Early Interleukin 4–Dependent Response Can Induce Airway Hyperreactivity before Development of Airway Inflammation in a Mouse Model of Asthma

Allergic asthma is a chronic airway inflammatory response to different triggers like inhaled allergens. Excessive ATP in fluids from asthmatic patients is considered an inflammatory signal and an important autocrine/paracrine modulator of airway physiology. Here we investigated the deleterious effect of increased extracellular ATP (eATP) concentration on the mucociliary clearance (MCC) effectiveness and determined the role of ATP releasing channels during airway inflammation in an ovalbumin (OVA)-sensitized mouse model. Our allergic mouse model exhibited high levels of eATP measured in the tracheal fluid with a luciferin-luciferase assay and reduced MCC velocity determined by microspheres tracking in the trachea ex vivo. Addition of ATP had a dual effect on MCC, where lower ATP concentration (µM) increased microspheres velocity, while higher concentration (mM) transiently stopped microspheres movement. Also, an augmented ethidium bromide uptake by the allergic tracheal airway epithelium suggests an increase in ATP release channel functionality during inflammatory conditions. The use of carbenoxolone, a non-specific inhibitor of connexin and pannexin1channels reduced the eATP concentration in the allergic mouse tracheal fluid and dye uptake by the airway epithelium, providing evidence that these ATP release channels are facilitating the net flux of ATP to the lumen during airway inflammation. However, only the specific inhibition of pannexin1 with 10Panx peptide significantly reduced eATP in bronchoalveolar lavage and decreased airway hyperresponsiveness in OVA-allergic mouse model. These data provide evidence that blocking eATP may be a pharmacological alternative to be explored in rescue therapy during episodes of airflow restriction in asthmatic patients.

Download Full-text

Inhaled Carbenoxolone Prevents Allergic Airway Inflammation and Airway Hyperreactivity in a Mouse Model of Asthma

International Archives of Allergy and Immunology ◽

10.1159/000176305 ◽

2008 ◽

Vol 149 (1) ◽

pp. 38-46 ◽

Cited By ~ 14

Author(s):

Arjun Ram ◽

Shashi Kant Singh ◽

Vijay Pal Singh ◽

Sarvesh Kumar ◽

Balaram Ghosh

Keyword(s):

Mouse Model ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Airway Hyperreactivity

Download Full-text

Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.187.9.1537 ◽

1998 ◽

Vol 187 (9) ◽

pp. 1537-1542 ◽

Cited By ~ 226

Author(s):

Toshihiko Akimoto ◽

Fumio Numata ◽

Misato Tamura ◽

Yoshimi Takata ◽

Noriko Higashida ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Hyperreactivity ◽

Interleukin 4 ◽

Wild Type ◽

Airway Reactivity ◽

Signal Transducers ◽

Signal Transducers And Activators

Signal transducers and activators of transcription 6 (STAT6) is essential for interleukin 4–mediated responses, including class switching to IgE and induction of type 2 T helper cells. To investigate the role of STAT6 in allergic asthma in vivo, we developed a murine model of allergen-induced airway inflammation. Repeated exposure of actively immunized C57BL/6 mice to ovalbumin (OVA) aerosol increased the level of serum IgE, the number of eosinophils in bronchoalveolar lavage (BAL) fluid, and airway reactivity. Histological analysis revealed peribronchial inflammation with pulmonary eosinophilia in OVA-treated mice. In STAT6-deficient (STAT6−/−) C57BL/6 mice treated in the same fashion, there were no eosinophilia in BAL and significantly less peribronchial inflammation than in wild-type mice. Moreover STAT6−/− mice had much less airway reactivity than wild-type mice. These findings suggest that STAT6 plays a crucial role in the pathogenesis of allergen-induced airway inflammation.

Download Full-text

Proteomic Analysis of Anti-inflammatory Effects of a Kampo (Japanese Herbal) Medicine “Shoseiryuto (Xiao-Qing-Long-Tang)” on Airway Inflammation in a Mouse Model

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep151 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 26

Author(s):

Takayuki Nagai ◽

Marino Nakao ◽

Yuliko Shimizu ◽

Yoshio Kodera ◽

Masamichi Oh-Ishi ◽

...

Keyword(s):

Herbal Medicine ◽

Mouse Model ◽

Airway Inflammation ◽

Bronchial Asthma ◽

Antibody Titer ◽

Lung Tissue ◽

Proteomic Analysis ◽

Allergic Airway Inflammation ◽

Airway Hyperreactivity ◽

Japanese Herbal Medicine

Effects of a Kampo (Japanese herbal) medicine “shoseiryuto (SST, xiao-qing-long-tang in Chinese)”, which has been used for the treatment of allergic bronchial asthma clinically, were examined on ovalbumin (OVA)-sensitized allergic airway inflammation model (i.e., bronchial asthma) in a mouse. When SST was orally administered at 0.5 g kg−1 day−1from day 1 to 6 after OVA inhalation, SST reduced the inflammation in lung tissue, the number of eosinophils and the OVA-specific immunoglobulin E (IgE) antibody titer in bronchoalveolar lavage (BAL) fluids at 7 days after the OVA inhalation. SST also reduced the airway hyperreactivity at 6 days after the OVA inhalation. Proteomic analysis with the agarose two-dimensional electrophoresis showed that the expression of spectrin α2 was reduced in the lung tissue of OVA-sensitized mice and SST recovered the expression. Western blot and immunohistochemical analyses of lung tissue also confirmed this result. When prednisolone was orally administered at 3 mg kg−1 day−1from day 1 to 6 after OVA inhalation, the inflammation in lung tissue, the number of eosinophils in BAL fluids and airway hyperreactivity were reduced in the OVA-sensitized mice. However, prednisolone did not reduce the OVA-specific IgE antibody titer in BAL fluids and did not recover the expression of spectrin α2 in lung tissue. These results suggest that at least a part of action mechanism of SST against OVA-sensitized allergic airway inflammation in a mouse model is different from that of prednisolone.

Download Full-text

IFN-γ-Inducible Protein 10 (CXCL10) Contributes to Airway Hyperreactivity and Airway Inflammation in a Mouse Model of Asthma

The Journal of Immunology ◽

10.4049/jimmunol.168.10.5278 ◽

2002 ◽

Vol 168 (10) ◽

pp. 5278-5286 ◽

Cited By ~ 143

Author(s):

Benjamin D. Medoff ◽

Alain Sauty ◽

Andrew M. Tager ◽

James A. Maclean ◽

R. Neal Smith ◽

...

Keyword(s):

Mouse Model ◽

Airway Inflammation ◽

Airway Hyperreactivity ◽

Ifn Γ ◽

Inducible Protein

Download Full-text

MicroRNA-21 Promotes Allergic Airway Inflammation and AHR and Inhibits Mesenchymal Stem Cell Migration in Cockroach Allergen Induced Asthma Model

10.21203/rs.3.rs-148622/v1 ◽

2021 ◽

Author(s):

Tianli Cheng ◽

jianfu heng ◽

Quanhui Mei ◽

Lijun Chen ◽

Feng Zeng

Keyword(s):

Mouse Model ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Airway Hyperreactivity ◽

Negative Regulator ◽

Mouse Bone Marrow ◽

Asthma Model ◽

Gene Assay

Abstract BackgroundMesenchymal stem cells (MSCs) have been used to treat asthma in a mouse model. However, the efficacy and mechanism of MSCs are not elucidated. MicroRNAs (miRNAs) play a key rolein asthma and related to the aim of this study was to illustrate the role of miR21 and its influence on MSC migration in asthma model. MethodsA mouse model of asthma was established using cockroach extract (CRE), and miR-21 expression was examined. A miR-21 lentivirus construct was used to investigate the role of miR-21 in vivo and in vitro in mouse bone marrow-derived (BM-) MSCs. A TOPFlash reporter gene assay was used to study the signaling downstream of miR-21. IL-4, IL-5, IL-13, IgE, and IgG1 levels in bronchoalveolar lavage fluids were determined by enzyme-linked immunosorbent assays.ResultsMiR-21 was upregulated in CRE-induced asthmatic mice. MiR-21 promoted allergic airway inflammation and airway hyperreactivity by inhibiting BM-MSC migration. β-Catenin was found to act downstream of miR-21 as a negative regulator of miR-21. Rescue experiments verified that miR-21 inhibited BM-MSC migration by suppressing Wnt/β-catenin signaling.ConclusionMiR-21 promotes allergic airway inflammation and AHR and inhibits BM-MSC migration through Wnt/β-catenin signaling, which may serve as an effective therapeutic target for asthma.

Download Full-text

Small Interfering RNAs Targeted to Interleukin-4 and Respiratory Syncytial Virus Reduce Airway Inflammation in a Mouse Model of Virus-Induced Asthma Exacerbation

Human Gene Therapy ◽

10.1089/hum.2013.142 ◽

2014 ◽

Vol 25 (7) ◽

pp. 642-650 ◽

Cited By ~ 22

Author(s):

Musa R. Khaitov ◽

Igor P. Shilovskiy ◽

Aleksandra A. Nikonova ◽

Nadezda N. Shershakova ◽

Oleg Y. Kamyshnikov ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Mouse Model ◽

Airway Inflammation ◽

Asthma Exacerbation ◽

Interleukin 4 ◽

Small Interfering Rnas ◽

Syncytial Virus

Download Full-text

Induction of Immune Tolerance in Asthmatic Mice by Vaccination with DNA Encoding an Allergen–Cytotoxic T Lymphocyte-Associated Antigen 4 Combination

Clinical and Vaccine Immunology ◽

10.1128/cvi.00434-10 ◽

2011 ◽

Vol 18 (5) ◽

pp. 807-814 ◽

Cited By ~ 7

Author(s):

Fang Zhang ◽

Gang Huang ◽

Bo Hu ◽

Yong Song ◽

Yi Shi

Keyword(s):

Airway Inflammation ◽

Dna Vaccine ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Treg Cells ◽

Airway Hyperreactivity ◽

Interleukin 4 ◽

High Dose ◽

Dna Encoding ◽

Allergen Specific Immunotherapy

ABSTRACTAllergen-specific immunotherapy is a potential treatment for allergic diseases. We constructed an allergen–cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)-encoding DNA vaccine, administered it directly to antigen-presenting cells (APCs), and investigated its ability and mechanisms to ameliorate allergic airway inflammation in an asthmatic mouse model. An allergen-CTLA-4 DNA plasmid (OVA-CTLA-4-pcDNA3.1) encoding an ovalbumin (OVA) and the mouse CTLA-4 extracellular domain was constructed and transfected into COS-7 cells to obtain the fusion protein OVA-CTLA-4, which was able to bind the B7 ligand on dendritic cells (DCs), and induced CD25+Foxp3+regulatory T (Treg) cells by the coculture of naive CD4+T cells with DCsin vitro. In an animal study, BALB/c mice were sensitized and challenged with OVA to establish the asthmatic model. Vaccination with a high dose of OVA-CTLA-4-pcDNA3.1significantly decreased interleukin-4 (IL-4) and IL-5 levels and eosinophil counts and prevented OVA-induced reduction of the gamma interferon level in the bronchoalveolar lavage fluid. In addition, these mice suffered less severe airway inflammation and had lower levels of OVA-specific IgE and IgG1 titers in serum. Also, high-dose OVA-CTLA-4-pcDNA3.1vaccination inhibited the development of airway hyperreactivity and prevented OVA-induced reduction of the percentages of Foxp3+Treg cells in the spleen. Our results indicate that a high dose of allergen-CTLA-4-encoding DNA vaccine was more effective in preventing an allergen-induced Th2-skewed immune response through the induction of Treg cells and may be a new alternative therapy for asthma.

Download Full-text