Asthma is a common respiratory disease that affects 300 million of people worldwide, posing a serious health risk and medical burden. Development of new anti-asthmatic drugs and alternative treatment regimens is therefore encouraged. Recent studies have shown that Epidermal Growth Factor Receptor (EGFR) is involved in asthma development. In order to construct nanoparticles targeting EGFR for asthma treatment, a single chain antibody fragment (scFv) against EGFR was genetically engineered and modified at the N-terminal end of the human ferritin H-chain (FTH1) to construct Anti EGFR scFv::FTH1/FTH1 nanoparticles. Transmission electron microscopy showed that the nanoparticles were self-assembled into hollow cage-like structures with the particle size of about 12 nm. Semi-quantitative analysis of the purified nanoparticles by SDS-PAGE revealed the mass ratio of FTH1 to Anti EGFR scFv::FTH1 was 7:3. In House Dust Mite (HDM) driven models, Anti EGFR scFv::FTH1/FTH1 nanoparticles efficiently attenuated several key features of asthma, including goblet cell hyperplasia, mucous metaplasia and subepithelial fibrosis, showing the potential of using ferritin based nanoparticle for asthma treatment.
Asthma/drug therapy* ; Ferritins ; Humans ; Nanoparticles ; Oxidoreductases ; Single-Chain Antibodies/genetics*

Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1* 301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.
Animals ; Asthma, Aspirin-Induced/drug therapy/*genetics/*immunology ; Eosinophils/metabolism ; Genetic Predisposition to Disease/genetics ; Humans ; Leukotriene Antagonists/therapeutic use ; Leukotrienes/metabolism ; Models, Biological ; Polymorphism, Genetic/genetics/physiology

The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are β2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.
Adrenergic beta-2 Receptor Agonists ; therapeutic use ; Asthma ; drug therapy ; genetics ; Glucocorticoids ; therapeutic use ; Leukotrienes ; genetics ; therapeutic use ; Metabolic Networks and Pathways ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Precision Medicine

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

Adolescent ; Asthma ; drug therapy ; genetics ; immunology ; Child ; Child, Preschool ; Female ; Gene Expression Regulation ; drug effects ; Glucocorticoids ; therapeutic use ; Humans ; Immunoglobulin E ; blood ; Infant ; Interleukin-12 ; genetics ; Interleukin-13 ; genetics ; Male ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction

This study investigated the expression of interleukin-17 (IL-17) and T cell immunoglobulin mucin and domain-containing molecule-3 (Tim-3) in bronchoalveolar lavage fluid (BALF) of asthmatic mice and the effect of dexamethasone (DEX) on these factors. Thirty-six mice were randomly divided into three groups: normal group, asthmatic group and DEX group. The mouse model of asthma was established by sensitization with ovalbumin in both the asthmatic and DEX groups. The levels of IL-6, IL-10, IL-17 and TGF-β were measured in BALF by enzyme-linked immunesorbent assay (ELISA). The mRNA expression level of Tim-3 was detected by reverse transcription polymerase chain reaction (RT-PCR). The ratio of Tim-3+CD4+ cells to total CD4+ cells in BALF was determined by flow cytometry. Differential inflammatory cells in BALF were detected. The correlations among IL-17, IL-6, IL-10, Tim-3 and inflammatory cells were analyzed. The results showed that the levels of IL-17, IL-6 and Tim-3 were substantially increased and the IL-10 level decreased in BALF in the asthmatic mice, which was significantly reversed by DEX treatment. IL-17 expression was positively correlated with IL-6 and Tim-3 expression and the number of inflammatory cells but negatively with IL-10 expression. These results indicate that the increased expression of IL-17 and Tim-3 in BALF may be implicated in the occurrence and development of asthmatic inflammation; the mechanism by which DEX suppresses asthmatic airway inflammation involves down-regulation of IL-17 and Tim-3 levels.
Animals ; Asthma ; drug therapy ; genetics ; metabolism ; Bronchoalveolar Lavage Fluid ; chemistry ; Dexamethasone ; pharmacology ; Female ; Gene Expression ; drug effects ; genetics ; Hepatitis A Virus Cellular Receptor 2 ; Interleukin-17 ; genetics ; metabolism ; Mice ; Mice, Inbred BALB C ; Receptors, Virus ; genetics ; metabolism

OBJECTIVETo evaluate the effect of Shen-reinforcing and qi-supplementing (SRQS) drugs on some ingredients of neuro-endocrine-immune (NEI) network in asthma rat model.

METHODSAsthma model was established by ovalbumin sensitization and long-term excitation. Forty healthy Brown Norway rats of clean grade were randomly divided into 4 groups by randomized digital table, the normal control group and the three treated groups treated by low, moderate and high dose of SRQS drugs respectively. Blood content of adrenocorticotrophic hormone (ACTH) was detected by RIA; interleukin-6 (IL-6) and corticosterone were determined by ELISA; and the mRNA expresion of corticosteroid release hormone (CRH) in hypothalamus was tested by Realtime-PCR.

RESULTSEosinophile inflammation was shown in the pathology of asthma model rats, and also shown a multiple level hypothalamic-pituitary-adrenal axis (HPA axis) disorder at the repeated attack of asthma. After treatment, levels of ACTH and CRH mRNA expression in the treated groups were significantly higher than those in the control group (P <0.05), but the corticosterone only showed a rising tendency. Level of IL-6 increased during the episode, showing a significant negative correlation with ACTH (r = - 0.325, P = 0.043), and had somewhat reduction after SRQS treatment.

CONCLUSIONSRQS drugs could improve the function of HPH axis independent of IL-6, suggesting that the action is possibly targeted on the neuro-endocrine axis, which might be the hypothalamus.

Animals ; Asthma ; drug therapy ; genetics ; immunology ; physiopathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; Humans ; Hypothalamus ; drug effects ; immunology ; metabolism ; Interleukin-6 ; genetics ; immunology ; Kidney ; drug effects ; physiopathology ; Male ; Pituitary-Adrenal System ; drug effects ; immunology ; Qi ; Random Allocation ; Rats

Background: Glucocorticoid (GC) is the first-line therapy for asthma, but some asthmatics are insensitive to it. Glucocorticoid-induced transcript 1 gene (GLCCI1) is reported to be associated with GCs efficiency in asthmatics, while its exact mechanism remains unknown. Methods: A total of 30 asthmatic patients received fluticasone propionate for 12 weeks. Forced expiratory volume in 1 s (FEV) and GLCCI1 expression were detected. Asthma model was constructed in wild-type and GLCCI1 knockout (GLCCI1) mice. Glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase 1 (MKP-1) expression were detected by polymerase chain reaction and Western blotting (WB). The phosphorylation of p38 mitogen-activated protein kinase (MAPK) was also detected by WB. Results: In asthmatic patients, the change of FEV was well positively correlated with change of GLCCI1 expression (r = 0.430, P = 0.022). In animal experiment, GR and MKP-1 mRNA levels were significantly decreased in asthmatic mice than in control mice (wild-type: GR: 0.769 vs. 1.000, P = 0.022; MKP-1: 0.493 vs. 1.000, P < 0.001. GLCCI1: GR: 0.629 vs. 1.645, P < 0.001; MKP-1: 0.377 vs. 2.146, P < 0.001). Hydroprednisone treatment significantly increased GR and MKP-1 mRNA expression levels than in asthmatic groups; however, GLCCI1 asthmatic mice had less improvement (wild-type: GR: 1.517 vs. 0.769, P = 0.023; MKP-1: 1.036 vs. 0.493, P = 0.003. GLCCI1: GR: 0.846 vs. 0.629, P = 0.116; MKP-1: 0.475 vs. 0.377, P = 0.388). GLCCI1 asthmatic mice had more obvious phosphorylation of p38 MAPK than wild-type asthmatic mice (9.060 vs. 3.484, P < 0.001). It was still higher even though after hydroprednisone treatment (6.440 vs. 2.630, P < 0.001). Conclusions: GLCCI1 deficiency in asthmatic mice inhibits the activation of GR and MKP-1 and leads to more obvious phosphorylation of p38 MAPK, leading to a decremental sensitivity to GCs. Trial Registration ChiCTR.org.cn, ChiCTR-RCC-13003634; http://www.chictr.org.cn/showproj.aspx?proj=5926.
Animals ; Asthma ; drug therapy ; metabolism ; Dual Specificity Phosphatase 1 ; genetics ; metabolism ; Forced Expiratory Volume ; genetics ; physiology ; Glucocorticoids ; therapeutic use ; Mice ; Mice, Knockout ; Phosphorylation ; genetics ; physiology ; Receptors, Glucocorticoid ; deficiency ; genetics ; metabolism ; p38 Mitogen-Activated Protein Kinases ; genetics ; metabolism

OBJECTIVETo observe the effect of three-stage sequential method (TSSM) on interleukin-5 (IL-5) mRNA expression in the lung tissue of asthmatic rat model treated with steroid.

METHODSSD rats were randomly divided into 8 groups, the normal control group (GA), the model group (GB), the model with steroid intervention group (GC) and the 5 treated groups (GD - GH). Excepting those in the GA, all rats were established into the asthma model and rats in GC-GH were intervened by dexamethasone, with the dosage reduced by 0.1 mg/kg per week starting from the 3rd week and withdrawn completely till the 7th week. At the same time, rats in GD - GH were treated with TSSM, and the 1st, 2nd and 3rd recipe of TSSM, as well as pulmicort respules (as positive control) respectively. IL-5 mRNA expression in the lung tissue of rats was detected at different time points by in situ hybridization.

RESULTSComparisons of GD with other groups in IL-5 mRNA expression showed: it was remarkably lowered than that in GB and GC at all time points (P < 0.01); compared to GH, the difference was insignificant at the end of the 2nd week, but significant at the end of the 7th and 9th week (P < 0.01); as for the difference between GD with GE, GF and GG, it showed very significant difference (P < 0.01) at all the time points besides that at the end of the 2nd week, it showed insignificance to GE (P > 0.05) and significance to GF (P < 0.05). The dynamic changes of IL-5 mRNA expression in GD during the steroid withdrawal period showed the lowering was more significantly at the end of the 7th and 9th week than that at the end of the 2nd week (P < 0.05, P < 0.01), but its levels were equal at the former two time points; its lowest level appeared at the end of the 9th week, which approaching the level in GA (P > 0.05).

CONCLUSIONThree-stage sequential method could remarkably inhibit IL-5 mRNA expression in the lung tissue of asthmatic rats undergoing steroid treatment.

Animals ; Asthma ; drug therapy ; Dexamethasone ; administration & dosage ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Interleukin-5 ; biosynthesis ; genetics ; Lung ; metabolism ; Male ; Phytotherapy ; RNA, Messenger ; biosynthesis ; genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the effects of bacterial lysates (OM-85BV) and all trans-retinoic acid (ATRA) on airway inflammation in asthmatic mice, and to investigate the immunoregulatory mechanism of OM-85BV and ATRA for airway inflammation in asthmatic mice.

METHODSForty female BALB/c mice were randomly divided into five groups: normal control, model, OM-85BV, ATRA, and OM-85BV+ATRA. A bronchial asthma model was established by intraperitoneal injection of ovalbumin (OVA) for sensitization and aerosol challenge in all mice except those in the normal control group. On days 25-34, before aerosol challenge, the model, OM-85BV, ATRA, and OM-85BV+ATRA groups were given normal saline, OM-85BV, ATRA, and OM-85BV+ATRA respectively by gavage. Normal saline was used instead for sensitization, challenge, and pretreatment before challenge in the normal control group. These mice were anesthetized and dissected at 24-48 hours after the final challenge. Bronchoalveolar lavage fluid (BALF) was collected from the right lung to measure the levels of interleukin-10 (IL-10) and interleukin-17 (IL-17) by ELISA. The left lung was collected to observe histopathological changes by hematoxylin-eosin staining. The relative expression of ROR-γT mRNA was measured by quantitative real-time PCR.

RESULTSCompared with the normal control group, the model group showed contraction of the bronchial cavity, increased bronchial secretions, and a large number of infiltrating inflammatory cells around the bronchi and alveolar walls, as well as a significantly reduced level of IL-10 (P<0.05) and significantly increased levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the model group, the OM-85BV, ATRA, and OM-85BV+ATRA groups showed a significant reduction in infiltrating inflammatory cells around the bronchi and alveolar walls; the OM-85BV group showed a significant increase in the level of IL-10 in BALF (P<0.05) and significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05); the ATRA group showed significant reductions in the levels of IL-17 and ROR-γT mRNA (P<0.05). Compared with the OM-85BV group, the OM-85BV+ATRA group had significantly increased relative expression of ROR-γT mRNA (P<0.05). Compared with the ATRA group, the OM-85BV+ATRA group had significantly increased levels of IL-10 and IL-17 in BALF (P<0.05).

CONCLUSIONSBoth OM-85BV and ATRA can reduce respiratory inflammation in asthmatic mice. However, a combination of the two drugs does not have a better effect than them used alone.

Animals ; Asthma ; drug therapy ; genetics ; immunology ; Cell Extracts ; administration & dosage ; Female ; Humans ; Interleukin-10 ; genetics ; immunology ; Interleukin-17 ; genetics ; immunology ; Lung ; drug effects ; immunology ; Mice ; Mice, Inbred BALB C ; Tretinoin ; administration & dosage