The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma

Tanaka, Hiroyuki; Masuda, Takeo; Tokuoka, Shota; Komai, Masato; Nagao, Kōichi; Takahashi, Yoshimasa; Nagai, Hiroichi

doi:10.1007/pl00000243

Cited by 133 publications

(119 citation statements)

References 35 publications

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“…To determine the severity of the inflammatory cell infiltration, peribronchial cell counts were performed based on a fivepoint scoring system described by Myou et al (19). The extent of mucus production was quantified using a five-point grading system described by Tanaka et al (20).…”

Section: Histological Analysismentioning

confidence: 99%

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Reber

Daubeuf

Plantinga

et al. 2012

The Journal of Immunology

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The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-κB and its subsequent recruitment onto the IκBα promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4–induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.

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Section: Histological Analysismentioning

confidence: 99%

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Reber

Daubeuf

Plantinga

et al. 2012

The Journal of Immunology

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“…Briefly, the scoring system was: 0, no cells; 1, a few cells; 2, a ring of cells 1 cell layer deep; 3, a ring of cells 2-4 cells deep; 4, a ring of cells Ͼ4 cells deep. To determine the extent of mucus production, goblet cell hyperplasia in the airway epithelium was quantified blind using a 5-point grading system described by Tanaka et al (18). The adopted grading system was: 0, no goblet cells; 1, Ͻ25%; 2, 25-50%; 3, 50 -75%; 4, Ͼ75%.…”

Section: Histologic Examinationmentioning

confidence: 99%

“…Histological examination of lung tissue eosinophilia (A-D, magnification ϫ400) and mucus secretion (E-H, magnification ϫ 400) 24 h after the last challenge of saline aerosol (A and E), OVA aerosol (B and F), OVA aerosol plus PEG (C and G), or OVA aerosol plus 30 mg/kg U0126 (D and H). Quantitative analyses of inflammatory cell infiltration (I) and mucus production (J) in lung sections were performed based on the methods of Myou et al (17) and Tanaka et al (18), respectively. Lung tissues were fixed, sectioned at 7 m thickness, and stained with H&E for tissue eosinophilia or periodic acid-Schiff for mucus production.…”

Section: Figurementioning

confidence: 99%

Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model

Duan

Chan

Wong

et al. 2004

The Journal of Immunology

261

206

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Mitogen-activated protein kinase (MAPK) signaling cascade plays a pivotal role in the activation of inflammatory cells. Recent findings revealed that the activity of p42/44 MAPK (also known as extracellular signal-regulated kinase (ERK)) in the lungs was significantly higher in asthmatic mice than in normal controls. We hypothesized that inhibition of ERK activity may have anti-inflammatory effects in allergic asthma. BALB/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation in cytokine and chemokine levels, up-regulation of VCAM-1 expression, and airway hyperresponsiveness. Intraperitoneal administration of U0126, a specific MAPK/ERK kinase inhibitor, significantly (p < 0.05) inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-4, IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. U0126 also substantially (p < 0.05) reduced the serum levels of total IgE and OVA-specific IgE and IgG1. Histological studies show that U0126 dramatically inhibited OVA-induced lung tissue eosinophilia, airway mucus production, and expression of VCAM-1 in lung tissues. In addition, U0126 significantly (p < 0.05) suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine in a dose-dependent manner. Western blot analysis of whole lung lysates shows that U0126 markedly attenuated OVA-induced tyrosine phosphorylation of ERK1/2. Taken together, our findings implicate that inhibition of ERK signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.

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“…Until now, it is reported that the decrease of eosinophil numbers in BALF was correlated with attenuation of asthma symptoms in animal models. 15,25) Many clinical studies have also documented a correlation between pulmonary eosinophilia and asthma, and the degree of eosinophils in BALF correlates with disease severity. 26) Thus, pulmonary eosinophilia has been closely related to asthma symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…To determine the extent of mucus production, goblet cell hyperplasia in the airway epithelium was quantified with a five-point grading system. 15,16) The adopted grading system was as follows: 0, no goblet cells; 1, Ͻ25%; 2, 25-50%; 3, 50-75%, and 4, Ͼ75%. The blinded quantitative analysis was performed with the described method previously.…”

Section: )mentioning

confidence: 99%

Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

Asano

Kumakura

Taki

et al. 2010

Biological & Pharmaceutical Bulletin

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Bronchial asthma has clinical manifestations, which include variable degrees of airflow obstruction, airway hyperresponsiveness, and airway inflammation.1) The inflammatory process in asthma is dominated by T helper-2 (Th2) cells which produce interleukin-4 (IL-4), IL-5, and IL-13. 2)Thalidomide was synthesized in 1954 by CIBA Pharmaceutical Company, and prescribed as a sedative, tranquiliser, and antiemetic for morning sickness. Because the highest risk for teratogenicity arose when the drug was taken between weeks 3 and 8 after conception, it was withdrawn from many countries including Japan. However, the drug was revived as an effective treatment for erythema nodosum leprosum lesions in 1965. The U.S.A. Food and Drug Administration approved it for this indication in 1998. 3)Thalidomide, which is metabolized by cytochrome P450, 3,4) has a wide range of pharmaceutical and biological activities. Currently, clinical investigations of thalidomide have been conducted in patients with diverse diseases, including multiple myeloma, rheumatoid arthritis, and human immunodeficiency virus infection. 5,6) The beneficial pharmacological effects elicited by thalidomide include anti-angiogenic, anti-viral, anti-inflammatory, and immunomodulatory activities, 5,7) although the precise mechanisms are unknown.8)It has been reported that thalidomide administered with albendazole suppressed eosinophilic infiltration in cerebrospinal fluid in a murine vermination model. 9) However, little is known about the effect of thalidomide on the airway hyperresponsiveness and eosinophilic inflammation in allergic asthma.The purpose of this study was to investigate the effects of thalidomide on airway inflammation and hyperresponsiveness in a murine model of allergic asthma. We hypothesized that thalidomide would have anti-inflammatory effects in allergic asthma. MATERIALS AND METHODS Sensitisation and Challenge with OvalbuminSevenweek-old female BALB/c mice (SLC, Shizuoka) were purchased and maintained in our specific pathogen-free animal facility. The mice were maintained at room temperature (23Ϯ2°C) and humidity (55Ϯ10%) in an air-conditioned room. They were fed a standard laboratory diet and given water ad libitum. They were sensitised by an intraperitoneal injection with 100 mg ovalbumin (OVA) and 1 mg alum in 200 ml of phosphate-buffered saline (PBS) on day 0, and then by a hypodermic injection with 10 mg OVA in 20 ml of PBS on day 14. They were then placed in an acrylic chamber and challenged with 1% OVA for 10 min daily by a nebulizer (IS-2; Paris, Starnberg, Germany) between days 21 and 25. 10)Saline was used in place of OVA during the sensitisation and challenge stages of the protocol as a negative control. All protocols described in this study were approved by the Animal Ethics Committee of Nagoya University Graduate School of Medicine, Nagoya, Japan.Treatment Protocols For in vivo animal experiments, thalidomide (30, 100, or 300 mg/kg) was suspended in 0.5% carboxymethylcellulose, vortexed for 5 min, and administered orally via a ...

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The effect of allergen-induced airway inflammation on airway remodeling in a murine model of allergic asthma

Abstract: These findings demonstrated that in this murine model airway eosinophilic inflammation is responsible for the development of airway remodeling as well as bronchial hyperresponsiveness in allergic bronchial asthma.

Cited by 133 publications

References 35 publications

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

A Dissociated Glucocorticoid Receptor Modulator Reduces Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model

Thalidomide Attenuates Airway Hyperresponsiveness and Eosinophilic Inflammation in a Murine Model of Allergic Asthma

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