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 (T NF) contributes to airway hyperresponsiveness (AHR) and migration of polymo rphonuclear leukocytes (PMN) into the airways following exposure to ozone ( O-3). Wild-type mice, TNF p55 or p75 receptor knockout mice (p55 TNFR -/- a nd p75 TNFR -/-), as well as double receptor knockout mice (p55/p75 TNFR -/ -), were exposed to O-3. Three hours after cessation of O-3, airway respons es to inhaled methacholine were determined by whole body plethysmography us ing changes in enhanced pause (Penh) as an index of airway narrowing. In wi ld-type mice, O-3 exposure (0.5 ppm, 3 h) caused a significant increase In airway responsiveness as indicated by a 1.2 log leftward shift in the metha choline dose-response curve. In contrast, in p55/p75 TNFR -/- mice, O-3 cau sed 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 contras t, O-3-induced airway hyperresponsiveness was not different in WT and p55 T NFR -/- mice. During O-3 exposure (1 pm, 3 h), minute ventilation (VE) decr eased by 64 +/- 4% in wild-type, but only 24 +/- 5% in p55/p75 TNFR -/- mic e, indicating that despite their reduced O-3-induced AHR, the TNFR-deficien t mice actually inhaled a greater dose of O-3. Similar results were obtaine d in p75 -/- mice, whereas changes in V(over bar)(E) induced by O-3 were th e same in wild-type and p55 -/- mice. PMN numbers in bronchoalveolar lavage fluid recovered 21 h after cessation of exposure to O-3 (2 ppm, 3 h) were significantly increased compared with after air exposure but were not diffe rent 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 O-3 expo sure.