Biomedical subjects

G H Gurtner

Publications and source records attributed to G H Gurtner.

At least 19 recordsLinked to original sources

PubMed1995

Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits.

We examined the effects of treatment with N-acetylcysteine (NAC) on pulmonary edema formation in isolated perfused rabbit lungs following in vivo phosgene exposure. This study focused on posttreatment intratracheal administration of NAC after exposure. Rabbits, 2 to 3 kg, were exposed to a cumulative dose of phosgene to attain a concentration x time exposure effect of 1,500 ppm/min. Lungs were perfused with Krebs-Henseleit buffer at 40 ml/min from 70 to 150 min after exposure. Pulmonary artery pressure (Ppa), tracheal pressure (Pt), and the rate of lung weight gain (LWG) were measured continuously. Perfusate concentration of peptide leukotrienes LTC4, D4, and E4 were measured every 20 min during perfusion. At the conclusion of the experiment, lung tissue was analyzed for reduced and oxidized glutathione (GSH and GSSG) and lipid peroxidation (thiobarbituric acid-reactive substances, TBARS). Exposure to phosgene significantly increased Pt, LWG, LTC4, D4, and E4, TBARS, and GSSG over time compared with controls. Compared with phosgene, intratracheal NAC lowered Ppa, LWG, LTC4, D4, and E4, TBARS, and GSSG. We conclude that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of glutathione, reducing both lipid peroxidation and production of arachidonic acid metabolites.

Acetylcysteine↗

PubMed1992

Hyperbaric oxygen toxicity: role of thromboxane.

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Interactions of oxidant stress and vascular reactivity.

Oxidants have complex effects on pulmonary vascular reactivity. They can stimulate production of vasoconstrictor arachidonate mediators and can also cause vasodilation through activation of guanylate cyclase. Oxidants can also inactivate vasomotor phenomenon by interfering with mechanisms of signal transduction or smooth muscle contraction. The final physiological response depends on the balance of these complex actions.

Animals↗

PubMed1991

Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3',5'-cyclic monophosphate.

Hydrogen peroxide (H2O2), but not tertbutyl hydroperoxide, produces a concentration-dependent vasodilation of the pulmonary circulation in isolated saline perfused rabbit lungs when pulmonary arterial pressures (PAP) are raised with the thromboxane analogue U-46619. This vasodilation was enhanced in the presence of indomethacin, suggesting that H2O2 possesses both a prostaglandin-mediated constrictor and an additional dilator mechanism. In isolated rabbit intrapulmonary arteries the endothelium did not alter the dose-dependent relaxation of arterial rings to H2O2, and indomethacin enhanced the relaxant response of the peroxide. The decrease in PAP and relaxation of isolated pulmonary arteries observed with H2O2 was attenuated with 10 microM methylene blue, an inhibitor of soluble guanylate cyclase activation. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor, enhanced the vasodilation or relaxation to the peroxide in both preparations. These changes were not endothelium dependent. Inhibition of the cGMP-associated endothelium-derived relaxant factor (EDRF) with nitro-L-arginine, did not alter relaxation of arterial rings to peroxide. Thus H2O2 appears to produce pulmonary vasodilation through the activation of guanylate cyclase and accumulation of cGMP. Both H2O2 and EDRF may function as tonic stimulators of guanylate cyclase in the pulmonary circulation and contribute to the maintenance of low basal pressures.

Animals↗

PubMed1990

Antioxidants and antioxidant enzymes protect against pulmonary oxygen toxicity in the rabbit.

Two major lines of defense exist against oxidant lung injury: tissue antioxidants and antioxidant enzymes. We studied pretreatment with the antioxidants, vitamin E and butylated hydroxyanisole (BHA), and the antioxidant enzymes, superoxide dismutase (SOD) and catalase, in rabbits exposed to 100% O2 for 48 h. BHA (200 mg/kg ip) or vitamin E (50-100 mg/kg po) were given for 2 or 3 days, respectively, before O2 exposure. Combined therapy with polyethylene glycol- (PEG) conjugated SOD (12 mg/kg) and catalase (200,000 U/kg) was given intraperitoneally 1 h before and 24 h after beginning 100% O2. Hyperoxia significantly increased the pulmonary content of malondialdehyde, indicating enhanced lipid peroxidation. One hundred percent O2 also increased lung weight gain and alveolar-capillary permeability to aerosolized 99mTc-labeled diethylenetriaminepentaacetate (99mTc-DTPA, 500 mol wt) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt). Pretreatment with vitamin E, BHA, or the combination of PEG-SOD and PEG-catalase prevented the increase in malondialdehyde, lung weight gain, and alveolar-capillary permeability caused by hyperoxia. These results indicate that augmenting either tissue antioxidants or antioxidant enzymes can prevent the pulmonary injury caused by 48 h of 100% O2 in rabbits.

Animals↗

PubMed1990

Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators.

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotension II and KCl.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1990

Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.

Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action.

Animals↗

PubMed1989

The effect of the antioxidant, butylated hydroxy anisole, on peroxide-induced and spontaneous activity of the uterus from the pregnant rat.

Chorioamnionitis is associated with preterm labor. Leukocytes infiltrate infected tissue and secrete hydrogen peroxide (H2O2) and other reactive oxygen products as part of their bactericidal activity. We have therefore investigated the effect of H2O2 on activity of in vitro uteri from pregnant rats. Uteri from 18-day pregnant rats exposed to H2O2 showed a dose-dependent increase in both contractile activity and production of prostaglandins (PG) E2 and F2 alpha compared to untreated controls. The antioxidant butylated hydroxy anisole (BHA) inhibited the H2O2-induced uterine activity. Furthermore, BHA inhibited contractions and PG production from spontaneously contracting uteri from 21-day pregnant rats. H2O2 increased chemiluminescence of uterine tissue, an index of oxygen or lipid radical formation, whereas BHA inhibited this effect. The BHA inhibition of uterine activity was reversed by addition of PGE2 to the incubation chamber. These data support the hypothesis that reactive oxygen can regulate PG production by the uterus and suggests a role for reactive oxygen in infection-induced labor and perhaps normal term labor as well.

Animals↗

PubMed1989

Barbiturate anesthetics inhibit thromboxane-, potassium-, but not angiotensin-induced pulmonary vasoconstriction.

Administration of the oxidant lipid peroxide tertiary butyl hydroperoxide (t-bu-OOH) in the isolated rabbit lung leads to acute pulmonary vasoconstriction, which is caused by the synthesis of thromboxane. The inhalational anesthetics, halothane, nitrous oxide, and cyclopropane, markedly enhance t-bu-OOH-induced pulmonary vasoconstriction and thromboxane production. The effects of the intravenous (iv) barbiturates thiopental and pentobarbital on t-bu-OOH-induced vasoconstriction were studied. Thiopental completely and pentobarbital partially blocked t-bu-OOH-induced vasoconstriction. Thiopental inhibited t-bu-OOH-induced synthesis of thromboxane and prostacyclin but pentobarbital did not. This inhibitory action of thiopental may be due to its antioxidant properties because similar inhibition has been observed of t-bu-OOH-induced thromboxane production with the antioxidants, vitamin E, or butylated hydroxylanisole. Thiopental and pentobarbital also inhibited the vasoconstriction induced by a thromboxane analog, epoxymethano prostaglandin H2 (U46619). Finally, both barbiturates partially inhibited the pulmonary vasoconstriction caused by potassium chloride, which requires calcium entry, but they did not inhibit the constriction caused by angiotensin II, which does not require calcium entry. These results suggest that pentobarbital and thiopental may block pulmonary vasoconstriction by inhibiting calcium entry.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1989

Oxidant-mediated activation of phospholipase A2 in pulmonary endothelium.

Exposure of bovine pulmonary arterial endothelial cells to the oxidant tert-butyl hydroperoxide (t-bu-OOH) caused a dose-dependent increase in the release of [14C]arachidonic acid and synthesis of the cyclooxygenase products, thromboxane, prostaglandin E2, prostaglandin D2, and prostacyclin. There was no detectable production of peptide leukotrienes before or after administration of t-bu-OOH. Pretreatment with the oxygen radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidino radical (HTP) or the antioxidants vitamin E and dithiothreitol prevented the increased arachidonic acid (AA) release caused by t-bu-OOH. t-bu-OOH increased the activity of phospholipase A2 by increasing its apparent maximum velocity without affecting its Michaelis constant. The increased AA release caused by t-bu-OOH did not appear to require new RNA or protein synthesis, because pretreatment of the cells with actinomycin D or cycloheximide did not reduce the increased release of AA or activation of phospholipase A2 caused by t-bu-OOH. Dexamethasone pretreatment of the cells prevented the increase in phospholipase A2 activity, and AA release produced by t-bu-OOH. t-bu-OOH increased the activity of phospholipase A2 and release of AA in both the presence and absence of extracellular calcium (Ca2+). Pretreatment with a nominal Ca2+-free buffer, the Ca2+ chelator ethylene glycolbis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, nifedipine, or verapamil did not reduce t-bu-OOH-stimulated AA release. In contrast, treatment with the intracellular Ca2+ chelator 8-N,N-diethyamino octyl 3,4,5-trimethoxybenzoate (TMB-8) prevented t-bu-OOH-stimulated AA release in both the presence and absence of extracellular Ca2+. Treatment with calmodulin antagonists also prevented the increased release of AA caused by t-bu-OOH.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Mepacrine attenuates pulmonary vasoreactivity in rabbits.

The organic peroxide tert-butyl hydroperoxide (t-bu-OOH) induces pulmonary vasoconstriction by stimulating production of thromboxane in the rabbit lung, possibly by activating phospholipase A2. t-bu-OOH-induced vasoconstriction and thromboxane production is augmented by inhalational anesthetic agents, perhaps due to an effect of anesthetic agents on membrane lipids. To further investigate the mechanism of thromboxane generation, we studied the influence of the phospholipase A2 inhibitor, mepacrine, in a dose known to inhibit the enzyme in other systems, on t-bu-OOH-induced pulmonary arterial vasoconstriction. We found that 10(-4) M mepacrine completely inhibited t-bu-OOH-induced vasoconstriction. We also found that mepacrine inhibited arachidonic acid-induced pulmonary vasoconstriction but did not inhibit thromboxane productions. We also investigated the effect of mepacrine on two other pulmonary vasoconstrictors, angiotensin II (ANG II) and KCl, which do not act through arachidonic acid metabolites in the rabbit lung. Mepacrine inhibited both ANG-II and KCl-induced vasoconstriction. The inhibition by mepacrine of pulmonary vasoconstriction is reversible if the drug is washed out of the lung. This effect of mepacrine cannot be explained by phospholipase inhibition alone and is consistent with prevention of smooth muscle contraction.

Angiotensin II↗

PubMed1989

Effect of pH on pulmonary vascular tone, reactivity, and arachidonate metabolism.

We studied the effects of perfusate pH on pulmonary vascular tone, reactivity, and thromboxane and prostacyclin synthesis in isolated buffer-perfused rabbit lungs. Extracellular acidosis did not affect base-line vascular tone, but alkalosis had a biphasic effect. Increasing the perfusate pH from 7.40 to 7.65 caused vasodilation, whereas raising pH to 7.70-8.10 caused vasoconstriction. Removing calcium (Ca2+) from the perfusate completely prevented the vasoconstriction caused by alkalosis. Perfusate pH strikingly affected pulmonary vascular reactivity. Acidosis inhibited the vasoconstriction caused by thromboxane and potassium chloride (KCl) but did not affect the response to angiotensin II. Alkalosis, in contrast, augmented the vasoconstriction caused by thromboxane and angiotensin II but reduced the vasoconstriction caused by KCl. Changes in pH also altered thromboxane and prostacyclin synthesis after the infusion of exogenous arachidonic acid (AA) or the endogenous release of AA by the lipid peroxide tert-butyl hydroperoxide.

Angiotensin II↗

PubMed1989

Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists protect against pulmonary edema caused by phosgene.

Phosgene is a toxic oxidant gas that causes the adult respiratory distress syndrome in exposed workers. Phosgene exposure markedly increased lung weight gain in buffer-perfused isolated rabbit lungs (31 +/- 5 g over 60 min after phosgene vs. 7.7 +/- 1.2 in control lungs, P less than 0.01) and markedly increased the lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.02 +/- 0.01 in control lungs, P less than 0.01). Pretreatment with dibutyryl adenosine 3',5' -cyclic monophosphate (DBcAMP), aminophylline, or terbutaline plus isoproterenol prevented the increase in lung weight caused by phosgene (31 +/- 5 g phosgene, 11.7 +/- 2.8 DBcAMP, 7.5 +/- 2.5 aminophylline, 6.1 +/- 1 terbutaline and isoproterenol, 6.1 +/- 1.2 control + aminophylline, and 7.7 +/- 1.2 control; all treatments were P less than 0.01 vs. the untreated phosgene group and not significantly different from control lungs). Pretreatment with aminophylline prevented the increase in lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.06 +/- 0.02 in aminophylline-treated lungs, P less than 0.01). Posttreatment with aminophylline and terbutaline also prevented the increase in lung weight caused by phosgene. These results indicate that phosgene dramatically increases the movement of fluid and protein across the pulmonary vasculature and that treatment with DBcAMP, aminophylline, terbutaline, or isoproterenol markedly reduces the pulmonary edema caused by phosgene.

Aminophylline↗

PubMed1988

Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs.

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.

Amiodarone↗

PubMed1988

Hydroperoxide-induced chemiluminescence in rabbit lungs: role of arachidonic acid enzymes.

Low-level chemiluminescence (C) is thought to be an index of oxidant stress. We measured the relationship between low-level C, pulmonary arterial pressure, and perfusate concentration of thromboxane B2 (TxB2) in isolated perfused rabbit lungs during challenge with tert-butyl hydroperoxide (t-bu-OOH). We also measured glutathione release as another index of oxidant stress. We found that C was correlated with each variable, suggesting that oxidant stress measured by C and by glutathione release stimulated TxB2 production and pulmonary vasoconstriction. We also investigated the contribution of active O2 metabolites produced by prostaglandin (PG) peroxidase to oxidant stress by studying the effects of t-bu-OOH before and after the use of cyclooxygenase and lipoxygenase inhibitors. We found that C was augmented after inhibition, perhaps due to metabolism of t-bu-OOH by peroxidases of both arachidonic acid (AA) metabolic pathways in the absence of their normal substrates. We studied phenylbutazone, thought to inhibit peroxidases, and AA. C during t-bu-OOH administration was not augmented after phenylbutazone and was markedly inhibited after AA administration perhaps because AA competes with t-bu-OOH. To further study the role of peroxidases we pretreated the lungs with the antioxidant dithiothreitol, which inhibits peroxidases involved in both the cyclooxygenase and lipoxygenase pathways. Dithiothreitol nearly abolished C produced by t-bu-OOH and also prevented the increased light caused by eicosatetrynoic acid. We directly tested the hypothesis that C occurred as a result of the interaction of t-bu-OOH and the cyclooxygenase and lipoxygenase enzymes; we measured C when t-bu-OOH was added to purified PGH2 synthase or soybean lipoxygenase. The combination of t-bu-OOH with PGH2 synthase or lipoxygenase led to C that was inhibited by dithiothreitol and by the antioxidant phenol. These results suggest that enzymes involved in AA metabolism can interact with t-bu-OOH and that the action of these enzymes on t-bu-OOH leads to C. The results may mean that lipid peroxides can indirectly contribute to tissue oxidant stress due to production of active O2 metabolites as by-products of their metabolism by AA peroxidases.

Animals↗

PubMed1988

The role of cyclooxygenase and lipoxygenase mediators in oxidant-induced lung injury.

Infusion of the oxidant lipid peroxide tert-butyl hydroperoxide (t-bu-OOH) causes pulmonary vasoconstriction and increases vascular permeability in isolated perfused rabbit lungs. We have previously shown that t-bu-OOH stimulates arachidonic acid metabolism, increasing the synthesis of the cyclooxygenase products. The current experiments were designed to determine the role that cyclooxygenase- and lipoxygenase-derived mediators play in the lung injury caused by t-bu-OOH. In the present experiments, we found that t-bu-OOH not only increased the synthesis of the cyclooxygenase-derived products thromboxane and prostacyclin but also increased the synthesis of the lipoxygenase-derived products leukotrienes B4, C4, D4, and E4. To determine the role that these arachidonic acid metabolites play in the increase in pressure and vascular permeability caused by t-bu-OOH, we studied the effect that inhibitors of arachidonic acid metabolism or a leukotriene receptor blocker had on the pulmonary edema. We compared an uninjured control group with 4 groups of lungs given t-bu-OOH: a t-bu-OOH control group; a group pretreated with the cyclooxygenase inhibitor indomethacin (14 microM); a group pretreated with an analogue of arachidonic acid, 5-, 8-, 11-, 14-eicosatetraynoic acid (ETYA) (100 microM), that inhibits both the cyclooxygenase and lipoxygenase pathways; and a group pretreated with the leukotriene receptor antagonist FPL 55712 (38 microM). To produce lung injury, t-bu-OOH (300 microM) was infused throughout the first minute of 4 successive 10-min periods.(ABSTRACT TRUNCATED AT 250 WORDS)

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1987

Pharmacological modification of pulmonary vascular injury: possible role of cAMP.

Experiments were designed to test the hypothesis that drugs which increase adenosine 3',5'-cyclic monophosphate (cAMP) in the lung would prevent the pulmonary hypertension and the increase in vascular permeability caused by the infusion of the oxidant lipid peroxide, tert-butyl hydroperoxide (t-bu-OOH), in isolated rabbit lungs perfused with Krebs-Henseleit buffer. Pretreatment with indomethacin or verapamil was also studied, since these drugs block the increase in pulmonary arterial pressure caused by t-bu-OOH. Indomethacin or verapamil prevented the pulmonary hypertension but did not prevent the increase in permeability caused by t-bu-OOH. Consequently, indomethacin or verapamil treatment partially reduced the gain in lung weight caused by t-bu-OOH. In contrast, pretreatment with isoproterenol, prostaglandin E1, or a cAMP analogue not only prevented the pulmonary hypertension but also inhibited the increase in vascular permeability caused by t-bu-OOH. Consequently, these drugs completely blocked the gain in lung weight caused by t-bu-OOH. Posttreatment with aminophylline or the cAMP analogue also significantly reduced the gain in lung weight caused by t-bu-OOH. These results indicate that pharmacological therapy can reduce the pulmonary hypertension and the increase in vascular permeability caused by the infusion of a lipid hydroperoxide. Since isoproterenol, aminophylline, prostaglandin E1, and a cAMP analogue all had similar effects, the results suggest that the likely common mechanism for their protective effect is an increase in cAMP.

Alprostadil↗

PubMed1987

O2 radicals mediate reperfusion lung injury in ischemic O2-ventilated canine pulmonary lobe.

This study was undertaken to determine whether lung injury after a period of ischemia reperfusion is caused by O2 ventilation during ischemia and whether this injury is mediated by reactive O2 metabolites. Isolated canine left lower pulmonary lobes were subjected to room temperature ischemia for 6 h while being ventilated with either 100% O2, room air, or 100% N2. After the ischemic period, all lobes were perfused with autologous blood and ventilated with 100% O2 for an additional 4 h. In lobes ventilated with 100% O2 during the ischemic period, massive weight gain (228%) occurred 4 h after reperfusion. A marked increase in pulmonary shunt was noted. Lobes ventilated with room air behaved similarly. In contrast, lobes ventilated with 100% N2 gained significantly less weight (54%) and did not manifest any increase in pulmonary shunt. When lobes ventilated with 100% O2 or room air were pretreated with superoxide dismutase (SOD), the injury was significantly reduced. Pressure-volume deflation study of lobes, after ischemia only, demonstrated that ventilation with 100% O2 and with 100% N2 both equally decreased pulmonary compliance. We conclude that lung ischemia-reperfusion injury is related to O2 ventilation during ischemia and that injury can be prevented by administration of SOD or ventilation with 100% N2. This suggests that the injury is related to O2 metabolites produced during O2 ventilation in the absence of the circulation.

Animals↗