Interleukin-1 Receptor Antagonist Attenuates Airway Hyperresponsiveness Following Exposure to Ozone

Abstract

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.

Signal Transduction Pathways of Tumor Necrosis Factor–mediated Lung Injury Induced by Ozone in Mice

“…Presence of functional AP-1 and NF-B binding sites in mouse MIP-2 (34, 53) and TNF-␣ (54, 55) gene promoters further supports TNF-mediated MIP-2 and TNF-␣ regulation via these transcription factors. The injurious effects of TNF-dependent IL-1␤ have also recently been determined after acute O 3 exposure (56). Interestingly, in the present study, IL-6 mRNA was overexpressed in O 3 -resistant Tnfr Ϫ/Ϫ mice, which may suggest a protective role for this cytokine.…”

Interleukin-1 receptor antagonist prevents murine bronchopulmonary dysplasia induced by perinatal inflammation and hyperoxia

“…Several studies identified an association between elevated levels of IL-1β and development of BPD or an adverse clinical outcome (6,9). An imbalance between IL-1β and IL-1Ra contributes to prolonged inflammation in BPD (11), and treatment with IL-1Ra protects from loss of function and structural damage in an ozone model of lung disease (35). Neonatal mice in which IL-1β was conditionally overexpressed in airway epithelial cells suffered from BPD-like disrupted alveolar septation and capillary growth and featured elevated levels of MIP-2 (8)-findings consistent with our data.…”

Interleukin-1R antagonist gene and pre-natal smoke exposure are associated with childhood asthma

“…This response is abrogated when the product of the IL-1 receptor antagonist gene, IL-1Ra, competitively binds to the receptor but does not elicit the downstream signal transduction cascade. The pro-inflammatory effect of IL-1 and the antiinflammatory effect of IL-1Ra in asthma have been documented in a number of human and animal studies [9][10][11][12][13].…”