The role of endothelin-1 in hyperoxia-induced lung injury in mice

BACKGROUND: As prolonged hyperoxia induces extensive lung tissue damage, we set out to investigate the involvement of endothelin-1 (ET-1) receptors in these adverse changes. METHODS: Experiments were performed on four groups of mice: control animals kept in room air and a group of mice exposed to hyperoxia for 60 h were not subjected to ET-1 receptor blockade, whereas the dual ETA/ETB-receptor blocker tezosantan (TEZ) was administered via an intraperitoneal pump (10 mg/kg/day for 6 days) to other groups of normal and hyperoxic mice. The respiratory system impedance (Zrs) was measured by means of forced oscillations in the anesthetized, paralyzed and mechanically ventilated mice before and after the iv injection of ET-1 (2 μg). Changes in the airway resistance (Raw) and in the tissue damping (G) and elastance (H) of a constant-phase tissue compartment were identified from Zrs by model fitting. RESULTS: The plasma ET-1 level increased in the mice exposed to hyperoxia (3.3 ± 1.6 pg/ml) relative to those exposed to room air (1.6 ± 0.3 pg/ml, p < 0.05). TEZ administration prevented the hyperoxia-induced increases in G (13.1 ± 1.7 vs. 9.6 ± 0.3 cmH(2)O/l, p < 0.05) and H (59 ± 9 vs. 41 ± 5 cmH(2)O/l, p < 0.05) and inhibited the lung responses to ET-1. Hyperoxia decreased the reactivity of the airways to ET-1, whereas it elevated the reactivity of the tissues. CONCLUSION: These findings substantiate the involvement of the ET-1 receptors in the physiopathogenesis of hyperoxia-induced lung damage. Dual ET-1 receptor antagonism may well be of value in the prevention of hyperoxia-induced parenchymal damage

Site of Allergic Airway Narrowing and the Influence of Exogenous Surfactant in the Brown Norway Rat

Background: The parameters RN (Newtonian resistance), G (tissue damping), and H (tissue elastance) of the constant phase model of respiratory mechanics provide information concerning the site of altered mechanical properties of the lung. The aims of this study were to compare the site of allergic airway narrowing implied from respiratory mechanics to a direct assessment by morphometry and to evaluate the effects of exogenous surfactant administration on the site and magnitude of airway narrowing. Methods: We induced airway narrowing by ovalbumin sensitization and challenge and we tested the effects of a natural surfactant lacking surfactant proteins A and D (InfasurfH) on airway responses. Sensitized, mechanically ventilated Brown Norway rats underwent an aerosol challenge with 5 % ovalbumin or vehicle. Other animals received nebulized surfactant prior to challenge. Three or 20 minutes after ovalbumin challenge, airway luminal areas were assessed on snap-frozen lungs by morphometry. Results: At 3 minutes, RN and G detected large airway narrowing whereas at 20 minutes G and H detected small airway narrowing. Surfactant inhibited RN at the peak of the early allergic response and ovalbumin-induced increase in bronchoalveolar lavage fluid cysteinyl leukotrienes and amphiregulin but not IgE-induced mast cell activation in vitro. Conclusion: Allergen challenge triggers the rapid onset of large airway narrowing, detected by RN and G, and subsequen

Optimal mean airway pressure during high-frequency oscillatory ventilation determined by measurement of respiratory system reactance.

The aims of the present study were (i) to characterize the relationship between mean airway pressure (PAW) and reactance measured at 5 Hz (reactance of the respiratory system (X RS), forced oscillation technique) and (ii) to compare optimal PAW (P opt) defined by X RS, oxygenation, lung volume (VL), and tidal volume (VT) in preterm lambs receiving high-frequency oscillatory ventilation (HFOV).Nine 132-d gestation lambs were commenced on HFOV at PAW of 14 cmH2O (P start). PAW was increased stepwise to a maximum pressure (P max) and subsequently sequentially decreased to the closing pressure (Pcl, oxygenation deteriorated) or a minimum of 6 cmH2O, using an oxygenation-based recruitment maneuver. X RS, regional V L (electrical impedance tomography), and V T were measured immediately after (t 0 min) and 2 min after (t 2 min) each PAW decrement. P opt defined by oxygenation, X RS, V L, and V T were determined.The PAW-X RS and PAW-VT relationships were dome shaped with a maximum at Pcl+6 cmH2O, the same point as P opt defined by VL. Below Pcl+6 cmH2O, X RS became unstable between t 0 min and t 2 min and was associated with derecruitment in the dependent lung. P opt, as defined by oxygenation, was lower than the P opt defined by X RS, V L, or V T.X RS has the potential as a bedside tool for optimizing PAW during HFOV