Abstract
Background: Late-phase airway hyperresponsiveness (AHR) in asthma is considered the event leading to persistent inflammation in the lungs, but the molecular mechanisms involved in this process are poorly understood. Objective: To examine the role of TNF-α in the development of a late AHR and airway inflammation in asthma. Methods: We established a murine model of asthma with not only biphasic AHR to methacholine but also airway eosinophilia. The effect of TNF-α blockade was determined by using anti-TNF-α antibody and TNF-α knockout mice. Cytosolic phospholipase A2 (cPLA 2) mRNA expression and activity were assessed by using RT-PCR and 1-stearoyl-2-[1-14C] arachidonyl-sn-glycero-3-phosphocholine as the substrate, respectively. Results: TNF-α blockade resulted in significant inhibition of the late AHR without affecting the early AHR, and reduction in airway eosinophilia and inflammation. cPLA2 activity was increased in asthmatic lungs in a TNF-α-dependent way, and cPLA2 inhibitor blocked late AHR and airway eosinophilia. TNF-α also stimulated the synthesis of cPLA2 metabolites such as leukotriene B4 and platelet-activating factor in the airway. Specific inhibitors of cPLA 2 metabolites inhibited the late AHR and airway eosinophilia. Conclusions: TNF-α is the proximal key cytokine capable of developing late-phase AHR and subsequent airway inflammation through expression/activation of cPLA2.
Original language | English |
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Pages (from-to) | 537-543 |
Number of pages | 7 |
Journal | Journal of Allergy and Clinical Immunology |
Volume | 116 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2005 Sep |
Keywords
- 5-lipoxygenase
- Airway inflammation
- Asthma
- Cyclooxygenase
- Cytosolic phospholipase A
- Late airway response
- Platelet-activating factor
- TNF-α
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology