the first day of the every San Fu and San Jiu, and dialectical therapy of Bufeitang combined with Shengesan were given at the first day of San Fu and San Jiu for 2 months. The course of treatment was 12 months. Before and after treatment, FEV1% of self-assessment questionnaire of patients with COPD (CAT), 6-min walking distance, St George's respiratory questionnaire (SGRQ), severity of dyspnea (mMRC) and index of BODE were assessed. And levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase inhibitor-1 (TIMP-1) were detected. Result::After treatment, scores of CAT, the total score of SGRQ, scoring of each dimension and index of BODE in observation group were all lower than that in control group (P<0.01), while FEV1% was higher than that in control group (P<0.01). And 6-min walking distance was more than that in control group (P<0.01), and the numbers of acute exacerbations were less than that in control group (P<0.01). The severity of dyspnea was lighter than that in control group (Z=2.047, P<0.05). And levels of MMP-9, TNF-α, IL-6 and ratio of MMP-9/TIMP-1 were lower than those in control group (P<0.01), whereas the level of TIMP-1 was higher than that in control group (P<0.01). Conclusion::Dialectical therapy of Bufei decoction combined with Shenge powder and Fujiu application can alleviate the current symptoms of dyspnea, improve exercise tolerance, quality of life and pulmonary function, reduce the number of acute exacerbations, relieve inflammation damage and airway remodeling. The comprehensive clinical efficacy is better than that of conventional western medicine.

Comparison of mild-to-moderate chronic obstructive pulmonary disease and asthma with quantitative CT / 中国医学影像技术

Objective: To investigate the differences of proximal airway structure and CT pulmonary function between steady mild-to-moderate chronic obstructive pulmonary disease (COPD) and asthma patients. Methods: Thirty patients with mild-to-moderate COPD (mtmCOPD group), 30 patients with mild-to-moderate asthma (mtmAs group) and 30 healthy controls (normal control group) underwent low-dose paired inspiratory and expiratory CT scans and quantitative analysis. The differences of airway parameters, emphysema index and air trapping index were analyzed among 3 groups. Results: The mean lumen area (LA)/ body surface area (BSA) of the proximal airway of both mtmCOPD group and mtmAs group ([10.93±2.58]mm2/m2, [10.81±3.20]mm2/m2) were lower than that of normal control group ([12.56±2.98]mm2/m2), and statistically significant difference was found between mtmAs group and normal control group (P=0.04). The mean WA% of both mtmCOPD group and mtmAs group ([63.02±2.34]%, [63.85±2.48]%) were higher than that of normal control group ([61.55±3.54]%), while statistically significant difference was observed between mtmAs group and normal control group (P<0.01). The paired inspiratory and expiratory VI-910 (%) and VI-950 (%) of mild-to-moderate COPD were higher than those of healthy controls (all P<0.01). The expiratory absolute value of mean lung density (MLD), expiratory VI-856 (%) and MLD E/I of mtmCOPD group were also higher than those of normal control group (all P<0.05). There was no significant difference in airway structural parameters, emphysema nor air trapping index between mtmCOPD group and mtmAs group. Conclusion: The lumen area of proximal bronchus of mild-to-moderate COPD and asthma patients were both smaller than that of healthy controls to a certain extent. Meanwhile, their percentage of proximal airway wall area were both larger than that of healthy controls, which were more obviously in patients with mild-to-moderate asthma. There were obvious emphysema and air trapping in mild-to-moderate COPD patients than in healthy subjects.

Expression of Muscarinic Receptors and the Effect of Tiotropium Bromide in Aged Mouse Model of Chronic Asthma / 결핵및호흡기질환

BACKGROUND: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling. METHODS: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M2 and M3 receptors were examined. RESULTS: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M2 but decreased expression of M3 in all aged groups of OVA. CONCLUSION: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M3 and M2 muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.

Auxo action and mechanism of tgf-β1 up-regulating smad3 phosphorylation on the expression of thymic stromal lymphopoietin in human bronchial Epithelia / 解放军医学杂志

[Abstract] Objective To discuss the effect and the corresponding mechanism of transforming growth factor β1 (TGF-β1) in promoting the bronchial epithelia synthesis and the expression of thymic stromal lymphopoietin (TSLP), so seek out a potential therapeutic target for asthma. Methods Human bronchial epithelia cells (HBEc) were cultured in vitro, and then divided into 0h group, 3h group, 6h group, 12h group, 24h group and 48h group to evaluate the effect of TGF-β1 stimulation in different time points; and divided into 0ng/ml group, 0.1ng/ml group, 1ng/ml group and 10ng/ml group to evaluate the effect of TGF-β1 stimulation in different concentrations. SB431542, a TGF-β1 antagonist, was used to block the effect of TGF-β1, HBEc were divided into negative control group, TGF-β1 group (1ng/ml TGF-β1) and TGF-β1+SB431542 group (1ng/ml TGF-β1+10μmol/L SB431542). Western blotting was performed to detect the protein expression level of TSLP, p-Smad3 and Smad3, while qRT-PCR was performed to determine the mRNA transcription level of TSLP. Concentrations of TSLP in HBEc culture supernatants were measured by ELISA. Results As the co-culture time with TGF-β1 prolonged, the expression of TSLP in HBEc increased. The relative expression of TSLP protein was significantly higher in 24h group (0.803±0.022) than in 0h group (0.350±0.032, P<0.05), and the relative expression of TSLP mRNA also increased (4.957±0.391 vs. 1.002±0.086, P<0.05). The levels of TSLP mRNA transcription and protein expression were significantly higher in 1ng/ml TGF-β1 group (7.954±2.004; 1.522±0.003) than in 0ng/ml TGF-β1 group (1.008±0.152; 0.758±0.014, P<0.05). The concentrations of TSLP in HBEc culture supernatants were markedly higher in 1ng/ml TGF-β1 group than in 0ng/ml TGF-β1 group (160.157±7.050 vs. 138.817±1.940, P<0.05). The ratio of p-Smad3/Smad3 declined obviously in TGF-β1+SB431542 group than in TGF-β1 group (0.808±0.063 vs. 1.116±0.049, P<0.05). Meanwhile, the relative expression of TSLP protein was significantly lower in TGF-β1+SB431542 group than in TGF-β1 group (1.016±0.030 vs. 1.186±0.045, P<0.05). Conclusion TGF-β1 may induce the expression of TSLP in HBEc by up-regulating Smad3 phosphorylation, which may be a novel method in curing asthma.

Quantitative computed tomography measurement of cross-sectional area of small pulmonary vessels in asthmatic patients / 中华医学杂志(英文版)

Background@#Cross-sectional area (CSA) for small pulmonary vessels is considered a parameter of pulmonary vessel alterations in patients with chronic obstructive pulmonary disease. This study was to evaluate the correlation of CSA with airflow obstruction parameters in asthma. Furthermore, we aimed to measure the difference in vascular alteration between asthma phenotypes and evaluate its relation with cytokine levels.@*Methods@#We consecutively enrolled 20 adult asthmatic patients (13 women: age range, 26–80 years) and 20 healthy controls (8 women: age range, 23–61 years) from Peking University Third Hospital. Total CSA <5 mm2 (CSA<5) was measured with 64-slice spiral computed tomography, and the percentage CSA <5 for the lung area (%CSA<5) was calculated. Data were corrected for body surface area to obtain sixth-generation airway luminal diameter (LDcor), luminal area (Aicor), and airway wall thickness, and airway wall area percentage (WA%) was calculated. Enzyme-linked immunosorbent assay was used to detect the expression of leptin, total immunoglobulin E, periostin, and transforming growth factor β1 in serum and matrix metalloproteinase 9 in induced sputum supernatant of asthmatic patients. The differences in %CSA<5 between subgroups were assessed by independent samples Student’s t test, and Spearman correlation analysis was used to analyze the correlation of %CSA<5 with clinical indexes and inflammatory cytokine levels.@*Results@#Patients with asthma and controls did not differ in %CSA<5. In asthma patients, %CSA<5 was lower with initial onset age ≤12 years old, airflow restriction and uncontrolled Global Initiative for Asthma classification (all P < 0.05). Moreover, it was positively correlated with forced vital capacity ratio in 1 s (FEV1)/forced expiratory volume ratio, FEV1%, LDcor, Aicor, and serum leptin level (all P < 0.05) and negatively with total lung WA% (P = 0.007).@*Conclusions@#%CSA<5 of pulmonary small vessels was well correlated with airflow limitation indexes and sixth-generation airway parameters. It has certain significance in predicting the clinical control of asthma.

Effect of Volatile Oil from Xanthii Fructus on Airway Remodeling of Rats with Bronchial Asthma / 中国实验方剂学杂志

Objective:To discuss the effect of volatile oil from Xanthii Fructus on airway remodeling of rats with bronchial asthma, in order to discuss the mechanism of action through matrix metalloteinases-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), platelet derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), Smad2, Smad3 and Smad7 mRNA expressions. Method:Forty-eight rats (half males and half females) were randomly divided into six groups (n=8), namely normal saline group, model group, volatile oil from Xanthii Fructus (7.5, 15, 30 mg·kg-1) groups and dexamethasone group (0.5 mg·kg-1). Except for normal saline group, airway remodeling of rats were established through ovalbumin sensitization and atomization inhalation method. At volatile oil group, rats got volatile oil spray since the first time (the 4th week after modeling) of inspiration of asthma to the last day before the end of test. Histopathological changes of bronchus and lung were analyzed by htoxylin eosin (HE) stain. And airway remodeling was observed, and perimeter of bronchial lumen (Pi), smooth muscle area of bronchi (S), tube wall area (W) and nuclei of smooth muscle cells (N) were recorded. And levels of endothelin-1 (ET-1) and insulin-like growth factor-1(IGF-1) in irrigation solution of Alveoli (BALF) were detected. And mRNA expressions of MMP-9, TIMP-1, PDGF, TGF-β1, Smad2, Smad3 and Smad7 were detected by real-time quantitative-polymerase chain reaction (Real-time PCR). Result:In the model group, infiltration of a large number of inflammatory cells were found at the peribronchial wall, airway smooth muscle thickness and basement membrane increased, and bureaucratic cavity was narrower and flatter. Volatile oil from Xanthii Fructus can ameliorate pathological damage of bronchopulmonary tissue. Levels of S/Pi, W/Pi and N/Pi, BALF, ET-1, IGF-1 and MMP-9/TIMP-1 and mRNA expressions of MMP-9 and PDGF in volatile oil group and dexamethasone group were lower than those in model group (Pβ1, Smad2 and Smad3 were less than those in model group (PPConclusion:Volatile oil from Xanthii Fructus can regulate levels of MMP-9, TIMP-1, MMP-9/TIMP-1, TGF-β1/Smad, inhibit expressions of PDGF, ET-1 and IGF-1, and suppress subepithelial fibrosis, extracellular matrix synthesis, proliferation and migration of airway smooth muscle cells to relieve or inhibit airway remodeling, so as to prevent and treat asthma.

Clinical Efficacy of Modified Qingqi Huatan Wan in Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease and Its Effect on Inflammatory Reaction, Airway Remodeling and Thrombokinesis / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of Modified Qingqi Huatan Wan in treatment of acute exacerbation of chronic obstructive pulmonary disease and its effect on inflammatory reaction, airway remodeling and thrombokinesis. Method:A total of 80 patients of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) were randomly divided into control group (40 cases) and therapy group (40 cases) by random number table. The control group was treated with conventional therapy. In addition to the therapy for the control group, the patients in therapy group also received modified Qingqi Huatan Wan. The treatment course was 14 days for both groups. Scores of traditional Chinese medicine(TCM) syndrome, chronic obstructive pulmonary disease and asthma physiology Score (CAPS), and chronic obstructive pulmonary disease patients self-assessment test questionnaire (CAT) were compared. The secondary indicators were pulmonary function, arterial blood gas analysis, and blood rheology indexes. In addition, the levels of serum nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), transforming growth factor-beta1 (TGF-β1) and plasma tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), von-willebrand factor (v-WF), clinical efficacy and safety were evaluated. Result:The total clinical effective rate was 94.74% in therapy group,which was higher than 78.38% in control group (χ2=4.341,P2, serum NF-κB, IL-6, IL-8, MMP-2, TIMP-2, TGF-β1 and plasma PAI-1, v-WF in therapy group were lower than those in control group(P2, PaO2, FEV1, FEV1%, FEV1/FVC in therapy group were higher than those in control group(PPConclusion:Modified Qingqi Huatan Wan can control the symptoms safely, alleviate CAPS and lung function, effectively reduce the inflammatory response and inhibit the formation of airway remodeling and thrombosis, and its mechanism may be protect the lung tissue by reducing the level of inflammatory cytokines, regulating the balance of MMP-2/TIMP-2 and t-PA/PAI-1 and improving extracellular matrix and vascular endothelial function.

Signal Pathways Relating to Prevention and Treatment of Airway Remodeling in Chronic Obstructive Pulmonary Disease with Traditional Chinese Medicine / 中国实验方剂学杂志

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with a high morbidity, disability and mortality. At the same time, COPD is always accompanied by pulmonary hypertension, pulmonary fibrosis, chronic pulmonary heart disease, right heart failure and other common serious complications. All of these cause serious financial burden for the family of patients. Airway remodeling plays an important role in the pathogenesis of COPD. It is the progressive development of airflow restriction that induces the main symptoms of COPD, such as cough, asthma and depression. Therefore, it is of great research value to explore the intervention of traditional Chinese medicine(TCM) in the development of COPD by alleviating airway remodeling. Studies have shown that multiple signaling pathways can induce progressive airway remodeling, and the therapeutic effect of TCM has been frequently confirmed by experimental studies. TCM often has a therapeutic effect on COPD through multi-target and multi-channel mediation. This paper mainly includes five signaling pathways that traditional Chinese medicine can intervene COPD airway remodeling, namely matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinase (TIMPs), transforming growth factor (TGF)-beta 1/Smads, RhoA/Rho-associated kinase (ROCK), vascular endothelial growth factor (VEGF)/b-fibroblast growth factor (b-FGF) and nuclear factor (NF)-κB. This paper briefly reviews the research progress of these five signaling pathways, and discusses other signaling pathways that may be involved, in order to provide reference and ideas for future experimental research.

The relationship between the expression of IL-13 and periostin and the severity of airway remodeling in asthmatic patients / 中国医师杂志

Objective By detecting the expression of interleukin-13 (IL-13 and periostin in the airway of asthmatic patients,the pathological changes and pulmonary functions of airway tissues in asthmatic patients were evaluated,and the role of IL-13 and periostin airway remodeling in bronchial asthma was preliminarily explored.Methods The bronchial tissues adjacent to tumor nest were obtained from 12 patients with lung cancer complicated with bronchial asthma (asthmatic group) and 12 lung cancer patients without bronchial asthma (non-asthmatic group) after lung cancer resection.Pulmonary function was measured for all subjects before surgery.Pathological changes of airway tissues and degree of airway remodeling were assessed by hematoxylin-eosin (H&E) staining,masson's trichrome staining,and periodic acid-silver methenamine (PASM) staining of paraffin-embedded sections.The expression of IL-13 and periostin in bronchial tissues were evaluated by immunohistochemistry.Results Values of the forced expiratory volume in 1 second of the predicted value (FEV1％ pred) and FEV1/forced vital capacity (FEV1/FVC％) in asthmatic patients were significantly decreased compared with the non-asthmatic patients (P ＜ 0.05),indicating that lung function was impaired in asthmatic patients.There was more severe airway remodeling representing as thickening of basement membranes,collagen deposition,and increasing of goblet cells and fibroblasts in asthmatic patients than in non-asthmatic patients (all P ＜ 0.05).The expression of IL-13 and periostin were higher in asthmatic tissues than in non-asthmatic tissues (P ＜ 0.05).The immunohistochemical expression of IL-13 and periostin in bronchial tissues were positively correlated with the degree of airway remodeling in asthmatic patients,and the expression of IL-13 and periostin in bronchial tissues were positively correlated with each other.Conclusions The expression of IL-13 and periostin were increased in bronchial tissue in patients with asthma.They work together to promote the occurrence of airway remodeling,which eventually lead to a decline in lung function.