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 (O(3)). 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 O(3). Three hours after cessation of O(3), 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, 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 methacholine dose- response curve. In contrast, in p55/p75 TNFR -/- mice, O(3) 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, O(3)-induced airway hyperresponsiveness was not different in WT and p55 TNFR -/- mice. During O(3) exposure (1 pm, 3 h), minute ventilation (V E) decreased by 64 +/- 4% in wild-type, but only 24 +/- 5% in p55/p75 TNFR -/- mice, indicating that despite their reduced O(3)-induced AHR, the TNFR-deficient mice actually inhaled a greater dose of O(3). Similar results were obtained in p75 -/- mice, whereas changes in V E induced by O(3) were the 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 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 O(3) exposure. Keywords: whole body plethysmography; polymorphonuclear leukocytes; minute ventilation; knockout mice; methacholine     

Acute intranasal osteopontin treatment in male rats following TBI increases the number of activated microglia but does not alter lesion characteristics

Intranasal recombinant osteopontin (OPN) has been shown to be neuroprotective in different models of acquired brain injury but has never been tested after traumatic brain injury (TBI). We used a model of moderate-to-severe controlled cortical impact in male adult Sprague Dawley rats and tested our hypothesis that OPN treatment would improve neurological outcomes, lesion and brain tissue characteristics, neuroinflammation, and vascular characteristics at 1 day post-injury. Intranasal OPN administered 1 hr after the TBI did not improve neurological score, lesion volumes, blood–brain barrier, or vascular characteristics. When assessing neuroinflammation, we did not observe any effect of OPN on the astrocyte reactivity but discovered an increased number of activated microglia within the ipsilateral hemisphere. Moreover, we found a correlation between edema and heme oxygenase-1 (HO-1) expression which was decreased in OPN-treated animals, suggesting an effect of OPN on the HO-1 response to injury. Thus, OPN may increase or accelerate the microglial response after TBI, and early response of HO-1 in modulating edema formation may limit the secondary consequences of TBI at later time points. Additional experiments and at longer time points are needed to determine if intranasal OPN could potentially be used as a treatment after TBI where it might be beneficial by activating protective signaling pathways.