Mechanism of Yanghe Pingchaun granules on airway remodeling in asthmatic rats based on IL-6/JAK2/STAT3 signaling axis

Objective: To investigate the effects of Yanghe Pingchuan Granules on airway remodeling in asthmatic rats, and to explore the mechanism of Interleukin-6/Janus kinase 2/ Signal transducing activator of transcription 3(IL-6/JAK2/STAT3) signal axis. Methods: We separated 42 healthy male SD rats into two groups, a control group (7) and a model group (35).The model group was sensitized with a combination of ovalbumin (OVA) and aluminum hydroxide for 2 weeks, while the control group was given an equal amount of physiological saline.After 2 weeks, the modeling group was randomly divided into Model group, Yanghe Pingchuan Granules high, medium and low dose groups and Dexamethasone group, each group consisted of 7 animals. After 4 weeks, OVA atomization and gavage were used for stimulation and treatment. Yanghe Pingchuan Granules high, middle and low groups were given 15.48, 7.74, 3.87 g∙kg-1 Yanghe Pingchuan Granules daily, dexamethasone group was given 0.0625 mg∙kg-1 dexamethasone daily, and the other groups were given the same amount of normal saline. HE, PAS and Masson staining were used to observe the lung histopathological changes in rats. The levels of interleukin-6, IL-23 and IL-17A were detected by ELISA. The expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 in lung tissues were detected by Western blot. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of IL-6, JAK2 and STAT3 in rat lung tissue. Results: The lung tissue structure of the model group was severely damaged compared to the control group, accompanied by a great many of inflammatory cell infiltration, goblet cell hyperplasia, subepithelial collagen fiber deposition and airway epithelial thickening were more obvious. The expressions of IL-6, IL- 23 and IL-17A in serum were significantly increased (P<0.01), the protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and the mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly increased (P<0.01);Compared with the model group, inflammatory cell infiltration, goblet cell proliferation, subepithelial collagen fiber deposition and airway epithelial thickening were significantly reduced in each administration group, and the expressions of IL-6, IL-23 and IL-17A in serum were significantly decreased (P< 0.01). The protein expression levels of JAK-2, P-JAK2, STAT3 and P-STAT3 and mRNA expression levels of IL-6, JAK2 and STAT3 in lung tissue were significantly decreased (P<0.01). Conclusion: Yanghe Pingchuan Granules can significantly alleviate airway remodeling in asthmatic rats, and its mechanism may be through inhibiting the IL-6/JAK2/STAT3 signal axis.

Effect of Nuclear Factor-κB on Airway Remodeling in Asthmatic Rats

In order to investigate the effect of nuclear factor κB (NF κB) on airway remodeling in asthmatic rats, 18 Wistar rats were divided into three groups: asthmatic group; pyrrolidine dithiocarbamate (PDTC) group, in which rats were injected intraperitoneally with NF κB specific inhibitor PDTC (100 mg/kg) before ovalbumin (OVA) challenge; control group. The NF κB activity and the expression of inhibitory protein κBα (I κBα) in airway were detected by electrophoretic mobility shift assay (EMSA), Western blot and immunohistochemistry respectively. The infiltration of inflammatory cells, the number of Goblet cells, the area of collagen and smooth muscle in airway were measured by means of image analysis system. The results showed that with the up regulation of airway NF κB activity in asthmatic group, the number of goblet cells (3.08±0.86/100 μm basement membrane (BM)), the area of collagen (24.71±4.24 μm 2/μm BM) and smooth muscle (13.81±2.11 μm 2/μm BM) in airway were significantly increased ( P <0.05) as compared with control group (0.14±0.05/100 μm BM, 14.31 ±3.16 μm 2/μm BM and 7.67±2.35 μm 2/μm BM respectively) and PDTC group (0.33±0.14/100 μm BM, 18.16±2.85 μm 2/μm BM and 8.95±2.16 μm 2/μm BM respectively). However, there was no significant difference between PDTC group and control group ( P >0.05). It was concluded that the activity of NF κB is increased in airway of asthmatic rats. Inhibition of NF κB activation can attenuate constructional changes in asthma airway, suggesting NF κB may contribute to asthmatic airway remodeling.

Theory discussion on airway remodeling of bronchial asthma

According to modern research,the pathogenesis of asthma mainly includes airway inflammation,airway hyperresponsiveness,airway remodeling,etc.Airway remodeling is the key factor that leads to the progress of asthma,and it is also the main factor that leads to airway hyperresponsiveness and irreversible airflow restriction.Traditional Chinese medicine believes that"phlegm and blood stasis"block the airway and narrow the lumen is the most important factor in the treatment of asthma.

A study on the rule of Chinese medicine use for airway remodeling based on data mining

Objective:Use data mining techniques to explore the rule of Chinese medicine used for airway remodeling.Methods:Search the literature on Chinese medicine use for airway remodeling in the past 20 years.With the help of WPS Office Excel 11.1,IBM SPSS Statistics 23.0 and SPSS Modeler 18.0 software,prescriptions were analyzed for the frequency of drug use,the four natures,the five flavours and the channel tropism,cluster analysis and association analysis of high-frequency drugs.Results:There were 58 Chinese medicine prescriptions for airway remodeling be found,involving 105 Chinese medicines,the most frequent channel tropism were spleen,stomach,lung,large intestine,liver and gallbladder,the most frequent use of the five flavors was sour,sweet and pungent,the highest frequency of the four natures was cold and hot,cluster analysis yielded eight drug aggregation groups,and association rule analysis yielded five groups of high-frequency drug pairs.Conclusion:The main TCM treatments for airway remodeling are expelling phlegm,relieving cough,asthma calming,expelling blood stasis and deficiency tonifying.The results of this study can provide ideas for compounding and drug selection for subsequent studies.

HMGB 1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

The pro-inflammation factor high-mobility group box protein 1 （HMGB1） has been implicated in the pathogenesis of asthma. In this study, we used a murine model of chronic asthma to evaluate the effects of HMGB 1 on airway remodeling. Female BALB/c mice were randomly divided into four groups： control, ovalbumin （OVA） asthmatic, OVA＋ isotype antibody and OVA＋anti-HMGB 1 antibody. Anti-HMGB 1 antibody therapy was started on day 21 and was administered three times per week for 6 weeks before intranasal challenge with OVA. In this mouse model, HMGB1 expression is significantly elevated. The anti-HMGB1 antibody group exhibited decreased levels of immunoglobulin E （IgE） and inflammatory mediators and reduced inflammatory cell accumulation, airway hyperresponsiveness （AHR）, mucus synthesis, smooth muscle thickness and lung collagen content compared with the OVA groups. Treatment with HMGB1 increased proliferation, migration, collagen secretion and a-smooth muscle actin （SMA） expression in MRC-5 ceils. Treatment with the HMGB1/IL-1β complex significantly increased the expression and secretion of transforming growth factor （TGF-βl）, matrix metalloproteinase （MMP）-9 and vascular endothelial growth factor （VEGF）. Altogether, these results suggest that blocking HMGB1 activity may reverse airway remodeling by suppressing airway inflammation and modulating lung fibroblast phenotype and activation.

Montelukast improves air trapping, not airway remodeling, in patients with moderate-to-severe asthma： a pilot study

Background Evidence has demonstrated that the distal lung,which includes airways of 〈2 mm in diameter and lung parenchyma,constitutes an important component of asthma pathology.Cysteinyl leukotrienes （CysLTs） are potent proinflammatory mediators and bronchoconstrictors involved in the asthmatic process.Guidelines recommend the leukotriene-modifying agents for asthma treatment.We hypothesized that a leukotriene receptor antagonist with an inhaled corticosteroid （ICS） and long-acting β2 agonist （LABA） combination would improve small airways function in moderate-tosevere asthmatics evaluated by physiological tests and high-resolution computed tomography （HRCT） analysis.This study was performed at a tertiary university hospital in Beijing.Methods This was a randomized,double-blind,parallel study performed in 38 patients with moderate-to-severe asthma treated with salmeterol/fluticasone （SFC） plus montelukast （SFC＋M） or SFC plus placebo over 24 weeks.Small airway function was assessed by physiological studies and HRCT image analysis.Results Montelukast significantly improved air trapping as expressed by the residual volume （RV）/total lung capacity （TLC）.Over 24 weeks of treatment,RV/TLC was improved by （15.41±6.67）% in patients receiving SFC＋M while RV/TLC was decreased by （8.57±10.26）% in patients receiving SFC alone,the difference between the two groups was significant （P=0.02）.There was a trend towards a significant difference in forced expiratory volume in the first second （FEV1）/forced vital capacity （FVC） in the SFC＋M group compared to that in the SFC group （（17.87±8.17）% vs.（12.28±9.20）%,P=0.056）.There was no significant change in percentage wall area （WA%） after 24 weeks of add-on treatment with montelukast.Patients receiving SFC＋M showed significant improvement in the ratio of CT-determined values at full expiration to those at full inspiration （E/I ratio） （0.894±0.005 vs.0.871±0.003,P=0.002）.Conclusion We have shown,using lung function tests and HRCT image technique,that add-on therapy with montelukast improves distal lung function reflected by air trapping,but not airway wall thickness in moderate-to-severe asthma.（ClinicalTrials.gov number,NCT00699062）

Respiratory syncytial virus:the possible trigger of airway remodeling through matrix metaUoproteinase activation?

Respiratory syncytial virus （RSV） is a leading cause of .epidemic respiratory tract illness in children. Severe RSV infections involving the lower respiratory tract are primarily seen in young children with naive immune systems and/or genetic predispositions. However, RSV was not recognized as a potentially serious problem in older adults until the 1970s, when outbreaks of the virus infection occurred in long-term care facilities. Since then, additional studies in hospitalized adults have suggested that RSV may be an important cause of illness in community-dwelling elderly people, patients with suppressed T-cell immunity （such as heart transplant recipients）.

The relationship between the expression of transient receptor potential vanilloid 1 and the airway remodeling in elderly patients with chronic obstructive pulmonary disease

Objective To investigate the relationship between the expression of trannsient receptor potential vanilloid(TRPV1)and the severity of airway remodeling in elderly patients with chronic obstructive pulmonary disease(COPD).Methods According to airflow obstruction severity,totally 100 cases of elderly patients with

Serum Neutrophil Gelatinase-associated Lipocalin(NGAL)Is Elevated in Patients with Asthma and Airway Obstruction

Neutrophilic airway inflammation is one of the features of severe asthma.Neutrophil gelatinase-associated lipocalin(NGAL),or lipocalin-2,is a glycoprotein associated with neutrophilic inflammation and can be detected in blood.Recently,blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease.However,the clinical significance of serum NGAL levels in patients with asthma has not been elucidated.The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma.Sixty.one non-smoking people with stable asthma were enrolled in this study.All patients underwent blood ollction and pulmonary function tests.The associations between serum NGAL levels and clinical parameters were analyzed retrospectively.Serum NGAL levels in patients with asthma and obstructive ventilatory defect were higher than those in patients with asthma without obstructive ventilatory defect(76.4±51.4 ng/mL vs.39.3±27.4 ng/mL,P=0.0019).Serum NGAL levels were correlated with forced expired flow at 50%of vital capacity%predicted and forced expired flow at 75%of vital capacity%predicted(r=-0.3373,P=0.0078 and r=0.2900,P=0.0234,respectively).Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory defect.Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory defect.NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.

Anti-asthmatic mechanism of the Huashanshen dripping pill via suppressing contraction of the airway smooth muscle

Background:The Huashanshen(HSS)dripping pill has been widely used in asthma for a long time in China.However,the relaxant mechanism of HSS is not well understood.Methods:In this report,high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to identify the constituents in rat plasma after oral administration of HSS.Ovalbumin-sensitized allergic asthma and isolated trachea were studied for the anti-asthmatic mechanism of HSS.Results:D-anisodamine,L-anisodamine,scopolamine and atropine were detected in the rat plasma containing HSS.It was clear that the HSS inhibited the release of inflammatory mediators,regulated the balance of T-helper 1 and T-helper 2 to reduce the airway inflammation,and relaxed the tracheal smooth muscle by controlling the KCa channel,Ca^(2+)influx and release to reduce the airway hyperresponsiveness.Conclusion:Atropine,anisodamine and scopolamine might be active compounds of HSS which inhibited the release of inflammatory mediators,regulated the balance of Th1/Th2,and relaxed the tracheal smooth muscle to reduce airway hyperresponsiveness.

Chemokine-like factor 1,a novel cytokine,contributes to airway damage,remodeling and pulmonary fibrosis

Background Chemokine-like factor 1 (CKLF1) was recently identified as a novel cytokine The full-length CKLF1 cDNA contains 530 bp encoding 99 amino acid residues with a CC motif similar to that of other CC family chemokines Recombinant CKLF1 exhibits chemotactic activity on leucocytes and stimulates proliferation of murine skeletal muscle cells We questioned whether CKLF1 could be involved in the pathogenesis of inflammation and proliferation in the lung Therefore we used efficient in vivo gene delivery method to investigate the biological effect of CKLF1 in the murine lung Methods CKLF1-expressing plasmid, pCDI-CKLF1, was constructed and injected into the skeletal muscles followed by electroporation Lung tissues were obtained at the end of week 1,2,3 and 4 respectively after injection The pathological changes in the lungs were observed by light microscope Results A single intramuscular injection of CKLF1 plasmid DNA into BALB/c mice caused dramatic pathological changes in the lungs of treated mice These changes included peribronchial leukocyte infiltration, epithelial shedding, collagen deposition, proliferation of bronchial smooth muscle cells and fibrosis of the lung Conclusions The sustained morphological abnormalities of the bronchial and bronchiolar wall, the acute pneumonitis and interstitial pulmonary fibrosis induced by CKLF1 were similar to phenomena observed in chronic persistent asthma, acute respiratory distress syndrome and severe acute respiratory syndrome These data suggest that CKLF1 may play an important role in the pathogenesis of these important diseases and the study also implies that gene electro-transfer in vivo could serve as a valuable approach for evaluating the function of a novel gene in animals

Low-intensity aerobic exercise training attenuates airway inflammation and remodeling in a rat model of steroid-resistant asthma

Background Aerobic exercise can improve symptoms,reduce airway inflammation,and even ameliorate airway remodeling in asthmatic animals and patients.However,previous studies have focused mainly on the effect of aerobic exercise on steroid-sensitive asthma （SSA）.The goals of this study were to determine the effect of low-intensity aerobic exercise training on airway hyperresponsiveness,inflammation,and remodeling in a rat model of steroid-resistant asthma （SRA） and to identify the potential mechanisms underlying these effects.Methods Endotoxin-free ovalbumin with or without lipopolysaccharide were applied to establish rat models of SRA and SSA,respectively.Airway hyperresponsiveness,inflammation,remodeling,expression of interleukin （IL）-25,IL-33,thymic stromal lymphopoietin （TSLP）,high mobility group box-1 （HMGB1）,and IL-17 in bronchoalveolar lavage fluid （BALF）,and the role of dexamethasone （DXM） were compared between these two asthmatic rat models.The effect of low-intensity aerobic exercise training and anti-HMGB1 treatment on airway hyperresponsiveness,inflammation,and remodeling in SRA rats also was evaluated.Results SRA rats developed neutrophil-dominated airway inflammation （（29.5±4.1）％ of the total cell numbers in BALF）,whereas SSA rats developed eosinophil-dominated airway inflammation （（24.0±6.1）％ of the total cell numbers in BALF）.Compared with SSA rats,SRA rats had more severe airway hyperresponsiveness,lower levels of IL-25 （（33.6±10.3） vs.（104.8±24.9） pg/ml）,IL-33 （（87.5±25.0） vs.（226.6±40.7） pg/ml）,and TSLP （（1 933.2±899.5） vs.（7 224.0±992.1） pg/ml）,and higher levels of HMGB1 （（21.2±4.5） vs.（5.4±1.6） ng/ml） and IL-17 （（780.5±261.7） vs.（291.4±76.4） pg/ml） in BALF （all P ＜0.05）.However,there was no significant difference in goblet cell hyperplasia,subepithelial collagen thickness,and airway smooth muscle remodeling between the two groups.Compared with control SSA rats,airway hyperresponsiveness,inflammation,and remodeling in SRA rats were less sensitive to DXM treatment.Anti-HMGB1 treatment attenuated airway hyperresponsiveness,inflammation,and remodeling in SRA rats to a certain extent and was accompanied by lower levels of IL-17 （（369.2±126.7） vs.（780.5±261.7） pg/ml in control SRA rats） in BALF （P ＜0.05）.Low-intensity aerobic exercise training decreased the expression of both HMGB1 （（14.1±2.9） vs.（21.2±4.5） ng/ml in control SRA rats） and IL-17 （（545.3±148.6） vs.（780.5±261.7） pg/ml in control SRA rats） in BALF （all P ＜0.05） and was accompanied by improved airway hyperresponsiveness,inflammation,and remodeling in SRA rats （all P ＜0.05）.Conclusions Low-intensity aerobic exercise training attenuated airway hyperresponsiveness,inflammation,and remodeling in a rat model of SPA.Decreased HMGB1 and IL-17 levels in BALF by aerobic exercise training at least partly contributed to the improvements of SPA.

Shenmai Injection(参麦注射液) Inhibiting the Extracellular Signal Regulated Kinase-lnduced Human Airway Smooth Muscle Proliferation in Asthma

Objective： To investigate the relationship between the proliferation of sensitized human airway smooth muscle cells （HASMCs） and the expression of extracellular signal regulated kinase （ERK） and the effect of Shenmai Injection （参麦注射液, SMI） on HASMCs. Methods： The HASMCs cultured in vitro were divided into three groups： （1） control group; （2） sensitized group： containing 10% asthmatic serum; （3） SMI group： further divided into three different concentration subgroups interferred with 10 μL/mL, 50 μL/mL, and 100 μL/mL SMI, respectively. The proliferation of HASMCs was detected using MTT method, the expression of proliferating cell nucleus antigen （PCNA） in HASMCs was detected using immunocytochemical staining, and the expression of phosphoration-ERK1/2 （p-ERK1/2） protein was detected using Western-blot. Results： After passive sensitization, the optical density value （A49o value） of HASMCs was significantly increased from 0.366± 0.086 to 0.839 ± 0.168 （P〈0.05）. In addition, the expression of PCNA was significantly increased from 28.7% ± 5.9% in the control group to 69.8% ±7.5% in the sensitized group （P〈0.05）. At the same time, the expression of p-ERK1/2 in passively sensitized HASMCs was significantly increased compared with the control group （all P〈0.05）. Affer application of 10 μL/mL, 50 μL/mL, and 100 μL/mL SMI to the cultured media of passively sensitized group, the A570 value was significantly decreased from 0.839 ±0.168 to 0.612 ±0.100, 0.412 ± 0.092, and 0.339 ± 0.077, respectively （P〈0.05）. Moreover, the expression of PCNA was significantly decreased from 69.8% ±7.5% to 57.8% ± 6.2%, 40.7%±5.4%, and 26.1% ± 5.2%, respectively. At the same time, the expression of p-ERK1/2 in each SMI group was significantly decreased compared with the sensitized group （all ,P〈0.05）. Conclusion： ERK signal transduction pathway may be involved in the airway remodeling in asthma. The expression of ERK can be inhibited by SMI in a dose-dependent manner, thus preventing the proliferation of HASMCs.

Effects of angiotensin Ⅱ receptor antagonist on expression of collagen Ⅲ,collagen Ⅴ,and transforming growth factor β_1 in the airway walls of sensitized rats

Background Repeated attacks of bronchial asthma lead to different degrees of airway remodeling,the mechanism of which is not yet clear. Some evidences indicate that it is related to the excessive expression of some growth promotion factors. Angiotensin Ⅱ is a polypeptide that may be involved in airway remodeling. To evaluate its role in airway remodeling in asthma,we observed the effects of an angiotensin Ⅱ type 1 receptor antagonist (valsartan) on the expression of collagen Ⅲ,collagen Ⅴ,and transforming growth factor β_1 (TGF-β_1) mRNA and protein in the airway walls of sensitized rats.Methods Forty Wistar rats were randomly divided into 5 groups: control group,sensitized group,and valsartan groups 1,2,and 3. The rats in the sensitized group and in valsartan groups 1,2,and 3 were sensitized and challenged with ovalbumin. Rats in control group were sensitized and challenged with 0.9% NaCl. Rats from valsartan groups 1,2,and 3 were drenched with valsartan (10 μg, 20 μg,or 30 μg,respectively) at the time of the ovalbumin challenges. The expression of collagen Ⅲ,collagen Ⅴ,and TGF-β_1 protein were detected using immunohistochemical method in combination with image analysis methods. The expression of TGF-β_1 mRNA was detected by in situ hybridization. Results The expression in the airways of collagen Ⅲ and collagen Ⅴ was significantly higher in rats from the sensitized group (7.73±0.81, 1.34±0.28) and from valsartan groups 1,2,and 3 (5.73±0.64, 1.13±0.15; 4.96±0.51, 0.98±0.08; 4.43±0.35, 0.93±0.06,respectively) than those in the control group (2.65±0.38, 0.67±0.08,P <0.05). In addition,collagen levels were significantly lower in valsartan groups 1,2,and 3 than those from the sensitized group ( P <0.05). The expression of TGF-β_1 mRNA and protein in the airways was significantly higher in rats from the sensitized group (20.49%±3.46%,29.73%±3.25%) and from valsartan groups 1,2,and 3 (16.47%±1.94%, 19.41%±1.87%; 14.38%±1.58%, 18.29%±1.43%; 12.96%±1.73%, 18.63%±1.11%,respectively) than that from the control group (7.84%±1.61%, 5.63%±1.07%,P <0.05). TGF-β_1 mRNA and protein levels were significantly lower in valsartan groups 1,2,and 3 than that in the sensitized group ( P <0.05). Conclusions Angiotensin Ⅱ receptor antagonist valsartan can suppress synthesis of collagen Ⅲ and collagen Ⅴ by downregulating TGF-β_1 mRNA and protein expression. Valsartan can decrease airway remodeling and could play a role in asthma therapy.

Effect of basic fibroblast growth factor on the proliferation, migration and phenotypic modulation of airway smooth muscle cells

Background Proliferation, cell migration and phenotypic modulation of airway smooth muscle cells （ASMCs） are important features of airway remodelling in asthma. The precise cellular and molecular mechanisms that regulate ASMCs proliferation, migration and phenotypic modulation in the lung remain unknown. Basic fibroblast growth factor （bFGF）, a highly specific chemotactic and mitogenic factor for many cell types, appears to be involved in the development of airway remodelling. Our study assessed whether bFGF directly stimulates the proliferation, migration and phenotypic modulation of ASMCs. Methods Confluent and growth arrested human ASMCs were treated with human recombinant FGF. Proliferation was measured by BrdU incorporation and cell counting. Migration was examined using Boyden chamber apparatus. Expressions of smooth muscle （sm）-α-actin and sm-myosin heavy chain （MHC） isoform 1 were determined by RT-PCR and Westem blot analysis. Results It was found that hrbFGF （10 ng/ml）, when added to ASMCs, induced a significant increase in BrdU uptake and cell number by ASMCs as compared to controls and a significant increase in ASMCs migration with respect to controls. The mRNA and protein expressions of sm-α-actin and sm-MHC in ASMCs that were stimulated with hrbFGF decreased with respect to controls. Conclusion It appears that bFGF can directly stimulate proliferation and migration of ASMCs, however, the expressions of cells＇ contractive phenotype decreased.

The multifaceted role of placental growth factor in the pathogenesis and progression of bronchial asthma and pulmonary fibrosis:Therapeutic implications

Placental growth factor(PlGF)is a glycosylated dimeric protein that is homologous to vascular endothelial growth factor(VEGF).PlGF expression is upregulated in patients with bronchial asthma,suggesting that it plays a role in the pathogenesis of asthma.Bronchial asthma is characterized by chronic airway inflammation and airway hyperresponsiveness(AHR).After recurrent asthma attacks,pulmonary fibrosis develops and leads to airway remo-deling and a further decline in lung function.In this review,we focused on the pivotal role of PlGF in chronic airway inflammation,AHR,and airway remodeling during bronchial asthma.Furthermore,we summarized data showing that PlGF may be a potential therapeutic target in bronchial asthma.

Rosuvastatin attenuates mucus secretion in a murine model of chronic asthma by inhibiting the gamma-aminobutyric acid type A receptor

Background Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control, but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. A substantial amount of evidence suggests that statins have anti-inflammatory properties and immunomodulatory activity. In this study, we investigated the effect of rosuvastatin on airway inflammation and its inhibitory mechanism in mucus hypersecretion in a murine model of chronic asthma. Methods BALB/c mice were sensitized and challenged by ovalbumin to induce asthma. The recruitment of inflammatory cells into bronchoalveolar lavage fluid （BALF） and the lung tissues were measured by Diff-Quik staining and hematoxylin and eosin （H＆E） staining. ELISA was used for measuring the levels of IL-4, IL-5, IL-13 and TNF-a in BALE Periodic acid-Schiff （PAS） staining was used for mucus secretion. Gamma-aminobutyric acid type A receptor （GABAAR） β2 expression was measured by means of immunohistochemistry, reverse transcription-polymerase chain reaction （RT-PCR） and Western blotting. Results Rosuvastatin reduced the number of total inflammatory cells, lymphocytes, macrophages, neutrophils, and eosinophils recruited into BALF, the levels of IL-4, IL-5, IL-13 and TNF-a in BALF, along with the histological mucus index （HMI） and GABAAR 132 expression. Changes occurred in a dose-dependent manner. Conclusions Based on its ability to reduce the inflammatory response and mucus hypersecretion by regulating GABAAR activity in a murine model of chronic asthma, rosuvastatin may be a useful therapeutic agent for treatment of asthma.

Effects of Fengbaisan(丰白散) on the Expression of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Lung Tissue of Rats with Chronic Obstructive Pulmonary Disease

Objective： To observe effects of Fengbaisan （丰白散, FBS） on the expression of matrix metalloproteinase-9 （MMP-9） and tissue inhibitor of metalloproteinase-1 （TIMP-1） in lung tissue of rats with chronic obstructive pulmonary disease （COPD） and to investigate the preventive and therapeutic mechanisms of FBS. Methods： The COPD rat model was established by cigarette smoke exposure and lipopolysaccharide （LPS） intra-tracheal dripping. The histopathological changes of lung tissue was observed via hematoxylin/eosin staining. The expression of MMP-9 and TIMP-1 in lung tissue was measured by reverse transcription polymerase chain reaction （RT-PCR） and immunohistochemistry. Results： The typical histopathological changes of COPD were displayed in the model group, Ambroxol Hydrochloride group and FBS group, and the pathological lesions in the FBS group were less than those in the model group. The expression of MMP-9 and TIMP-1 in the model group increased significantly compared with those in the normal group （P〈0.05）. After treatment for successive 28 days, the expression of MMP-9 and TIMP-1 in the FBS group decreased remarkably as compared with the model group （P〈0.05）. Conclusions： FBS can regulate MMP-9/TIMP-1 imbalance to prevent airway and lung parenchyma remodeling process via reducing the expression of MMP-9 and TIMP-1 in the lung tissue of COPD rats, and this may be a possible therapeutic mechanism of FBS on COPD. KEYWORDS chronic obstructive pulmonary disease, Fengbaisan, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, airway remodeling, Chinese medicine

Effect of valsartan on the expression of angiotensin II receptors in the lung of chronic antigen exposure rats

Background Many studies have suggested that angiotensin Ⅱ （Ang Ⅱ） and its receptors may be involved in the development of asthma. However, the expression of angiotensin Ⅱ receptors （AGTR） is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma. Methods Rats were sensitized with ovalbumin （OVA） for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan （15, 30, 50 mg.kg-1.d-1） or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine （Ach）-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid （BALF） and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 （TGF-β1） and platelet-derived growth factor （PDGF） in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting. Results AGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness （mainly in small airways） in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats （50 mg.kg-1.d-1） were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway （including total airway wall thickness and smooth muscle area） and the levels of TGF-β1 and PDGF in BALE Conclusions AGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang Ⅱ and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.

Inhibitory effects of sunitinib on ovalbumin-induced chronic experimental asthma in mice

Background Tyrosine kinase signaling cascades play a critical role in the pathogenesis of allergic airway inflammation. Sunitinib, a multitargeted receptor tyrosine kinase inhibitor, has been reported to exert potent immunoregulatory, anti-inflammatory and anti-fibrosis effects. We investigated whether sunitinib could suppress the progression of airway inflammation, airway hyperresponsiveness （AHR）, and airway remodeling in a murine model of chronic asthma. Methods Ovalbumin （OVA）-sensitized mice were chronically challenged with aerosolized OVA for 8 weeks. Some mice were intragastrically administered with sunitinib （40 mg/kg） daily during the period of OVA challenge. Twelve hours after the last OVA challenge, mice were evaluated for the development of airway inflammation, AHR and airway remodeling. The levels of total serum immunoglobulin E （IgE） and Th2 cytokines （interleukin （IL）-4 and IL-13） in bronchoalveolar lavage fluid （BALF） were measured by ELISA. The expression of phosphorylated c-kit protein in the lungs was detected by immunoprecipitation/Western blotting （IP/WB） analysis. Results Sunitinib significantly inhibited eosinophilic airway inflammation, persistent AHR and airway remodeling in chronic experimental asthma. It reduced levels of total serum IgE and BALF Th2 cytokines and also lowered the expression of phosphorylated c-kit protein in remodelled airways. Conclusions Sunitinib may inhibit the development of airway inflammation, AHR and airway remodeling. It is potentially beneficial to the prevention or treatment of asthma.