Tomokazu Yuizono

Activation of polymorphonuclear leukocytes in oleic acid-induced lung injury

AbstractObjective: Oleic acid (OA) can produce a lung injury similar to the adult respiratory distress syndrome (ARDS). Elastase and superoxides are thought to have an effect in ARDS. However, the effect that elastase and superoxide have in OA lung injury is unclear. To examine their involvement in OA lung injury, we tested the effects of methoxysuccinyl-alanyl-alanyl-prolyl-valyl chloromethyl ketone (MAAPVCK), an elastase inhibitor, and N-acetyl-L-cysteine (NAC), an active oxygen scavenger, on the increase in pulmonary vascular permeability caused by OA. We also examined whether OA stimulated elastase and/or superoxide release from polymorphonuclear leukocytes (PMNs). Design: Prospective trial. Setting: University laboratory. Interventions: (1) Guinea pigs were anesthetized. MAAPVCK (2.5 mg/kg) or NAC (150 mg/kg) was infused over OA (15 µl/kg) injection. Evans blue was used to measure vascular permeability. (2) PMNs were isolated from the blood of guinea pigs and rats. Elastase release was measured with MeO-Suc-Ala-Ala-Pro-Val-7-amino-4-methyl-coumarin. Superoxide production was measured by the ferricyto-chrome c reduction method. Measurements and results: OA caused pulmonary hemorrhage and an increase in vascular permeability. MAAPVCK and NAC significantly attenuated the increase in vascular permeability in distal bronchus and trachea, respectively. OA induced superoxide production from PMNs in guinea pigs, but elastase release from PMNs was not detected. Conclusions: These results suggest that elastase and superoxide are involved in OA lung injury.

Pentoxifylline prevents a decrease in arterial oxygen tension in oleic acid-induced lung injury

OBJECTIVES a) To determine whether pentoxifylline has a preventive effect on the decrease in PaO2 that is caused by oleic acid, and whether pentoxifylline facilitates normalization of PaO2 from the decreased state. b) To examine whether pentoxifylline can attenuate an increase in pulmonary vascular permeability that is induced by oleic acid. DESIGN Prospective trial. SETTING University laboratory. SUBJECTS a) A total of 48 guinea pigs (700 to 1100 g) for blood gas analysis. b) A total of 28 guinea pigs (390 to 670 g) for measurement of pulmonary vascular permeability. INTERVENTIONS a) For blood gas analysis, the guinea pigs were mechanically ventilated. Oleic acid (15 microL/kg) was injected into the guinea pigs to decrease PaO2. Pentoxifylline (5 or 20 mg/kg) was administered 40 or 3 mins before oleic acid injection or 13 mins after oleic acid injection. b) For measurement of pulmonary vascular permeability, the guinea pigs were anesthetized with pentobarbital and catheterized via the external jugular vein for drug administration. Pentoxifylline (20 mg/kg) plus Evans blue (30 mg/kg) or theophylline (20 mg/kg) plus Evans blue (30 mg/kg) were administered at 40- and 1-min intervals before oleic acid (15 microL/kg) injection, respectively. Perfusion with saline was performed through the aorta 90 mins after the oleic acid injection. The airways were removed and separated into the trachea, the main bronchus, the proximal bronchus, and the distal bronchus. Evans blue was extracted from the airways with formamide for 18 hrs and measured. MEASUREMENTS AND MAIN RESULTS a) We measured PaO2, PaCO2, and pH, and recorded airway pressure and systemic blood pressure at 15, 10, and 5 mins before oleic acid injection and at 6, 10, 15, 35, 55, and 75 mins after oleic acid injection. Compared with the control groups, a decrease in PaO2 by oleic acid was significantly prevented when pentoxifylline (5 or 20 mg/kg) was administered 40 mins before oleic acid injection. However, a decrease in PaO2 by oleic acid was not significantly reduced when pentoxifylline was administered 3 mins before oleic acid injection. Pentoxifylline administered 13 mins after oleic acid injection did not affect the recovering course of PaO2 significantly. b) An increase in pulmonary vascular permeability by oleic acid was significantly attenuated by both pentoxifylline and theophylline. The effect of theophylline was significantly stronger than the effect of pentoxifylline in the main bronchi. The effect of theophylline was not significantly different from the effect of pentoxifylline in other areas. CONCLUSION Pentoxifylline is a noteworthy drug that could be a candidate as a therapy to help prevent hypoxemia in lung injuries that share a common mechanism with oleic acid-induced lung injury.

Tranexamic acid attenuates oleic-acid-induced pulmonary extravasation

ObjectiveActivation of fibrinolysis is implicated in the development of vascular injury in certain lung injuries. It has yet to be reported that activation of plasmin is involved in extravasation caused by oleic acid (OA). We examined whether or not plasmin is involved in pulmonary extravasation by OA.DesignProspective trial.SettingUniversity laboratory.SubjectsA total of 78 guinea pigs (498.9±10.6 g).InterventionsEvans blue (EB) was administered to anesthetized guinea pigs. Subsequently four protocols were followed: (1) After 1 min, 60 μl/kg of OA was injected. Perfusion was performed 30, 60 or 90 min after OA injection to wash out intravascular EB. (2) After 1 min, 15, 30 or 60 μl/kg of OA was injected. (3) Tranexamic acid (TA) (2 g/kg) or saline was administered 30 min before OA (15 μl/kg) injection. (4) Diphenhydramine hydrochloride (2.9 mg/kg) or saline was administered 7 min before OA (15 μl/kg) injection.Measurement and resultsExcept in protocol 1, the chest cavity was opened 90 min after OA injection. Perfusion was then performed. Airway was separated into four parts from trachea to distal bronchus. EB was extracted from the tissues and measured. OA caused an extravasation throughout airways in a time-and dose-dependent manner. Extravasation was more conspicuous in peripheral tissues. TA significantly attenuated extravasation, while diphenhydramine hydrochloride did not.ConclusionsIt is suggested that plasmin, but not histamine, is involved in extravasation by OA. Inhibition of plasmin can be an effective strategy for treatment of this kind of lung injury.