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Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation 査読

S Matsubara, T Koya, K Takeda, A Joetham, N Miyahara, P Pine, ES Masuda, CH Swasey, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 34 ( 4 ) 426 - 433 2006年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.

DOI： 10.1165/rcmb.2005-0298OC

The leukotriene B4 receptor (BLT1) is required for effector CD8(+) T cell-mediated, mast cell-dependent airway hyperresponsiveness 査読

C Taube, N Miyahara, Ott, V, B Swanson, K Takeda, J Loader, LD Shultz, AM Tager, AD Luster, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 176 ( 5 ) 3157 - 3164 2006年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Studies in both humans and rodents have suggested that CD8(+) T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8(+) T cells (T-EFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8(+) T cell-mediated AHR. C57BL/6(+/+) and CD8-deficient (CD8(-/-)) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6(+/+) mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8(-/-) mice failed to do so. CD8(-/-) mice reconstituted with CD8(+) T-EFF developed AHR in response to challenge. In contrast, CD8(-/-) mice reconstituted with BLT1-deficient effector CD8(+) T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8(+) TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8(+) T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8(+) T cell-mediated allergic responses in the lung.

DOI： 10.4049/jimmunol.176.5.3157

Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure 査読

T Koya, T Kodama, K Takeda, N Miyahara, ES Yang, C Taube, A Joetham, JW Park, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 173 ( 1 ) 42 - 55 2006年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice.
Methods: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or I I occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors.
Results: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5. and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia.
Conclusions: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.

DOI： 10.1164/rccm.200505-783OC

Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness 査読

S Matsubara, GM Li, K Takeda, JE Loader, P Pine, ES Masuda, N Miyahara, S Miyahara, JJ Lucas, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 173 ( 1 ) 56 - 63 2006年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor-mediated signaling.
Objective: To determine the activity of a specific Syk inhibitor (11406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo.
Methods: AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, Fc epsilon RI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMCs) before crosslinking with allergen.
Results: The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine IBMMCs and inhibited the production of interieukin (IL)-13, tumor necrosis factor a, IL-2, and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR, which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive d (20 min/d), as well as pulmonary eosinophilia and goblet cell metaplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge.
Conclusion: This study delineates a functional role for Syk in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.

DOI： 10.1164/rccm.200503-361OC

Physiologic assessment of allergic rhinitis in mice: Role of the high-affinity IgE receptor (Fc epsilon RI) 査読

S Miyahara, N Miyahara, K Takeda, A Joetham, EW Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 116 ( 5 ) 1020 - 1027 2005年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Background: There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains.
Objective: We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes.
Methods: After sensitization and challenge, both wild-type and Fe epsilon RI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R-NA) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase).
Results: After challenge of sensitized mice, R-NA significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R-NA-Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged Fc epsilon RI alpha-chain-deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates.
Conclusions: These data indicate that Fc epsilon RI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

DOI： 10.1016/j.jaci.2005.08.020

S-carboxymethylcysteine normalises airway responsiveness in sensitised and challenged mice 査読

K Takeda, N Miyahara, T Kodama, C Taube, A Balhorn, A Dakhama, K Kitamura, A Hirano, M Tanimoto, EW Gelfand

EUROPEAN RESPIRATORY JOURNAL 26 ( 4 ) 577 - 585 2005年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：EUROPEAN RESPIRATORY SOC JOURNALS LTD

S-carboxymethylcysteine (S-CMC) has been used as a mucoregulator in respiratory diseases. However, the mechanism of action of S-CMC on allergic airway inflammation has not yet been defined.
In the present study, BALB/c mice were initially sensitised and challenged to ovalbumin (OVA) and, weeks later, re-challenged with OVA (secondary challenge). S-CMC (5-100 mg.kg(-1)) was administered from 2 days before the secondary challenge through to the day of assay.
Mice developed airway hyperresponsiveness (AHR) 6 h after the secondary challenge and increased numbers of neutrophils were present in the bronchoalveolar lavage (BAL) fluid. At 72 h after secondary challenge, mice again developed AHR, but the BAL fluid contained large numbers of eosinophils. S-CMC treatment was found to reduce AHR and neutrophilia at 6 h, as well as eosinophilia and AHR at 72 h. These effects appeared to be dose dependent. Goblet cell hyperplasia, observed at 72 h, was reduced by S-CMC. In BAL fluid, increased levels of interferon-gamma, interleukin (IL)-12 and IL-10 and decreased levels of IL-5 and IL-13 were detected.
In conclusion, the data indicate that S-carboxymethylcysteine is effective in reducing airway hyperresponsiveness and airway inflammation at two distinct phases of the response to the secondary allergen challenge in sensitised mice.

DOI： 10.1183/09031936.05.00090304

The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production 査読

A Dakhama, JW Park, C Taube, A Joetham, A Balhorn, N Miyahara, K Takeda, EW Gelfand

JOURNAL OF IMMUNOLOGY 175 ( 3 ) 1876 - 1883 2005年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of postbronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.

DOI： 10.4049/jimmunol.175.3.1876

Airway hyperresponsiveness in the absence of CD4+T cells after primary but not secondary challenge 査読

A Joetham, K Takeda, C Taube, N Miyahara, A Kanehiro, A Dakhama, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 33 ( 1 ) 89 - 96 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

CD4+ T cells have been shown to play a role in the development of airway hyperresponsivness (AHR) and airway eosinophilia in mice using ablation as well as adoptive transfer experiments. However, as other T cell subsets (CD8, NKT) may play a role in these models, we examined the responses of sensitized CD4-deficient mice after either primary or secondary airway allergen challenge. After sensitization, CD4-deficiency in mice was not associated with airway eosinophilia, allergen-specific IgE, or elevated levels of interleukin (IL)-4 or IL-13. Increases in lung CD8 T cells and IL-5 were observed and shown to be essential for AHR as demonstrated after CD8 T cell depletion or anti-IL-5 treatment. In contrast to the response of sensitized CD4-deficient mice to primary allergen challenge, they failed to develop AHR after secondary allergen challenge. Although the importance of this CD4+ T cell-independent pathway in normal mice is unclear at this time, these studies identify the diversity of the cellular pathway, which may contribute to the development of AHR after primary allergen exposure of sensitized mice.

DOI： 10.1165/rcmb.2004-0414OC

Requirement for leukotriene B-4 receptor 1 in allergen-induced airway hyperresponsiveness 査読

N Miyahara, K Takeda, S Miyahara, S Matsubara, T Koya, A Joetham, E Krishnan, A Dakhama, B Haribabu, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 172 ( 2 ) 161 - 167 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Rationale: Leukotriene B-4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4-BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. Objectives: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. Methods: BLT1-deficient (BLT1(-/-)) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. Results: Compared with wild-type mice, BLT1(-/-) mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-1 3 levels and numbers of IL-13(+)/CD4(+) and IL-13(+)/CD8(+) T cells were also reduced in BLT1 (-/-) mice. Reconstitution of sensitized and challenged BLT1(-/-) mice with allergen-sensitized BLT1(+/+) T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. Conclusion: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.

DOI： 10.1164/rccm.200502-205OC

Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8(+) T cells and airway hyperresponsiveness 査読

N Miyahara, K Takeda, S Miyahara, C Taube, A Joetham, T Koya, S Matsubara, A Dakhama, AM Tager, AD Luster, EW Gelfand

JOURNAL OF IMMUNOLOGY 174 ( 8 ) 4979 - 4984 2005年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

Recent studies in both human and rodents have indicated that in addition to CD4(+) T cells, CD8(+) T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8(-/-)) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8(+) T cells or in vitro-generated effector CD8(+) T cells (T-EFF). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T-EEF recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8(+) T cell-mediated allergic AHR and inflammation. Adoptive trans fer of in vivo-primed BLT1(+/+), but not BLTI-/-, CD8(+) T cells into sensitized and challenged CD8(-/-) mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8(-/-) mice, in vitro-generated BLTI+/+, but not BLT1(-/-), T-EFF accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8(+) T-EFF recruitment into the lung and development of AHR and airway inflammation.

DOI： 10.4049/jimmunol.174.8.4979

Alteration of airway neuropeptide expression and development of airway hyperresponsiveness following respiratory syncytial virus infection 査読

A Dakhama, JW Park, C Taube, M El Gazzar, T Kodama, N Miyahara, K Takeda, A Kanehiro, A Balhorn, A Joetham, JE Loader, GL Larsen, EW Gelfand

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 288 ( 4 ) L761 - L770 2005年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER PHYSIOLOGICAL SOC

The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of airway sensory neuropeptides, thereby contributing to the development of altered airway function. BALB/c mice were infected with RSV followed by assessment of airway function, inflammation, and sensory neuropeptide expression. After RSV infection, mice developed significant airway inflammation associated with increased airway resistance to inhaled methacholine and increased tracheal smooth muscle responsiveness to electrical field stimulation. In these animals, substance P expression was markedly increased, whereas calcitonin gene-related peptide ( CGRP) expression was decreased in airway tissue. Prophylactic treatment with Sendide, a highly selective antagonist of the neurokinin-1 receptor, or CGRP, but not the CGRP antagonist CGRP( 8 - 37), inhibited the development of airway inflammation and AHR in RSV-infected animals. Therapeutic treatment with CGRP, but not CGRP( 8 - 37) or Sendide, abolished AHR in RSV-infected animals despite increased substance P levels and previously established airway inflammation. These data suggest that RSV-induced airway dysfunction is, at least in part, due to an imbalance in sensory neuropeptide expression in the airways. Restoration of this balance may be beneficial for the treatment of RSV-mediated airway dysfunction.

DOI： 10.1152/ajplung.00143.2004

The role of virus-specific immunoglobulin E in airway hyperresponsiveness 査読

A Dakhama, JW Park, C Taube, K Chayama, A Balhorn, A Joetham, XD Wei, RH Fan, C Swasey, N Miyahara, T Kodama, A Alvarez, K Takeda, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 170 ( 9 ) 952 - 959 2004年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.

DOI： 10.1164/rccm.200311-1610oc

Effector CD8(+) T cells mediate inflammation and airway hyper-responsiveness 査読

N Miyahara, BJ Swanson, K Takeda, C Taube, S Miyahara, T Kodama, A Dakhama, VL Ott, EW Gelfand

NATURE MEDICINE 10 ( 8 ) 865 - 869 2004年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyperresponsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells(1). Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T-EFF) and central memory (T-CM) cells, have been described(2-5). After adoptive transfer into CD8-deficient mice, T-EFF, but not T-CM, cells restored AHR, eosinophilic inflammation and IL-13 levels. T-EFF, but not T-CM, cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T-EFF cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.

DOI： 10.1038/nm1081

Interleukin-1 receptor antagonist attenuates airway hyperresponsiveness following exposure to ozone 査読

JW Park, C Taube, C Swasey, T Kodama, A Joetham, A Balhorn, K Takeda, N Miyahara, CB Allen, A Dakhama, SH Kim, CA Dinarello, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 30 ( 6 ) 830 - 836 2004年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O-3 exposure in mice was investigated. Exposure of C57/BL6 mice to O-3 at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O-3 exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O-3 exposure. Administration of (human) IL-1Ra before, and after O-3 exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O-3 exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O-3 exposure. In summary, acute exposure to O-3 induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.

DOI： 10.1165/rcmb.2003.0373OC

Mast cells, Fc epsilon RI, and IL-13 are required for development of airway hyperresponsiveness after aerosolized allergen exposure in the absence of adjuvant 査読

C Taube, XD Wei, CH Swasey, A Joetham, S Zarini, T Lively, K Takeda, J Loader, N Miyahara, T Kodama, LD Shultz, DD Donaldson, EH Hamelmann, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 172 ( 10 ) 6398 - 6406 2004年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (Fcis an element ofRI) in the development of AHR, mice with a disruption of the a subunit of the high affinity IgE receptor (Fcis an element ofRI(-/-)) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth muscle to electrical field. stimulation (EFS). After the 10-day OVA challenge protocol, wild-type mice demonstrated increased responsiveness to EFS, whereas similarly challenged Fcis an element ofRI(-/-) mice showed a low response to EFS, similar to nonexposed animals. Further, allergen-challenged Fcis an element ofRI(-/-) mice showed less airway inflammation, goblet cell hyperplasia, and lower levels of IL-13 in lung homogenates compared with the controls. IL-13-deficient mice failed to develop an increased response to EFS or goblet cell hyperplasia after the 10-day OVA challenge. We transferred bone marrow-derived mast cells from wild-type mice to Fcis an element ofRI(-/-) mice 1 day before initiating the challenge protocol. After the 10-day OVA challenge, recipient Fcis an element ofRI(-/-) mice demonstrated EFS-induced responses similar to those of challenged wild-type mice. Transferred mast cells could be detected in tracheal preparations. These results show that Fcis an element ofRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through Fcis an element ofRI on mast cells and production of IL-13 in the lung.

DOI： 10.4049/jimmunol.172.10.6398

Contribution of antigen-primed CD8(+) T cells to the development of airway hyperresponsiveness and inflammation is associated with IL-13 査読

N Miyahara, K Takeda, T Kodama, A Joetham, C Taube, JW Park, S Miyahara, A Balhorn, A Dakhama, EW Gelfand

JOURNAL OF IMMUNOLOGY 172 ( 4 ) 2549 - 2558 2004年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8(+) T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8(+) T cells in the development of these allergen-induced responses. CD8-deficient (CD8(-/-)) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type. mice, CD8(-/-) mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8(-/-) mice with allergen-sensitized CD8(+) T cells fully restored the development of AHR, BAL cosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8(+) T cells or allergen-sensitized CD8(+) T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8(+) T cells were a source of IL-13. These data suggest that Ag-primed CD8(+) T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells. The Journal of Immunology, 2004, 172: 2549-2558.

DOI： 10.4049/jimmunol.172.4.2549

Respiratory syncytial virus-induced airway hyperresponsiveness is independent of IL-13 compared with that induced by allergen 査読

JW Park, C Taube, ES Yang, A Joetham, A Balhorn, K Takeda, N Miyahara, A Dakhama, DD Donaldson, EW Gelfand

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 112 ( 6 ) 1078 - 1087 2003年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Background: IL-13 is a central mediator of allergen-induced airway hyperresponsiveness, (AHR), but its role in respiratory syncytial virus (RSV)-induced AHR is not defined. The combination of allergen exposure and RSV infection is known to increase AHR and lung inflammation, but whether IL-13 regulates this increase is similarly not known.
Objective: Our objective was to determine the role of RSV infection and IL-13 on airway responsiveness and lung inflammation on sensitized and challenged mice.
Methods: Using a murine model of RSV infection and allergen exposure, we examined the role of IL-13 in the development of AHR and lung inflammation in IL-13 knockout mice, as well as using a potent IL-13 inhibitor (IL-13i). Mice were sensitized and challenged to allergen, and 6 days after the last challenge, they were infected with RSV. IL-13 was inhibited using an IL-13 receptor alpha(2)-human IgG fusion protein. AHR to inhaled methacholine was measured 6 days after infection, as was bronchoalveolar lavage fluid and lung inflammatory and cytokine responses.
Results: RSV-induced AHR was unaffected by the IL-13i, despite prevention of goblet cell hyperplasia. Similar results were seen in IL-13-deficient mice. In sensitized and challenged mice, RSV infection significantly increased AHR, and after IL-13i treatment, AHR was significantly reduced, but to the levels seen in RSV-infected mice alone.
Conclusions: These results indicate that despite some similarities, the mechanisms leading to AHR induced by RSV are different from those that follow allergen sensitization and challenge. Because IL-13 inhibition is effective in preventing the increases in AHR and mucus production in sensitized and challenged mice infected with RSV, IL-13i could play an important role in preventing the consequences of viral infection in patients with allergic asthma.

DOI： 10.1016/j.jaci.2003.08.046

Surfactant protein D regulates airway function and allergic inflammation through modulation of macrophage function 査読

K Takeda, N Miyahara, YH Rha, C Taube, ES Yang, A Joetham, T Kodama, AM Balhorn, A Dakhama, C Duez, AJ Evans, DR Voelker, EW Gelfand

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 168 ( 7 ) 783 - 789 2003年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER THORACIC SOC

The lung collectin surfactant protein D (SP-D) is an important component of the innate immune response but is also believed to play a role in other regulatory aspects of immune and inflammatory responses within the lung. The role of SP-D in the development of allergen-induced airway inflammation and hyperresponsiveness (AHR) is not well defined. SP-D levels progressively increased up to 48 hours after allergen challenge of sensitized mice and then subsequently decreased. The levels of SP-D paralleled the development of airway eosinophilia and AHR. To determine if this association was functionally relevant, mice were administered rat SP-D (rSP-D) intratracheally. When given to sensitized mice before challenge, AHR and eosinophilia were reduced by rSP-D in a dose-dependent manner but not by mutant rSP-D. rSP-D administration resulted in increased levels of interleukin (IL)-10, IL-12, and IFN-gamma in bronchoalveolar lavage fluid and reduced goblet cell hyperplasia. Culture of alveolar macrophages together with SP-D and allergen resulted in increased production of IL-10, IL-12, and IFN-gamma. These results indicate that SP-D can (negatively) regulate the development of AHR and airway inflammation after airway challenge of sensitized mice, at least in part, by modulating the function of alveolar macrophages.

DOI： 10.1164/rccm.200304-548OC

Pneumonitis induced by rifampicin 査読国際誌

N Kunichika, N Miyahara, K Kotani, H Takeyama, M Harada, M Tanimoto

THORAX 57 ( 11 ) 1000 - 1001 2002年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BRITISH MED JOURNAL PUBL GROUP

An 81 year old man was admitted to hospital with pulmonary Mycobocterium tuberculosis infection and was treated with rifampicin (UP), isoniazid (INH), and ethambutol (EB). On day 9 he developed fever and dyspnoea. Chest radiographs showed new infiltration shadows in the right lung. Bronchoalveolar lavage (BAL) was performed and increased numbers of lymphocytes were recovered. Drug induced pneumonitis was suspected so the antituberculous regimen was discontinued and methylprednisolone was administered. The symptoms and infiltration shadows improved. INH and EB were reintroduced without any recurrence of the abnormal shadows. T cell subsets in the BAL fluid and a positive lymphocyte stimulation test for RFP suggest that RFP induced pneumonitis may be related to a complex immunological response.

Respiratory variation in superior vena cava flow in patients with chronic obstructive pulmonary disease: Estimation of pulmonary hypertension using Doppler flow index 査読国際誌

N Kunichika, N Miyahara, M Harada, M Tanimoto

JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY 15 ( 10 ) 1165 - 1169 2002年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MOSBY, INC

Patients with chronic obstructive pulmonary disease (COPD) are difficult to assess by conventional transthoracic echocardiography (TTE) because of emphysematous lungs or mediastinal deviation. We hypothesized that superior vena cava (SVC) flow is related to pulmonary circulation and may be useful for the detection of pulmonary hypertension (PH) in patients with COPD that cannot been assessed by direct evaluation using the tricuspid regurgitant Doppler velocity. SVC Doppler flow velocities were examined in 46 patients with COPD and the pressure gradient between the right ventricular and right atrial. pressure (RV-RADeltaP) was calculated by tricuspid regurgitant Doppler velocities. The patients were divided into 2 groups: 11 patients with PH (RV-RADeltaP > 25 min Hg) were compared with 35 without PH. There was no significant difference in the maximal SVC peak systolic forward flow velocity during inspiration (INS) between these 2 groups. However, the minimal SVC peak systolic forward flow velocity during expiration (EXP) in the group with PH was significantly higher than that in the group without PH (37.4 +/- 20.0 cm/s vs 26.4 +/- 8.5 cm/s, P = .01). Linear regression analysis revealed a significant correlation between RV-RADeltaP and the EXP/INS ratio (r = 0.61, P < .001). in COPD patients with PH, the increased expiratory SVC systolic flow supplemented the preload for the impaired right ventricular filling flow caused by PH, thereby maintaining the transtricuspid driving pressure. Our observation suggests that respiratory variation in SVC systolic forward flow may be a sensitive Doppler flow index for evaluating severity of PH in patients with COPD that cannot been assessed by conventional TTE.

DOI： 10.1067/mje.2002.122355

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