Attenuation of Airway Inflammation and Airway Remodeling in Ovalbumin Asthmatic Rats by Artemisinin through PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the molecular mechanism of action of artemisinin in attenuating asthmatic airway inflammation and airway remodeling through the phosphoinositide 3-kinase（PI3K）/protein kinase B（Akt） signaling pathway. MethodFifty male SD rats were randomly divided into blank group， model group， and low-dose， medium-dose， and high-dose groups of artemisinin， with 10 rats in each group. The ovalbumin （OVA）-induced asthma model of the rats was established， and after successful modeling， the blank group and model group received tail vein injection of 1.0 mL·kg-1 normal saline， while the low-dose， medium-dose， and high-dose groups of artemisinin received tail vein injection of 12.5， 25， and 50 mg·kg-1 artemisinin daily for seven days. Airway resistance was measured by the acetylcholine chloride method. Cell number and species changes in the alveolar lavage fluid of each group were determined by flow cytometry. Morphological changes in airway endothelial tissue were determined by the hematoxylin-eosin （HE） staining method. Apoptosis was determined by CytoTox 96 method， and enzyme-linked immunosorbent assay （ELISA） method was used to determine the NOD-like receptor thermal protein domain associated protein 3 （NLRP3） inflammasome， interleukin-1β （IL-1β）， and interleukin-10 （IL-10） expression. Western blot method was used to detect the （p）-PI3K/p-Akt level in the alveolar bronchial tissue of each group. ResultCompared with the blank group， the total number of cells， total number of macrophages， total number of eosinophils， total number of lymphocytes， and total number of neutrophils were significantly higher in the model group （P<0.05）. HE staining showed that the airway mucosa of the rats had obvious edema， and a large number of inflammatory cells were infiltrated （P<0.05）. The rate of apoptosis was significantly higher （P<0.05）， and the levels of the inflammasome NLRP3， IL-1β， and IL-10 increased significantly （P<0.05）. p-PI3K/p-Akt level increased significantly （P<0.05）. Compared with the model group， the total number of cells， total number of macrophages， total number of eosinophils， total number of lymphocytes， and total number of neutrophils were significantly decreased after the intervention of artemisinin at low， medium， and high concentrations （P<0.05）. HE staining showed that the degree of edema of the airway mucosa of the rats was reduced， and the area of the inflammatory cell infiltration was drastically reduced （P<0.05）. The apoptosis rate was significantly reduced （P<0.05）， and the levels of the inflammasome NLRP3， IL-1β， and IL-10 decreased significantly （P<0.05）. p-PI3K/p-Akt level decreased significantly （P<0.05）. ConclusionArtemisinin significantly inhibits NLRP3 inflammasome activation， reduces cellular pyroptosis and inflammatory cell expression， and attenuates airway inflammatory manifestations and airway remodeling in asthmatic rats， which may be related to the regulation of p-PI3K/p-Akt， and the results may provide laboratory insights and basis for the treatment of bronchial asthma with artemisinin.

Mechanism Study of Soufeng Yuchuan Formula on Regulating Airway Remodeling in Asthmatic Rats Based on Epithelial-Mesenchymal Transformation / 中药新药与临床药理

Objective To explore the mechanism of Suofeng Yuchuan Formula on inhibiting airway remodeling in asthma by regulating epithelial-mesenchymal transformation(EMT).Methods Sixty rats were randomly divided into normal control group,model control group,Dexamethasone group,high-,medium-and low-dose groups of Soufeng Yuchuan Formula,with 10 rats in each group.In addition to the normal control group,the other groups were injected and inhaled with ovalbumin(OVA)to replicate the asthma rat model.The rats in each group were killed after 21 days of administration of the corresponding drug.Hematoxylin-eosin(HE)staining was used to observe the pathological changes of lung tissue.The ultrastructure of epithelial cells in rat lung was observed by transmission electron microscope.The contents of transforming growth factor β1(TGF-β1)and interleukin-17(IL-17)in serum were detected by enzyme-linked immunosorbent assay(ELISA).Real-time fluorescence quantitative polymerase chain reaction(RT-PCR)was used to detect mRNA expressions of TGF-β1,α-smooth muscle actin(α-SMA),E-cadherin and N-cadherin in lung homogenate.Protein expression levels of TGF-β1,α-SMA,E-cadherin and N-cadherin in lung tissue were detected by Western Blot.Results Compared with the normal control group,the serum contents of TGF-β1 and IL-17 in the model control group were significantly increased(P＜0.01).The mRNA and protein expressions of TGF-β1,α-SMA and N-cadherin in lung tissues were significantly up-regulated(P＜0.01),while the mRNA and protein expressions of E-cadherin were significantly down-regulated(P＜0.01).HE staining showed thickening of airway wall and alveolar wall,and a large number of inflammatory cells infiltrated in the visual field,and the inflammation score was significantly increased(P＜0.01).Transmission electron microscopy showed that the epithelial cells of lung tissue had severe edema.Local dissolution and thinning of intracellular matrix,and obvious swelling of organelles were observed.Compared with model control group,the contents of TGF-β1 and IL-17 in serum of dexamethasone group and all doses of Soufeng Yuchuan Formula groups were significantly decreased(P＜0.05,P＜0.01).The mRNA and protein expressions of TGF-β1,α-SMA and N-cadherin were significantly down-regulated(P＜0.05,P＜0.01),while the mRNA and protein expressions of E-cadherin were significantly up-regulated(P＜0.05,P＜0.01).The inflammatory cell infiltration of lung tissue and thickening of bronchial wall and alveolar wall were found to be reduced.The inflammation score of dexamethasone group and high-dose group of Suofeng Yuchuan Formula was reduced(P＜0.05).Ultrastructure showed that the degree of edema of epithelial cells was significantly reduced,the cell membrane was intact,the intracellular matrix was uniform,and most of the organelles were slightly swollen.Conclusion Soufeng Yuchuan Formula can reduce the level of TGF-β1,thereby improve EMT in lung tissue,and achieve the purpose of preventing and treating airway remodeling in asthma.

Analysis of the relationship between serum lncRNA ANRIL and miR-423-5p and airway inflammation and remodeling in children with bronchial asthma and their predictive value / 国际检验医学杂志

Objective To analyze the relationship between serum long chain non coding ribonucleic acid(ln-cRNA)ANRIL,microRNA(miR)-423-5p and airway inflammation and remodeling in children with bronchial asthma and its predictive value.Methods A total of 98 children with bronchial asthma treated in Haikou Ma-ternal and Child Health Hospital from June 2020 to December 2022 were selected.46 children with acute at-tack were selected as the attack group and 52 children with clinical remission were selected as the remission group.Another 50 children who were healthy during physical examination in the same period were selected as the health group.The relative expression levels of serum lncRNA ANRIL and miR-423-5p were detected by real-time fluorescence quantitative polymerase chain reaction.The serum inflammatory factor indicators[in-terleukin-13(IL-13),transforming growth factor-β1(TGF-β1),vascular endothelial growth factor(VEGF)]were detected by enzyme-linked immunosorbent assay.Airway remodeling indicators[bronchial thickness(T/D),pipe wall area/total cross-sectional area of gas pipeline(WA)]and lung function indicators[first second forced expiratory volume(FEV1),peak expiratory flow(PEF),maximum mid expiratory flow(MMEF)]were measured.The correlation between expression of serum lncRNA ANRIL,miR-423-5p and airway inflam-mation and remodeling indicators were analyzed by the Pearson method.The predictive value of serum ln-cRNA ANRIL and miR-423-5p in the diagnosis of bronchial asthma was analyzed by receiver operating charac-teristic(ROC)curve.Results The relative expression level of serum lncRNA ANRIL in remission and attack groups was higher than that in healthy group,and the relative expression level of serum miR-423-5p was lower than that in healthy group,with statistical significance(P＜0.05).The relative expression level of serum ln-cRNA ANRIL in the attack group was higher than that in the remission group,and the relative expression lev-el of serum miR-423-5p was lower than that in the remission group,with statistical significance(P＜0.05).The levels of serum VEGF,IL-13 and TGF-β1 in attack and remission groups were higher than those in healthy group,and the difference was statistically significant(P＜0.05).The levels of serum VEGF,IL-13 and TGF-β1 in attack group were higher than those in remission group,and the difference was statistically sig-nificant(P＜0.05).The levels of T/D and WA in the remission and attack groups were higher than those in the healthy group,and the levels of FEV,,PEF and MMEF were lower than those in the healthy group,with statistical significance(P＜0.05).The levels of T/D and WA in the attack group were higher than those in the remission group,and the levels of FEV1,PEF and MMEF were lower than those in the remission group,with statistical significance(P＜0.05).The results of Pearson correlation analysis showed that serum ln-cRNA ANRIL expression was positively correlated with airway inflammation and remodeling indicators,and negatively correlated with lung function indicators(P＜0.05).The expression of miR-423-5p was negatively correlated with airway inflammation and remodeling indexes,and positively correlated with lung function inde-xes(P＜0.05).ROC curve analysis showed that the area under the curve of lncRNA ANRIL and miR-423-5p alone and combined detection were 0.772,0.707 and 0.865 respectively,the predictive value of combined de-tection in diagnosing bronchial asthma was higher.Conclusion The relative expression level of serum lncRNA ANRIL increase in children with bronchial asthma,and miR-423-5p decrease,which promote airway inflamma-tion,remodeling,lung function decrease,and which has high diagnostic efficacy for children with bronchial asthma.

Basic Study on Inhibitory Effect of Sulforaphane on Inflammatory Response and Alleviation of Airway Remodeling in COPD Rats / 广州中医药大学学报

Objective To investigate the ameliorative effect of sulforaphane on inflammatory response and airway remodeling in rats with chronic obstructive pulmonary disease(COPD).Methods Seventy-five SD rats were randomly divided into the normal group,the model group,and the low-,medium-,and high-dose groups of sulforaphane,with 15 rats in each group.Except for the normal group,the COPD model was prepared in the remaining group using aroma smoke inhalation combined with intratracheal droplet lipopolysaccharide(LPS)method.After the successful modelling,the rats were administered the drug by gavage for 28 days.At the end of the administration,the general conditions of the rats in each group were observed,and the lung function[forced vital capacity(FVC),peak expiratory flow-rate(PEF),forceful expiratory volume in 1 second(FEV1)]was examined,and the pathological changes of the lung tissues were observed by hematoxylin-eosin(HE)staining method,and the indexes of airway remodeling(thickness of the bronchial wall,thickness of the smooth muscle)were measured;the enzyme-linked immunosorbent assay(ELISA)was used to examine the lung function of the rats.The levels of inflammatory factors[tumor necrosis factor α(TNF-α),interleukin 1β(IL-1β)]were detected in lung tissue by enzyme-linked immunosorbent assay(ELISA),and changes in the protein expressions of Toll-like receptor 4(TLR4),myeloid differentiation factor 88(MyD88),and nuclear transcription factor κB(NF-κB)were detected in lung tissue by Western Blot.Results(1)The rats in the model group had dry and lack of glossy fur,obvious coughing and nose scratching,shortness of breath,slow movement,and preferred to arch their backs and lie curled up;the rats in the low-,medium-and high-dose groups of sulforaphane showed significant improvement in shortness of breath,coughing,and other abnormal manifestations.(2)HE staining showed that the airway wall and smooth muscle of rats in the model group were thickened,the airway epithelium was damaged,and alveolar destruction,fusion,and massive infiltration of inflammatory cells were seen;the histopathological changes in the lungs of rats in the low-,medium-and high-dose groups of sulforaphane improved to varying degrees,with the airway wall becoming thinner,the degree of alveolar destruction being reduced,and the infiltration of inflammatory cells being reduced.(3)Compared with the normal group,FVC,PEF and FEV1 were significantly reduced in the model group(P＜0.05),and the levels of TNF-α and IL-1β,bronchial wall thickness,smooth muscle thickness,and the expression levels of TLR4,MyD88 and NF-κB were significantly increased in the model group(P＜0.05);and in comparison with the model group,the levels of FVC,PEF,and FEV1 were significantly increased in the rats in the sulforaphane low-,medium-,and high-dose groups(P＜0.05),and the levels of TNF-α,IL-1β,bronchial wall thickness,smooth muscle thickness,and the expression levels of TLR4,MyD88,and NF-κB were significantly decreased(P＜0.05)compared with the model group.Conclusion Sulforaphane helps to inhibit the inflammatory response,attenuate airway remodeling,and improve the pathological injury and lung function of lung tissue in rats with COPD,and its mechanism may be related to the inhibition of TLR4,MyD88,and NF-κB protein expressions.

Effect of montelukast combined with budesonide in the treatment of children with intermittent asthma / 中国医师进修杂志

Objective:To analyze the effect of montelukast combined with budesonide in the treatment of children with intermittent asthma, and the impact on airway remodeling and T helper type 1 (Th1)/T helper type 2 (Th1/Th2) related cytokines.Methods:A prospective study was conducted among 120 children with intermittent asthma admitted to Huanghua Municipal People′s Hospital from December 2021 to February 2023. The children were randomly divided into the control group (60 children treated with budesonide atomizationinhalation) and the observation group (60 children treated with montelukast on the basis of the treatment of control group). Clinical efficacy, airway remodeling indicators [total area of airway (Ao), outer diameter of airway (D) and wall area to total airway cross-sectional area (WA%)], pulmonary function [peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV 1)/forced vital capacity (FVC) and the maximum expiratory flow at 25% of vital capacity (MEF25%)], Th1/Th2 related cytokines, inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), interleukin-6 (IL-6) and interferon-gamma (IFN-γ)], recurrence, and the incidence of adverse reactions were compared between the two groups. Results:The total effective rate in the observation group was higher than that in the control group: 90.00% (54/60) vs. 75.00% (45/60) ( P<0.05). After treatment, Ao, D and WA% in the observation group were lower than those in the control group: (17.58 ± 1.89) mm 2 vs. (19.22 ± 1.94) mm 2, (4.25 ± 0.48) mm vs. (4.48 ± 0.49) mm, (63.75 ± 6.49)% vs. (69.22 ± 7.14)% ( P<0.05). PEF, FEV 1/FVC and MEF25% in the observation group were higher than those in the control group: (3.13 ± 0.34) L/s vs. (2.86 ± 0.35) L/s, (87.45 ± 8.86) % vs. (83.59 ± 8.42) %, (87.63 ± 8.86)% vs. (82.15 ± 8.43)% ( P<0.05). The levels of Th1 and Th1/Th2 in the observation group were higher than those in the control group: (14.13 ± 1.46) % vs. (10.27 ± 1.25) %, 3.46 ± 0.39 vs. 1.88 ± 0.25, and the level of Th2 was lower than that in the control group: (3.96 ± 0.45)% vs. (5.48 ± 0.56)% ( P<0.05). After treatment, the levels of TNF-α and IFN-γ in the observation group were higher than those in the control group: (76.15 ± 7.78) ng/L vs. (66.38 ± 6.47) ng/L, (7.15 ± 0.74) ng/L vs. (6.14 ± 0.66) ng/L. The levels of IL-4 and IL-6 were lower than those in the control group: (77.85 ± 7.96) ng/L vs. (86.42 ± 8.74) ng/L, (37.25 ± 3.89) mg/L vs. (44.23 ± 4.57) mg/L ( P<0.05). The recurrence rate in the observation group was lower than that in the control group: 3.33% (2/60) vs. 15.00% (9/60) ( P<0.05). The incidence rates of adverse reactions in the two groups were without statistically significant difference between the groups ( P>0.05). Conclusions:Montelukast combined with budesonide can reduce airway remodeling in children with intermittent asthma, improve their pulmonary function, Th1/Th2 related cytokines and inflammatory response indicators, and reduce recurrence rate, with good safety.

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.

Effects of blistering cupping combined with thunder-fire moxibustion on the efficacy and airway remodeling of cold-wheezing syndrome in bronchial asthma / 中国针灸

OBJECTIVE@#To investigate the clinical efficacy of the combined application of blistering cupping with thunder-fire moxibustion in treating bronchial asthma of cold-wheezing syndrome, and its influences on airway remodeling, inflammatory factors, lung function, and quality of life on the base of conventional western medicine treatment.@*METHODS@#A total of 76 patients with bronchial asthma of cold-wheezing syndrome were randomly divided into an observation group and a control group, 38 cases in each group. In the control group, the basic treatment was used, i.e. budesonide formoterol powder inhalation. In the observation group, on the basis of the treatment as the control group, blistering cupping combined with thunder-fire moxibustion was supplemented, Dazhui (GV 14), Danzhong (CV 17) and bilateral Feishu (BL 13), Gaohuang (BL 43), and Zhongfu (LU 1) were selected; blistering cupping was administered once a day and thunder-fire moxibustion was given twice a day. One course of treatment was composed of 7 days in both groups, and 2 courses of treatment were required. Before and after treatment, the airway remodeling indexes (matrix metalloproteinase-9 [MMP-9], tissue inhibitor of matrix metalloproteinase-1 [TIMP-1], and transforming growth factor-β1 [TGF-β1]) and inflammatory indexes (interleukin [IL] -1β、IL-25) were detected by using radioimmunoassay in the patients of the two groups. The lung function, traditional Chinese medicine symptom score, and asthma quality of life questionnaire (AQLQ) score were observed in the patients of the two groups.@*RESULTS@#After treatment, the serum levels of MMP-9, TIMP-1, TGF-β1, IL-1β, IL-25, peak expiratory flow (PEFR), traditional Chinese medicine symptom scores, and AQLQ scores were decreased compared with those before treatment in the patients of the two groups (P<0.05), and the results in the observation group were lower than those in the control group (P<0.05). After treatment, the first second forced expiratory volume (FEV1) and peak expiratory flow rate (PEF) were increased compared with those before treatment in the two groups (P<0.05), and the results in the observation group were higher than those in the control group (P<0.05).@*CONCLUSION@#On the basis of the conventional western medicine treatment, the combination of blistering cupping with thunder-fire moxibustion can effectively ameliorate the clinical symptoms of patients, reduce inflammatory levels, inhibit airway remodeling and improve the lung function and quality of life in the patients with bronchial asthma.

Improvement effect of Shegan Mahuang Decoction on rats with cold-induced asthma based on TRPV1/NRF-1/mtTFA pathway / 中国中药杂志

This study investigated the therapeutic effect of Shegan Mahuang Decoction(SGMHD) on cold-induced asthma in rats and explored its underlying mechanism. Seventy-two healthy male SD rats of specific pathogen free(SPF) grade were randomly divided into a blank group, a model group, a positive control group(dexamethasone, 0.4 mg·kg~(-1)), and low-, medium-, and high-dose SGMHD groups(3.2, 6.4, and 12.8 g·kg~(-1)). The blank group received saline, while the other groups were sensitized by intraperitoneal injection of ovalbumin(OVA) solution. Subsequently, the rats were placed in a cold chamber adjustable to 0-2 ℃, and OVA solution was ultrasonically nebulized to induce cold-induced asthma in rats. After three weeks of treatment, the general behaviors of rats were observed. Hematoxylin-eosin(HE) staining was used to evaluate pathological changes in lung tissues, periodic acid-Schiff(PAS) staining assessed mucin changes, and Masson staining was performed to examine collagen deposition. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of the inflammatory factors interleukin-4(IL-4) and vascular endothelial growth factor(VEGF) in serum and bronchoalveolar lavage fluid(BALF). Real-time quantitative polymerase chain reaction(RT-PCR) was employed to assess the mRNA expression levels of transient receptor potential vanilloid subfamily member 1(TRPV1), nuclear respiratory factor 1(NRF-1), and mitochondrial transcription factor A(mtTFA) in lung tissues. Western blot was used to measure the protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues. Compared with the blank group, the model group exhibited signs of rapid respiration, increased frequency of defecation with looser stools, and disheveled and dull fur. Pathological results showed significant infiltration of inflammatory cells in lung tissues, narrowing of bronchial lumens, increased mucin secretion, and enhanced collagen deposition in the model group. Additionally, the levels of IL-4 and VEGF in serum and BALF were significantly elevated, and the mRNA and protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues were significantly increased. Compared with the model group, SGMHD improved the behaviors of rats, alleviated pathological changes in lung tissues, mucin production, and collagen deposition, significantly decreased the levels of IL-4 and VEGF in serum and BALF, and reduced the mRNA expression levels of TRPV1, NRF-1, and mtTFA in lung tissues, with the medium-dose SGMHD group showing the most significant effect. Moreover, the protein expression levels of TRPV1, NRF-1, and mtTFA in lung tissues were also reduced, with the medium-dose SGMHD group exhibiting the most significant effect. In conclusion, this study demonstrates that SGMHD can alleviate airway inflammation and inhibit airway remodeling in cold-induced asthma rats. These effects may be associated with the modulation of the TRPV1/NRF-1/mtTFA signaling pathway.

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).

Effects of lung rehabilitation based on Spiro-tiger training apparatus on respiratory mechanics and airway remodeling in stable COPD patients / 中国医学物理学杂志

Objective To explore the effects of lung rehabilitation using Spiro-tiger training apparatus on the respiratory mechanics and airway remodeling in patients with chronic obstructive pulmonary disease(COPD)in stable stage.Methods Ninety-three stable COPD patients admitted to Nanxiang Branch of Shanghai Ruijin Hospital were randomly divided into control group(46 cases)and observation group(47 cases).Control group was treated with the training for pursed lips breathing and abdominal breathing,and observation group was trained with Spiro-tiger training apparatus in addition to the treatment given to control group.Both groups were intervened continuously for 9 weeks.The two groups were compared in terms of respiratory mechanics(respiratory frequency,tidal volume,minute ventilation,and peak respiratory pressure),airway remodeling[matrix metalloproteinase-9(MMP-9),vascular endothelial growth factor(VEGF),and transforming growth factor-β1(TGF-β1)],and lung function[forced vital capacity(FVC),forced expiratory volume in the first second(FEV1),and FEV1/FVC],blood gas analysis indexes[arterial partial pressure of oxygen(PaO2),arterial partial pressure of carbon dioxide(PaCO2)],6-minute walking distance(6MWD)and health status[Borg scale and St.George's respiratory questionnaire(SGRQ)].The patients were followed up for 6 months,and the incidence of acute exacerbation of COPD was recorded.Results After 9 weeks of intervention,compared with control group,observation group had lower peak respiratory frequency and respiratory pressure,and higher tidal volume(P<0.05).There was no significant difference in minute ventilation between two groups(P>0.05).The levels of MMP-9,VEGF,TGF-β1 and PaCO2 were lower,and FVC,FEV1,FEV1/FVC and PaO2 were higher in observation group than in control group(P<0.05).Observation group had longer 6MWD,and lower Borg score and SGRQ score as compared with control group(P<0.05).After 6-month follow-up,the incidence of COPD acute exacerbation in observation group was lower than that in control group(4.26%vs19.57%,P<0.05).Conclusion Lung rehabilitation using Spiro-tiger training apparatus can effectively improve respiratory mechanics,lung function,blood gas analysis indexes and health status in stable COPD patients,alleviate airway remodeling,and avoid acute exacerbation of COPD.

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.

Fuganlin oral liquid ameliorates airway remodeling through TGF-β1/Smad3 signaling pathway in asthmatic mice / 中国药理学通报

Aim To explore the effect of Fuganlin on airway remodeling in obese asthmatic mice and its mechanism.Methods A model of chronic airway inflammation in C57 BL/6 mice with obese asthma induced by OVA and high-fat diet was established,and treated with Fuganlin 5.86,11.72 and 23.44 g·kg-1 by gavage.After the last challenge,the respiratory system resistance(Rrs),respiratory system elasticity(Ers),and respiratory system compliance(Crs)were measured with a lung function oscillator; the total number of white blood cells in whole blood was measured; tissue HE and MASSON staining were employed to observe the pathological changes.ELISA was used to detect the levels of IgE in serum and the levels of TGF-β1,Smad3 and SP in lung tissues; IHC was used to detect the expression levels of Smad3,SARA and protein in lung tissues.Results Fuganlin reduced the increase in the number of white blood cells in blood and inhibited the content of IgE in serum.Fuganlin could reduce the Rrs and Ers,enhance the Crs and regulate the respiratory function.Histopathological results showed that Fuganlin could reduce inflammatory cell infiltration and collagen deposition in the chronic airway inflammation model of obese mice,and inhibit bronchial mucosal proliferation; ELISA results showed that Fuganlin inhibited the expression of TGF-β1,Smad3,and SP; IHC results showed that Smad3 and SARA protein expression decreased.Conclusions The anti-obesity asthma effect of Fuganlin may help to improve respiratory function,control airway inflammation,and antagonize airway remodeling.

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.

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.

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.

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.

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.

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.

The anti-asthma effect of Mahuang decoction based on P38 MAPK/NF-KB signaling pathway and its mechanism / 中国药理学通报

Aim To explore the intervention effect of Mahuang decoction on airway remodeling and airway hyperresponsiveness in asthmatic rats based on the p38MAPK/NF-KB signaling pathway. Methods Network pharmacology was used to screen the potential signaling pathway of Mahuang decoction in treating asthma. The asthma model was replicated, and the airway reactivity and the pathologic changes of lung tissues of rats were observed. The concentrations of related indexes in rat serum and the expressions of key genes in murine pulmonary tissues were assessed. Results The results of network pharmacology identified 186 candidate targets, and pathway analysis showed that the treatment mechanism for asthma mainly involved Toll like receptor, mitogen activated protein kinase (MAPK), T cell receptor and so on. Mahuang decoction reduced the airway mucus secretion, attenuated the subcutaneous collagen deposition in the airway, and decreased the airway reactivity significantly. It also obviously inhibited the concentrations of VEGF, TGF-ßl, ET - 1, OPN and bJ-GF in rat serum, and the mRNA expressions of p38MAPK, NF-i

Correlation between airway remodeling and lung function in adult-onset eosinophilic asthma / 西安交通大学学报(医学版)

【Objective】 To investigate the airway parameters of adult-onset eosinophilic asthma （EA） and analyze the correlation between airway remodeling and lung function by quantitative CT. 【Methods】 From March 2015 to November 2016， totally 94 subjects from the “FACT-Digital Lung” Multi-research Center were divided into three groups： 30 normal subjects， 33 EA patients and 31 non-eosinophilic asthma （NEA） patients. We measured and recorded the bronchial parameters of RB1， LB1+2， RB10， and LB10， and small airway disease parameters. The indicators for quantitative evaluation of bronchial parameters include lumen area （LA）， wall thickness （WT）， wall area （WA）， and wall area percentage （WA%）. The parameters for the quantitative assessment of small airway disease included the percentage of inspiratory voxels below -950HU （IN-950）， the mean lung density （MLDin）， and the whole volume of the lung in inspiration （Vin）. Pearson or Spearman rank correlation analysis was used to evaluate the correlation between these parameters and lung function. 【Results】 The differences in LA/BSA， WT/√BSA， and WA/BSA between the three groups were statistically significant （P<0.05）. FEV1% had a significant correlation with IN-950 and MLDin （P<0.01）. FEV1/FVC had a significant correlation with Vin， IN-950， and MLDin （P<0.01）. EOS counts were positively related to IN-950 （r=0.343， P=0.011）， while EOS had a negative correlation with FEV1% （r=－0.343， P=0.015）. 【Conclusion】 With the increase of eosinophils counts in peripheral blood， the airway's stenosis in asthma patients gradually increased， and the extent of airflow limitation steadily increased. The IN-950 may be a sensitive imaging biomarker for evaluating the small airway disease in adult-onset eosinophilic asthma patients.