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* Department of Life Science, Postech Biotech Center, Pohang University of Science and Technology, Namgu, Pohang, Gyeongbuk, Republic of Korea;
Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University, Baltimore, MD 21224;
Department of Internal Medicine, Institute of Allergy and Clinical Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea; and
Division of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, Republic of Korea
Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-
expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 µg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 µg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN--deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-
expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF- receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.
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1 This work was supported in part by grants from the Ministry of Health and Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002, A050193, and A050288), and in part by the Postech Research Fund (1RC0660301).
2 Address correspondence and reprint requests to Dr. Zhou Zhu, Division of Allergy and Clinical Immunology, Asthma and Allergy Center, Johns Hopkins University, 5501 Hopkins Bayview Circle/1A.2, Baltimore, MD 21224; E-mail address: zzhu{at}jhmi.edu or Dr. Yoon-Keun Kim, Department of Life Science, Postech Biotech Center, Pohang University of Science and Technology, San 31 Hyojadong, Namgu, Pohang, Gyeongbuk 790-784, Republic of Korea; E-mail address: juinea{at}postech.ac.kr
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; FEV1, forced expiratory volume at 1 s; PFT, pulmonary function test; DRS, dose-response curve; Penh, enhanced pause; WT, wild type; BAL, bronchoalveolar lavage; IP-10, IFN--inducible protein 10.
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