Masking of Corticosteroid-induced Inhibition of NF-κB activation by (S)-Albuterol in Human Airway...

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544 Quality of Life of Children with Allergic Diseases Y. Adachi 1 , Y. Okabe 1 , T. Itazawa 1 , Y. S. Adachi 1 , M. Nakabayashi 1 , T. Fuchizawa 1 , T. Miyawaki 1 , H. Odajima 2 ; 1 Dept of Pediatrics, Toyama Medical & Pharmaceutical University, Toyama, JAPAN, 2 Dept of Pedi- atrics, Fukuoka National Hospital, Fukuoka, JAPAN. RATIONALE: It has not been well evaluated how allergic diseases impair the quality of life (QOL) of children compared with healthy ones. METHODS: We carried out a cross-sectional survey among the younger children aged 6-8 yr and elder ones aged 13-15 yr in a Japanese prefec- ture (Toyama), using a generic QOL questionnaire; Kid-KINDL ® . The survey was performed since May through August 2005. Asthma (A), allergic rhinitis (R), and eczema (E) were defined based on the ISSAC questionnaire. RESULTS: During the previous one year, 13.0, 38.6, and 19.4% of the younger children (n=1771), and 6.1, 57.4, and 13.5% of the elder ones (n=942) had been symptomatic for A, R, E, respectively. On the other hand, 42.3% of the younger children and 27.7% of the elder ones had never experienced any allergic symptoms in their lives. Comparing to these healthy children, the symptomatic children had impaired QOL, especially in “physical” and “friend” parts. The number of the impaired scales in the older group was higher than that of the younger one. CONCLUSIONS: Many children are suffered from allergic symptoms. Allergic diseases have a substantial impact on the QOL in children com- pared with healthy children. Supported by a grant from Japanese Ministry of Health, Labour and Welfare for Japanese Asthma Survey Group. 545 Impaired Quality of Life in Child Asthmatics in Tokyo, Japan N. Kojima 1,2 , Y. Ohya 1,2 , M. Futamura 1,2 , M. Akashi 1,2 , K. Akiyama 2 , K. Takahashi 2 , T. Nakagawa 2 , F. Kobayashi 2 , A. Eboshida 2 , H. Nakamura 2 , H. Odajima 2 , Y. Adachi 2 , A. Akasawa 1,2 ; 1 National Center for Child Health and Development, Tokyo, JAPAN, 2 Japanese Asthma Survey Group, Tokyo, JAPAN. RATIONALE: Asthma is the most common chronic diseases in school- aged children in Japan. Measuring of QOL is important to evaluate their school life. METHODS: School based survey was conducted by using KINDL-R quality of life(QOL) questionnaire and ISAAC questionnaire for children of 6-7 years old and 13-14 years old from May to June in 2005. Randomly selected public schools managed by local governments in Tokyo joined this investigation. RESULTS: Response rate of these questionnaire was 86%(22645 chil- dren) in 6-7 year old group and 64%(12879 children) in 13-14 year old group. Comparing asthmatics with non-asthmatics in the same age, QOL of children with asthma was significantly impaired (younger group: 96.7 vs 98.6, p<.001, elder group: 78.2 vs 83.0, p<.001). In addi- tion, QOL of children was significantly impaired by severity (severe asthmatics, moderate ones, mild ones and non-asthmatics was 95.1, 95.8, 97.9 and 98.6 respectively in younger children, and 76.2, 78.4, 78.3 and 83.0 respectively in elder ones. p<.001). Especially QOL of children with exercise-induced asthma (EIA) were more significantly impaired than ones without EIA (younger group: 95.7 vs 97.1, p<.001, elder group: 77.2 vs 81.1, p<0.01) and showed lower score in the cate- gories of school, emotional well-being and physical well-being than those without EIA. CONCLUSIONS: This is the first investigation to focus on the QOL comparison between Japanese children with asthma and those without it. QOL of children was impaired by having asthma even in the mild cases and more severely disturbed in elder cases and the cases with EIA. Funding: Ministry of Health, Labour and Welfare 546 Masking of Corticosteroid-induced Inhibition of NF-B acti- vation by (S)-Albuterol in Human Airway Smooth Muscle Cells and Human Blood Lymphocytes D. K. Agrawal 1 , G. Cheng 1 , P. W. Kelbe 2 ; 1 Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 2 Medical Liason, Sepracor Inc., Marlborough, MA. RATIONALE: Pro-constrictory and pro-inflammatory properties of (S)- albuterol have been widely reported. However, underlying mechanisms are unclear. We examined the effect of (S)-albuterol on corticosteroid- induced inhibition of NF-B in human airway smooth muscle cells (HASMCs) and human blood lymphocytes. We also investigated if (S)- Albuterol synergized response of TNF- to stimulate NF-B in HASMCs. METHODS: Lymphocytes were purified from the blood of normal vol- unteers using Percoll density gradient followed by non-adherence to cul- ture dish. Primary HASMCs were grown in culture. Lymphocytes or HASMCs were treated with various concentrations of albuterol enan- tiomers (0.1 - 1.0 microM). Dexamethasone (1 microM) and TNF- (100 nM) were used to stimulate cells. Activity of NF-B was measured by Western blot and TransAM method using antibodies to p65. RESULTS: Both (RS) and (S)-albuterol induced NF-B activation in both human blood lymphocytes and HASMCs in a dose-dependent man- ner. However (R)-albuterol (up to 10 microM concentration) had no effect. Short-term exposure (90 minutes) of the cells to dexamethasone significantly attenuated (25-35%) the activation of NF-B by (S)- and (RS)-albuterol. Interestingly, chronic exposure of the cells to (S)-albuterol for 8-24 hours significantly attenuated (42-60%) the effect of dexametha- sone to inhibit NF-B activity. However, prior exposure of the cells to (R)-albuterol did not affect dexamethasone-induced inhibition of NF-B. TNF- induced NF-B activity and this effect was amplified by (S)-albuterol (0.1 and 1.0 microM). CONCLUSIONS: Since NF-B is a potent transcription factor involved in airway inflammation, these data suggest that (S)-albuterol can either mask or antagonize the beneficial effect of dexamethasone and amplify the adverse effect of inflammatory cytokines. Funding: Sepracor Inc. 547 Expression of Cysteinyl Leukotriene Receptors by CD34+ Umbilical Cord Blood (CB) - Progenitor Cells: Relevance to Atopic Development J. A. ROA, A. J. BAATJES, L. D. SALEH, M. M. CYR, G. M. GAU- VREAU, J. A. DENBURG; Division of clinical immunology and allergy, department of medicine, FACULTYOF HEALTH SCIENCES, McMAS- TER UNIVERSITY, HAMILTON, ON, CANADA. RATIONALE: The cysteinyl leukotrienes (cysLTs) are potent, bioactive lipids that contribute to allergic and inflammatory diseases. Pharmacolog- ical studies have identified two classes of cysLT receptors (cysLTR1 and cysLTR2), which are expressed on a variety of cell types, including human peripheral blood CD34+ cells. However, no information is yet available regarding cysLTR expression on human umbilical CB progeni- tor cells. We examined the expression of cysLTR1 and cysLTR2 on human CB CD34+ progenitor cells, in order to be able to assess their potential relevance to the development of atopy. METHODS: Non-adherent mononuclear cells (NAMNC) were obtained from human CB. Flow cytometric staining of these cells was performed using monoclonal antibodies to CD34 and CD45, and polyclonal rabbit antibodies selective and specific for cysLTR1 and cysLTR2 (Caymen Chemical). Flow cytometric data were collected on a three-colour BD FACScan cytometer. WinMDI analysis software was used to evaluate the expression of cysLTR1 and cysLTR2. RESULTS: The mean expression on CD34+/CD45+ progenitor cells of cysLTR1 was 35% (SD ± 11; n=5) with a range of 21% to 44% and a median of 35. The mean expression of cysLTR2 was 40% (SD ± 20; n=5) with a range of 26% to 71% and a median of 36%. S140 Abstracts J ALLERGY CLIN IMMUNOL FEBRUARY 2006 SUNDAY

Transcript of Masking of Corticosteroid-induced Inhibition of NF-κB activation by (S)-Albuterol in Human Airway...

Page 1: Masking of Corticosteroid-induced Inhibition of NF-κB activation by (S)-Albuterol in Human Airway Smooth Muscle Cells and Human Blood Lymphocytes

544 Quality of Life of Children with Allergic Diseases

Y. Adachi1, Y. Okabe1, T. Itazawa1, Y. S. Adachi1, M. Nakabayashi1, T.

Fuchizawa1, T. Miyawaki1, H. Odajima2; 1Dept of Pediatrics, Toyama

Medical & Pharmaceutical University, Toyama, JAPAN, 2Dept of Pedi-

atrics, Fukuoka National Hospital, Fukuoka, JAPAN.

RATIONALE: It has not been well evaluated how allergic diseases

impair the quality of life (QOL) of children compared with healthy ones.

METHODS: We carried out a cross-sectional survey among the younger

children aged 6-8 yr and elder ones aged 13-15 yr in a Japanese prefec-

ture (Toyama), using a generic QOL questionnaire; Kid-KINDL®. The

survey was performed since May through August 2005. Asthma (A),

allergic rhinitis (R), and eczema (E) were defined based on the ISSAC

questionnaire.

RESULTS: During the previous one year, 13.0, 38.6, and 19.4% of the

younger children (n=1771), and 6.1, 57.4, and 13.5% of the elder ones

(n=942) had been symptomatic for A, R, E, respectively. On the other

hand, 42.3% of the younger children and 27.7% of the elder ones had

never experienced any allergic symptoms in their lives. Comparing to

these healthy children, the symptomatic children had impaired QOL,

especially in “physical” and “friend” parts. The number of the

impaired scales in the older group was higher than that of the younger

one.

CONCLUSIONS: Many children are suffered from allergic symptoms.

Allergic diseases have a substantial impact on the QOL in children com-

pared with healthy children. Supported by a grant from Japanese Ministry

of Health, Labour and Welfare for Japanese Asthma Survey Group.

545 Impaired Quality of Life in Child Asthmatics in Tokyo, Japan

N. Kojima1,2, Y. Ohya1,2, M. Futamura1,2, M. Akashi1,2, K. Akiyama2, K.

Takahashi2, T. Nakagawa2, F. Kobayashi2, A. Eboshida2, H. Nakamura2,

H. Odajima2, Y. Adachi2, A. Akasawa1,2; 1National Center for Child

Health and Development, Tokyo, JAPAN, 2Japanese Asthma Survey

Group, Tokyo, JAPAN.

RATIONALE: Asthma is the most common chronic diseases in school-

aged children in Japan. Measuring of QOL is important to evaluate their

school life.

METHODS: School based survey was conducted by using KINDL-R

quality of life(QOL) questionnaire and ISAAC questionnaire for children

of 6-7 years old and 13-14 years old from May to June in 2005. Randomly

selected public schools managed by local governments in Tokyo joined

this investigation.

RESULTS: Response rate of these questionnaire was 86%(22645 chil-

dren) in 6-7 year old group and 64%(12879 children) in 13-14 year old

group. Comparing asthmatics with non-asthmatics in the same age,

QOL of children with asthma was significantly impaired (younger

group: 96.7 vs 98.6, p<.001, elder group: 78.2 vs 83.0, p<.001). In addi-

tion, QOL of children was significantly impaired by severity (severe

asthmatics, moderate ones, mild ones and non-asthmatics was 95.1,

95.8, 97.9 and 98.6 respectively in younger children, and 76.2, 78.4,

78.3 and 83.0 respectively in elder ones. p<.001). Especially QOL of

children with exercise-induced asthma (EIA) were more significantly

impaired than ones without EIA (younger group: 95.7 vs 97.1, p<.001,

elder group: 77.2 vs 81.1, p<0.01) and showed lower score in the cate-

gories of school, emotional well-being and physical well-being than

those without EIA.

CONCLUSIONS: This is the first investigation to focus on the QOL

comparison between Japanese children with asthma and those without it.

QOL of children was impaired by having asthma even in the mild cases

and more severely disturbed in elder cases and the cases with EIA.

Funding: Ministry of Health, Labour and Welfare

546 Masking of Corticosteroid-induced Inhibition of NF-�B acti-vation by (S)-Albuterol in Human Airway Smooth MuscleCells and Human Blood Lymphocytes

D. K. Agrawal1, G. Cheng1, P. W. Kelbe2; 1Biomedical Sciences,

Creighton University School of Medicine, Omaha, NE, 2Medical Liason,

Sepracor Inc., Marlborough, MA.

RATIONALE: Pro-constrictory and pro-inflammatory properties of (S)-

albuterol have been widely reported. However, underlying mechanisms

are unclear. We examined the effect of (S)-albuterol on corticosteroid-

induced inhibition of NF-�B in human airway smooth muscle cells

(HASMCs) and human blood lymphocytes. We also investigated if (S)-

Albuterol synergized response of TNF-� to stimulate NF-�B in

HASMCs.

METHODS: Lymphocytes were purified from the blood of normal vol-

unteers using Percoll density gradient followed by non-adherence to cul-

ture dish. Primary HASMCs were grown in culture. Lymphocytes or

HASMCs were treated with various concentrations of albuterol enan-

tiomers (0.1 - 1.0 microM). Dexamethasone (1 microM) and TNF-� (100

nM) were used to stimulate cells. Activity of NF-�B was measured by

Western blot and TransAM method using antibodies to p65.

RESULTS: Both (RS) and (S)-albuterol induced NF-�B activation in

both human blood lymphocytes and HASMCs in a dose-dependent man-

ner. However (R)-albuterol (up to 10 microM concentration) had no

effect. Short-term exposure (90 minutes) of the cells to dexamethasone

significantly attenuated (25-35%) the activation of NF-�B by (S)- and

(RS)-albuterol. Interestingly, chronic exposure of the cells to (S)-albuterol

for 8-24 hours significantly attenuated (42-60%) the effect of dexametha-

sone to inhibit NF-�B activity. However, prior exposure of the cells to

(R)-albuterol did not affect dexamethasone-induced inhibition of NF-�B.

TNF-� induced NF-�B activity and this effect was amplified by

(S)-albuterol (0.1 and 1.0 microM).

CONCLUSIONS: Since NF-�B is a potent transcription factor involved

in airway inflammation, these data suggest that (S)-albuterol can either

mask or antagonize the beneficial effect of dexamethasone and amplify

the adverse effect of inflammatory cytokines.

Funding: Sepracor Inc.

547 Expression of Cysteinyl Leukotriene Receptors by CD34+Umbilical Cord Blood (CB) - Progenitor Cells: Relevance toAtopic Development

J. A. ROA, A. J. BAATJES, L. D. SALEH, M. M. CYR, G. M. GAU-

VREAU, J. A. DENBURG; Division of clinical immunology and allergy,

department of medicine, FACULTY OF HEALTH SCIENCES, McMAS-

TER UNIVERSITY, HAMILTON, ON, CANADA.

RATIONALE: The cysteinyl leukotrienes (cysLTs) are potent, bioactive

lipids that contribute to allergic and inflammatory diseases. Pharmacolog-

ical studies have identified two classes of cysLT receptors (cysLTR1 and

cysLTR2), which are expressed on a variety of cell types, including

human peripheral blood CD34+ cells. However, no information is yet

available regarding cysLTR expression on human umbilical CB progeni-

tor cells. We examined the expression of cysLTR1 and cysLTR2 on

human CB CD34+ progenitor cells, in order to be able to assess their

potential relevance to the development of atopy.

METHODS: Non-adherent mononuclear cells (NAMNC) were obtained

from human CB. Flow cytometric staining of these cells was performed

using monoclonal antibodies to CD34 and CD45, and polyclonal rabbit

antibodies selective and specific for cysLTR1 and cysLTR2 (Caymen

Chemical). Flow cytometric data were collected on a three-colour BD

FACScan cytometer. WinMDI analysis software was used to evaluate the

expression of cysLTR1 and cysLTR2.

RESULTS: The mean expression on CD34+/CD45+ progenitor cells of

cysLTR1 was 35% (SD ± 11; n=5) with a range of 21% to 44% and a

median of 35. The mean expression of cysLTR2 was 40% (SD ± 20; n=5)

with a range of 26% to 71% and a median of 36%.

S140 Abstracts J ALLERGY CLIN IMMUNOL

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