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in a Murine Model of Toluene Diisocyanate-Induced Asthma1
* Department of Internal Medicine, Airway Remodeling Laboratory, and
Department of Immunology, Chonbuk National University Medical School, Jeonju, South Korea
Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor 
(PPAR) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPAR in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPAR agonist, rosiglitazone, or pioglitazone, and PPAR on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-
1, and NF-
B in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPAR agonists or adenovirus carrying PPAR2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-1, and NF-B in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-B activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-1 after TDI inhalation. These findings demonstrate a protective role of PPAR in the pathogenesis of the TDI-induced asthma phenotype.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the National Research Laboratory Program of the Korea Science and Engineering Foundation, by a Korea Research Foundation Grant funded by the Korea Government (MOEHRD, Basic Research Promotion Fund, KRF-2005-201-E00014), by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A060169) (to Y.C.L.), and also by a grant from the Korea Health 21 R&D Project (0412-CR03-0704-0001) (to S.J.P.).
2 K.S.L. and S.J.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Yong Chul Lee, Department of Internal Medicine, Chonbuk National University Medical School, San 2-20 Geumam-dong, deokjin-gu, Jeonju, Jeonbuk 561-180, South Korea. E-mail address: leeyc{at}chonbuk.ac.kr
4 Abbreviations used in this paper: TDI, toluene diisocyanate; PPAR, peroxisome proliferator-activated receptor; BAL, bronchoalveolar lavage; Ad, adenovirus; p-Akt, phosphorylated Akt; PAS, periodic acid-Schiff; RL, airway resistance; AdPPAR, adenoviruses carrying PPAR2 cDNA.
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