Tumor necrosis factor receptor 2 contributes to ozone-induced airway hyperresponsiveness in mice

The purpose of this study was to determine whether tumor necrosis factor (TNF) contributes to airway hyperresponsiveness (AHR) and migration of polymorphonuclear leukocytes (PMN) into the airways following exposure to ozone (03). Wild-type mice, TNF p55 or p75 receptor knockout mice (p55 TNFR -/- and p75 TNFR -/-), as well as double receptor knockout mice (p55/p75 TNFR -/-), were exposed to O3. Three hours after cessation of O3, airway responses to inhaled methacholine were determined by whole body plethysmography using changes in enhanced pause (Penh) as an index of airway narrowing. In wild-type mice, O3 exposure (0.5 ppm, 3 h) caused a significant increase in airway responsiveness as indicated by a 1.2 log leftward shift in the methacholine dose-response curve. In contrast, in p55/p75 TNFR -/- mice, O3 caused only a 0.5 log shift in the dose-response curve (p < 0.05 compared with wild-type). Similar results were obtained in p75 TNFR -/mice. In contrast, O3-induced airway hyperresponsiveness was not different in WT and p55 TNFR -/- mice. During O3 exposure (1 pm, 3 h), minute ventilation (V̇e) decreased by 64 ± 4% in wild-type, but only 24 ± 5% in p55/p75 TNFR -/- mice, indicating that despite their reduced O3-induced AHR, the TNFR-deficient mice actually inhaled a greater dose of O3. Similar results were obtained in p75 -/- mice, whereas changes in V̇e induced by O3 were the same in wild-type and p55 -/- mice. PMN numbers in bronchoalveolar lavage fluid recovered 21 h after cessation of exposure to O3 (2 ppm, 3 h) were significantly increased compared with after air exposure but were not different in wild-type and p55/p75 TNFR -/- mice. Our results indicate that TNF contributes to the AHR but not the PMN emigration induced by acute O3 exposure