thromboxane-b2 and Hyperoxia

Premature infants often develop serious clinical complications associated with respiratory failure and hyperoxic lung injury that includes lung inflammation and alterations in lung development. The goal of these studies is to test the hypothesis that there are differences in the course of lung injury in newborn mice exposed to 85% or >95% oxygen that provide models to address the differential effects of oxidation and inflammation. Our results indicate differences between the 85% and >95% O2 exposure groups by day 14 in weight gain and lung alveolarization. Inflammation, assessed by neutrophil counts, was observed in both hyperoxia groups by day 3 but was dramatically greater in the >95% O2-exposed groups by day 14 and associated with greater developmental deficits. Cytoplasmic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase levels were elevated but no patterns of differences were observed between exposure groups. Prostaglandins D2, E2, and F2alpha were increased in the tissues from mouse pups exposed to >95% O2 at 7 d indicating a differential expression of cyclooxygenase-2 products. Our data indicate that there are differences in the models of 85% or >95% O2 exposure and these differences may provide mechanistic insights into hyperoxic lung injury in an immature system.

Topics: Acute Lung Injury; Animals; Animals, Newborn; Arachidonate 5-Lipoxygenase; Body Weight; Cyclooxygenase 2; Disease Models, Animal; Group IV Phospholipases A2; Hyperoxia; Lung; Mice; Mice, Inbred C3H; Neutrophil Infiltration; Oxygen; Prostaglandins; Pulmonary Alveoli; Thromboxane B2; Time Factors; Up-Regulation

To compare the effects of dexamethasone (Dex) and celecoxib (Cel) on F-isoprostane, prostacyclin (PGI2), and thromboxane A2 (TxA2) following hyperoxia, and hyperoxia followed by recovery in room air (RA), newborn rabbits were exposed to hyperoxia (80-100% oxygen) for 4 days, during which they were treated with saline (Sal, i.m.), Dex (i.m.), vehicle (Veh, PO), or Cel (PO, n = 12 per group). Six animals in each group were sacrificed immediately following hyperoxia, and the remainder allowed to recover in RA for 5 days. The control litters were treated simultaneously in RA with all conditions other than atmospheric oxygen being identical. Blood samples were assayed for 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha), 6-keto prostaglandin F1alpha (6-ketoPGF1alpha), and TxB2. Dex and Cel decreased 8-epi-PGF2alpha during hyperoxia and the recovery period. Dex increased 6-ketoPGF2alpha following hyperoxia, while similar increments were noted during recovery with Cel. Although TxB2 was decreased only during the recovery period, TxB2/6-ketoPGF1alpha ratio was lower during hyperoxia and recovery in both treated groups. The effect of Cel on 8-epi-PGF2. and TxA2/PGI2 ratio confirm the formation of a COX-derived F2-isoprostane that is possibly linked to TxA2 receptors. Further studies are required to examine whether Cel can be used as a therapeutic alternative to Dex for oxygen-induced injury in the newborn.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Dexamethasone; Dinoprost; Epoprostenol; F2-Isoprostanes; Hyperoxia; Oxidative Stress; Pyrazoles; Rabbits; Sulfonamides; Thromboxane B2

The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2 (TXB2) and 6-keto-prostaglandin (PG) F1alpha induced by inhibition of nitric oxide synthase with NG-nitro-L-arginine-methyl-ester (L-NAME) in a porcine model of endotoxaemia. Twenty-two domestic, random source pigs, weighing 15.4 +/- 2.7 kg (mean +/- standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end-tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2 (Control, n = 6); Escherichia coli lipopolysaccharide (5 microg/kg/h from 1 to 2 h followed by 2 microg/kg/h from 2 to 5 h) + 30% O2 (LPS, n = 4); L-NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2 (n = 6); and L-NAME + LPS + 30% O2 (n = 6). L-NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L-NAME + LPS + 30% O2 group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L-NAME + LPS-induced increases in TXB2 and 6-keto-PGF1alpha concentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L-NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L-NAME-induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxemia; Enzyme Inhibitors; Escherichia coli Infections; Hemodynamics; Hyperoxia; Lung; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pulmonary Circulation; Swine; Swine Diseases; Thromboxane B2; Vasoconstriction

Our purpose was to study the effect of dexamethasone (DEX) on choroidal (ChBF) and retinal blood flow (RBF) during normoxia and hyperoxia. Eighteen spontaneously breathing newborn piglets were examined. ChBF and RBF were measured using radiolabeled microspheres while the piglets were in normoxia before (RA1) and 45 min after either saline or DEX (2 mg/kg) infusion (RA2), and after 90 min of hyperoxia (O2) (Pao2 40-60 kPa). Vitreous prostanoids (prostaglandins F1 alpha and E2 and thromboxane B2) and leukotrienes (leukotriene B4) measurements were obtained during normoxia after either placebo or DEX infusion in an additional 22 piglets. Vitreous prostanoids were also studied after 90 min of hyperoxia. We found that RBF increased significantly after DEX infusion (p < 0.02). There was no change in RBF from RA1 to RA2, before and after saline infusion. RBF decreased significantly during hyperoxia in both groups (p < 0.03). ChBF did not change significantly between RA1 and RA2 in any of the groups. ChBF decreased significantly during hyperoxia in both groups (p < 0.03). Vitreous prostanoids and leukotrienes were reduced significantly after DEX infusion (p < 0.05). Prostanoids were similar in the two groups during hyperoxia. We concluded that DEX increases RBF significantly, but not ChBF. RBF and ChBF decreased in both groups during hyperoxia. Therefore, the metabolites of arachidonic acid do not seem to be involved as mediators of hyperoxic vasoconstriction.

Topics: Animals; Animals, Newborn; Blood Pressure; Carbon Dioxide; Cardiac Output; Choroid; Dexamethasone; Dinoprostone; Hemodynamics; Hydrogen-Ion Concentration; Hyperoxia; Infusions, Intravenous; Leukotriene B4; Microspheres; Muscle, Smooth, Vascular; Oxygen; Prostaglandins F; Regional Blood Flow; Retinal Vessels; Swine; Thromboxane B2; Vitreous Body