OBJECTIVETo study the effects of alltrans retinoic acid (ATRA) on airway responsiveness, airway remodeling and expression of matrix metalloproteinase-9 (MMP-9) protein in rats with asthma.

METHODSForty rats were randomly divided into five groups: asthma model, normal saline (control), ATRA treatment, cotton oil treatment and budesonide treatment (n=8 each). Asthma was induced by ovalbumin sensitization and challenge in the asthma model, and the ATRA, cotton oil or budesonide treatment groups. ATRA (50 μg/kg), cotton oil (1 mL) or budesonide (0.32 mg/kg) was administered before ovalbumin challenge in the three treatment groups. Airway responsiveness was assessed. The lung tissues were sampled to detect airway remodeling and the expression of MMP-9 protein by immunohistochemistry.

RESULTSThe expression of MMP-9 in lung tissues in the ATRA treatment group was significantly higher than that in the control group, but the airway responsiveness in the ATRA treatment group was not significantly different from that in the control group. The airway responsiveness and the expression of MMP-9 in lung tissues were significantly reduced in the ATRA treatment group compared with the asthma model group. The airway remodeling was significantly improved in the ATRA treatment group compared with the asthma model group.

CONCLUSIONSATRA may alleviate airway hyperresponsiveness and airway remodeling possibly through decreasing the protein expression of MMP-9 in rats with asthma.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; pathology ; physiopathology ; Bronchi ; drug effects ; pathology ; physiopathology ; Lung ; enzymology ; Matrix Metalloproteinase 9 ; analysis ; Rats ; Rats, Sprague-Dawley ; Tretinoin ; pharmacology

OBJECTIVETo study the expression of stromal cell derived factor-1(SDF-1) and CXC chemokine receptor 4 (CXCR4) in the airway and the effect of budesonide on their expression in mice with asthma.

METHODSThirty BALB/c male mices were randomly divided into three groups: placebo control, untreated asthma, and budesonide-treated asthma. The asthma group were induced by intraperitoneal injection of 10% ovalbumin (OVA ) on days 1, 8 and 15, and then from days 22 to 34, challenged by inhalation of 2% OVA aerosol every other day. The budesonide-treated asthma group received an inhalation of budesonide (1 mg ) before OVA challenge. The pathological changes of the airway were assessed by hematoxylin and eosin staining. The immunohistochemistry was used to estimate the expression of SDF-1 in the lung. RT-PCR was used to evaluate the expression of CXCR4 in the lung.

RESULTSCompared with the control group, SDF-1 and CXCR4 expression in the lung in the untreated asthma group increased significantly (p<0.05). The budesonide-treated asthma group demonstrated significantly decreased SDF-1 (0.426+/-0.052 vs 0.361+/-0.065; p<0.05) and CXCR4 (0.829+/-0.027 vs 0.723+/-0.094; p<0.05) expression in the lung as compared with the untreated asthma group. Both SDF-1 (r=0.744, p<0.01) and CXCR4 (r=0.553, p<0.01)were positively correlated with the thickness of the airway wall.

CONCLUSIONSSDF-1 and CXCR4 may be associated with airway remodeling in mice with asthma. Budesonide can improve airway remodeling, possibly by decreasing the expression of SDF-1 and CXCR4.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; metabolism ; pathology ; Budesonide ; pharmacology ; Chemokine CXCL12 ; analysis ; Male ; Mice ; Mice, Inbred BALB C ; Receptors, CXCR4 ; analysis ; genetics

Airway Remodeling ; drug effects ; Cholinergic Antagonists ; therapeutic use ; Humans ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; immunology ; metabolism ; Scopolamine Derivatives ; therapeutic use ; Tiotropium Bromide

OBJECTIVETo investigate the effect of bicuculline, a selective GABAA receptor antagonist, on airway remodeling in the murine model of chronic allergen-induced asthma.

METHODSForty BALB/C mice were randomized into 4 groups, namely the control group, asthmatic model (induced by ovalbumin sensitization and challenge) group, budesonide inhalation group and bicuculline inhalation group. The mice were sacrificed 24 h after the last ovalbumin inhalation, and the lungs were lavaged with PBS and the total cells, eosinophils and lymphocytes counts were examined. Periodic acid-Schiff (PAS) staining was used for counting mucin-positive goblet cells in the lung tissue, and Masson Trichrome staining was used to evaluate collagen deposition. GABAARbeta2 and VEGF were quantified by immunohistochemistry.

RESULTSThe numbers of the total cells, eosinophils and lymphocytes counts in BALF were significantly greater in the bicuculline group than in the control and budesonide groups (P<0.01), but comparable to those in the asthmatic model group (P>0.05). The airway collagen deposition in the bicuculline group was comparable to that in the control and budesonide group (P>0.05), but was significantly less than that in the asthmatic model group (P<0.05). Significant differences were found in the airway histological mucus index between the bicuculline group and the other 3 groups (P<0.05). The airway GABAARbeta2-positive cell percentage in the bicuculline group was significantly greater that those in the control and budesonide (P<0.01 and 0.05), but similar with that in the asthmatic model group (P>0.05). The percentage of pulmonary perivascular VEGF-positive cells in the bicuculline group was significantly greater in the control and budesonide groups (P<0.01 and P<0.05), but comparable to that in the asthmatic model group (P>0.05).

CONCLUSIONGABAARbeta2 is expressed in both the airway epithelium and smooth muscles. Bicuculline inhalation can effectively suppress collagen deposition with a stronger inhibitory effect on mucus hypersecretion than budesonide.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; pathology ; Bicuculline ; therapeutic use ; Disease Models, Animal ; GABA-A Receptor Antagonists ; therapeutic use ; Male ; Mice ; Mice, Inbred BALB C

OBJECTIVETo study the dynamic changes in the percentage of Th17 cells/CD4CD25regulatory T cells after intervention with montelukast sodium, a leukotriene receptor antagonist, in asthmatic mice and the association between them.

METHODSBalb/c mice were randomly divided into blank group, asthma group, and montelukast sodium group. The asthmatic mouse model of airway remodeling was established by sensitization with intraperitoneal injection of chicken ovalbumin (OVA) and aluminum hydroxide suspension and aerosol inhalation of OVA. The mice in the blank group were given normal saline, and those in the montelukast sodium group were given montelukast sodium by gavage before aerosol inhalation. Eight mice were randomly sacrificed within 24 hours after 2, 4, and 8 weeks of aerosol inhalation. The pathological sections of lung tissue were used to observe the degree of airway remodeling. Flow cytometry was used to measure the percentages of Th17 cells and CD4CD25regulatory T cells in CD4T cells.

RESULTSThe asthma group and the montelukast sodium group had significantly higher bronchial wall thickness and smooth muscle thickness at all time points compared with the blank group (P<0.05). At 8 weeks of intervention, the montelukast sodium group had significantly greater improvements in the above changes compared with the asthma group (P<0.05). Compared with the blank group, the asthma group and the montelukast sodium group had significant increases in Th17 cells (positively correlated with airway remodeling) and significant reductions in CD4CD25regulatory T cells (negatively correlated to airway remodeling) at all time points (P<0.05). At 8 weeks of intervention, the montelukast sodium group had a significant reduction in the number of Th17 cells and a significant increase in the number of CD4CD25regulatory T cells compared with the asthma group (P<0.05).

CONCLUSIONSMontelukast sodium intervention can alleviate airway remodeling and achieve better improvements over the time of intervention. The possible mechanism may be related to the improvement of immunologic derangement of CD4CD25regulatory T cells and inhibition of airway inflammation.

Acetates ; pharmacology ; Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; immunology ; Female ; Lung ; pathology ; Mice ; Mice, Inbred BALB C ; Quinolines ; pharmacology ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology

OBJECTIVETo establish a mouse model of asthmatic airway remodeling and investigate the effects of 1,25-(OH)2D3 on airway structure and T cell immunoglobulin mucin protein-4 (TIM-4) expression in asthmatic mice.

METHODSThirty female mice (BALB/c strain) were randomly divided into control, asthma and 1,25-(OH)2D3 intervention groups. An asthmatic mouse model was induced using ovalbumin. Lung tissue of the mice was collected, mRNA expression of TIM-4 was evaluated by RT-PCR and airway remodeling and protein expression of TIM-4 were observed by hematoxylineosin staining and immunohistochemistry.

RESULTSTypical airway remodeling was found in the asthma group, and TIM-4 expression in this group was significantly higher than in the control group (105±9 vs 42±5; P<0.05). Compared with the asthma group, the 1,25-(OH)2D3 intervention group showed improvement in airway remodeling and a decrease in TIM-4 expression (78±6) (P<0.05).

CONCLUSIONSTIM-4 may be involved in the airway remodeling of mice. As a new type of immunoregulator, 1,25-(OH)2D3 can downregulate expression of TIM-4 in the lungs and improve airway remodeling in asthmatic mice.

Airway Remodeling ; Animals ; Asthma ; metabolism ; Calcitriol ; pharmacology ; Female ; Gene Expression Regulation ; drug effects ; Lung ; metabolism ; Membrane Proteins ; analysis ; genetics ; physiology ; Mice ; Mice, Inbred BALB C ; RNA, Messenger ; analysis

OBJECTIVETo investigate the effect of anti-miR-145 on human airway smooth muscle cell (HASMC) proliferation and osteopontin systhesis in vitro and explore the mechanisms.

METHODSHASMCs were treated with 10-100 nmol/L anti-miR-145, and the cell proliferation and apoptosis were investigated using a CCK-8 assay and flow cytometry, respectively. The changes in osteopontin synthesis after the treatment was quantified with Western blotting.

RESULTSTreatment with 10 and 50 nmol/L anti-miR-145 significantly promoted the proliferation and osteopontin synthesis in HASMCs (P<0.05 or <0.01), and 50 nmol/L anti-miR-145 obviously inhibited the cell apoptosis (P<0.01).

CONCLUSIONAnti-miR-145 promotes HASMC proliferation and osteopontin synthesis and inhibits HASMC apoptosis in vitro, indicating the important role of anti-miR-145 in the pathogenesis of airway remodeling.

Airway Remodeling ; Apoptosis ; Cell Proliferation ; Cells, Cultured ; Humans ; MicroRNAs ; antagonists & inhibitors ; Myocytes, Smooth Muscle ; drug effects ; Osteopontin ; biosynthesis ; Respiratory System ; cytology

OBJECTIVETo study the changes in the migration of airway smooth muscle cells (ASMC) in asthmatic rats with airway remodeling and the effect of NK-1R inhibitor WIN62577 on the migration of ASMC.

METHODSSprague-Dawley rats were randomly assigned into two groups: airway remodeling induced by asthma and normal control. ASMC from rats with asthma and airway remodeling induced by ovalbumin (OVA) inhalation for 8 weeks were primary cultured and purified. Immunofluorescence and real-time PCR were used to measure the expression of NK-1R. With NK-1R inhibitor WIN62577 treatment, the changes in the migration of ASMC were measured by transwell chambers.

RESULTSNK-1R in ASMC was expressed mainly in the cytoplasm and cell membrane in the airway remodeling group, and the mRNA expression of NK-1R was higher than the normal control group (P<0.01). The number of the migrated ASMC in the airway remodeling group was significantly higher than that in the normal control group (P<0.01). Various concentrations (10-11 mol/L, 10-10 mol/L, 10-9 mol/L and 10-8 mol/L) of WIN62577 treatment decreased the number of the migrated ASMC (P<0.05).

CONCLUSIONSNK-1R may affect airway remodeling possibly through promoting the migration ability of ASMC in rats with asthma.

Airway Remodeling ; drug effects ; Androstenes ; pharmacology ; Animals ; Asthma ; pathology ; Benzimidazoles ; pharmacology ; Cell Movement ; drug effects ; Female ; Myocytes, Smooth Muscle ; drug effects ; physiology ; Neurokinin-1 Receptor Antagonists ; pharmacology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effects of lipopolysaccharide (LPS) on airway inflammation, airway remodeling and the expression of Toll-like receptor 4 (TLR4) mRNA in asthmatic rats.

METHODSTwenty-four SPF level SD rats were randomly divided into four groups (n = 6): control group, low dose of LPS group, high dose of LPS group and asthma group. Using ovalbumin (OVA) to sensitize and challenge to establish asthmatic rat model. Observed pathological changes of lung tissue by HE staining, inflammatory cell infiltration was observed by airway wall eosinophils (EOS) counts; airway resistance was determined; image analysis software was used to determine the thickness of airway wall, detected airway smooth muscle TLR4 expression levels by RT-PCR.

RESULTSThe rat airway resistance and the EOS number of airway wall and the thickness of airway wall in asthma group, low dose of LPS group and high dose of LPS group were significantly higher than those in control group (P < 0.01). The above-mentioned parameters of high dose of LPS group showed significantly lower than those in asthma group and low dose of LPS group (P < 0.05). The expression of rat airway smooth muscle TLR4 mRNA in low dose of LPS group and high dose of LPS group were significantly higher than those in asthma group (P < 0.01). And the expression of rat airway smooth muscle TLR4 mRNA in high dose of LPS group was significantly higher than that in low dose of LPS group (P < 0.05).

CONCLUSIONTLR4 plays an important role in asthmatic airway inflammation and airway remodeling, LPS may play double-sided regulation in asthmatic airway inflammation and airway remodeling by activated TLR4.

Airway Remodeling ; drug effects ; Animals ; Asthma ; metabolism ; pathology ; physiopathology ; Inflammation ; metabolism ; Lipopolysaccharides ; adverse effects ; pharmacology ; Lung ; metabolism ; physiopathology ; Male ; Muscle, Smooth ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Toll-Like Receptor 4 ; metabolism

OBJECTIVETo investigate the roles of signal transduction and activator of transcription 6 (STAT6) and orosomucoid 1-like 3 (ORMDL3) in airway remodeling among asthmatic mice and to observe the effects of budesonide (BUD) on their expression.

METHODSThirty BALB/c mice were randomly divided into control, asthma, and BUD intervention group. The mice were sensitized and challenged with ovalbumin (OVA) to establish a mouse model of asthma. The BUD intervention group received aerosol inhalation of BUD dissolved in normal saline 30 minutes before each OVA challenge, while normal saline was used instead of OVA solution in the control group. The pathological changes in the airway were observed by hematoxylin-eosin staining and Masson staining. The interleukin-13 (IL-13) level in lung homogenate was measured by enzyme-linked immunosorbent assay. The mRNA expression of STAT6 and ORMDL3 was measured by RT-PCR.

RESULTSThe asthma group showed more pathological changes in the airway than the control and BUD intervention groups, and the BUD intervention group had reduced pathological changes in the airway compared with the asthma group. The asthma and BUD intervention groups had significantly higher IL-13 levels and mRNA expression of STAT6 and ORMDL3 than the control group (P<0.05), and these indices were significantly higher in the asthma group than in the BUD intervention group (P<0.05). The Pearson correlation analysis showed that STAT6 mRNA expression was positively correlated with ORMDL3 mRNA expression (r=0.676, P=0.032).

CONCLUSIONSSTAT6 and ORMDL3 may be involved in the airway remodeling of mice, and BUD can reduce airway remodeling in asthmatic mice, possibly by down-regulating mRNA expression of STAT6 and ORMDL3.

Airway Remodeling ; drug effects ; Animals ; Asthma ; drug therapy ; pathology ; Budesonide ; pharmacology ; Down-Regulation ; Female ; Gene Expression Regulation ; drug effects ; Interleukin-13 ; analysis ; Lung ; metabolism ; Membrane Proteins ; genetics ; Mice ; Mice, Inbred BALB C ; STAT6 Transcription Factor ; genetics