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J A Cook

Publications and source records attributed to J A Cook.

At least 271 records · Page 15Linked to original sources
PubMed1986

Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance.

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C4/D4 and prostaglandin (PG)E2 production by tolerant cells was greater than that by non-tolerant controls (p less than 0.001). However, A23187-stimulated i-6-keto-PGF1 alpha levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B2 synthesis by endotoxin or glucan was significantly less in tolerant macrophages compared to controls (p less than 0.05). iLTC4/D4 production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis of iLTB4 by control macrophages was stimulated by endotoxin (p less than 0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

The effects of alpha adrenergic blockade on arachidonic acid metabolism and shock sequelae in endotoxemia.

Previous studies have suggested that increased alpha adrenergic activity stimulated prostaglandin synthesis and may be involved in the modulation of eicosanoid metabolism. These observations prompted investigation of the effect of the alpha adrenergic receptor antagonist phenoxybenzamine and the cyclo-oxygenase inhibitor indomethacin on endotoxin-induced shock severity, and on plasma immunoreactive iTxB2 and i6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively. Pretreatment with indomethacin alone blunted the endotoxin- (8 mg/kg) induced hypoglycemia. Phenoxybenzamine pretreatment also blunted endotoxin-induced mortality (LD80), hypoglycemia, hemoconcentration, and decreased plasma beta-glucuronidase (BG). The combination of phenoxybenzamine and indomethacin resulted in the improvement of all indices of shock severity. Rats pretreated with phenoxybenzamine and indomethacin alone or conjointly also exhibited significantly (P less than 0.05) enhanced survival compared to that of shocked control rats. Percent survival at 48 hr was 24, 64, 80, and 92 in untreated, indomethacin, phenoxybenzamine, and indomethacin + phenoxybenzamine treated, respectively. Mean plasma iTxB2 values at 30 min postendotoxin (15 mg/kg i.v.) were 1,532 +/- 319 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10) (P less than 0.05). Plasma i6-keto-PGF1 alpha was increased 4 hr after endotoxin in shocked controls to 4,161 +/- 885 pg/ml (N = 5) and attenuated by phenoxybenzamine to a value of 1,184 +/- 363 pg/ml (N = 4) (P less than 0.05). The results suggest that increased alpha adrenergic activity may be an important stimulus for arachidonic acid metabolism during endotoxemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Effects of essential fatty acid deficiency and indomethacin on histologic, ultrastructural, and phagocytic responses of hepatic macrophages to glucan.

Glucan administration in the rat induces a hyperplasia and hypertrophy of the reticuloendothelial system (RES) and a concomitant leukocytosis. Increased phagocytic function and lysozymal immunoreactivity of macrophages are also characteristic of the glucan effect. The potential role of arachidonic acid metabolites in mediating this hepatic inflammatory response induced by the RES stimulant glucan was assessed in the present study by two experimental approaches. In one study, rats were depleted of arachidonic acid by rendering them deficient in essential fatty acids (EFA). In another study, rats were pretreated with the fatty acid cyclooxygenase inhibitor indomethacin. Both treatment interventions markedly attenuated the hepatic Kupffer cell proliferative and granulomatous response to glucan and the associated leukocytosis. Lysozyme immunoreactivity of the Kupffer cells and rates of colloidal carbon clearance (T/2), however, were enhanced by the above treatments. Supplementation of EFA-deficient rats with ethyl arachidonate restored their glucan response to an extent that was not significantly different from nondeficient rats. Marked hepatic proliferative responses were apparent only in those treatment groups characterized by leukocytosis, which suggests that extrahepatic recruitment is an important component of the glucan response in normal, nutritionally adequate rats. Collectively these data suggest that arachidonic acid metabolites may play a role in modulating this extrahepatic recruitment and the associated cellular proliferative and granulomatous responses following glucan administration of the rat.

Animals↗
PubMed1985

Sulindac does not preserve renal prostacyclin synthesis during endotoxemia.

Previous reports have suggested that sulindac is a unique non-steroidal anti-inflammatory (NSAID) agent, because it does not inhibit renal prostaglandin synthesis in doses that inhibit platelet thromboxane B2 synthesis when tested ex vivo. NSAIDS are of potential therapeutic benefit in the treatment of septic or endotoxic shock. Therefore, this study was designed to investigate the proposed unique action of sulindac in experimental endotoxemia. In the current study, the effect of sulindac on aortic, portal and renal venous immunoreactive (i) 6-keto-PGF1 alpha levels, the stable metabolite of prostacyclin, was investigated during endotoxemia in the rat. In doses sufficient to reduce the elevation in aortic and portal venous plasma i6-keto-PGF1 alpha levels, sulindac also significantly (p less than 0.05) attenuated the elevated renal venous plasma 6-keto-PGF1 alpha levels, compared to the vehicle group. Using lower doses, sulindac failed to reduce the endotoxin associated increase in either aortic or renal venous plasma i6-keto- PGF1 alpha levels. Thus, sulindac failed to demonstrate any selective sparing effect on renal prostacyclin generation during endotoxemia.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Elevated plasma 6-keto-prostaglandin F1 alpha in patients in septic shock.

Central venous plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha), the stable hydrolysis product of prostacyclin (PGI2, a vasodilator and antiaggregatory metabolite of arachidonic acid), were determined in patients with septic shock. In eight nonsurvivors, the median plasma 6-keto-PGF1 alpha level was 229 pg/ml (range 31 to 21,998), compared to 30 pg/ml (range 22 to 194) in six survivors. In three control patients who were not septic or in shock, the levels were less than 4 pg/ml. This study demonstrates that human septic shock is associated with elevated plasma levels of 6-keto-PGF1 alpha, and raises the possibility that increased PGI2 formation may play a role in human septic shock.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Experimental endotoxemia in the rat: efficacy of prostacyclin or the prostacyclin analog iloprost.

The purpose of this study was to examine the effects of PGI2 and iloprost, a prostacyclin analog, on the sequelae of experimental endotoxic shock. Endotoxemia was produced in rats by IV injection of 20 mg/kg Salmonella enteritidis (LPS). Mean arterial blood pressure fell from 117 +/- 5 mmHg (N = 22) to 92 +/- 5 mmHg and 71 +/- 10 mmHg at 30 and 180 min post-LPS, respectively. In LPS vehicle-treated rats, blood glucose levels fell from 100 +/- 10 mg/dl to 36 +/- 8 mg/dl at 180 min. Plasma glutamate-oxaloacetate transaminase and lactate dehydrogenase (liver fraction) activities were significantly elevated above concentrations in nonshocked animals, increasing to 426 +/- 86 IU/ml and 1,019 +/- 339 IU/ml, respectively. Infusion of PGI2 or iloprost (0.5 micrograms/kg/min) did not alter the blood pressure response to LPS compared to vehicle controls. PGI2 significantly prevented the LPS-induced hypoglycemia while neither treatment significantly reduced the elevations in plasma enzymes nor prevented the lethality of LPS. Thus, the hemodynamic and biochemical indices of shock severity were not significantly improved by either prostacyclin or iloprost. It is suggested that the beneficial effects of PGI2 or prostacyclin analogs observed in other species during endotoxemia does not extend to the rat.

Animals↗
PubMed1985

Protective effect of a selective leukotriene antagonist in endotoxemia in the rat.

The role of lipoxygenase metabolites as inflammatory mediators in endotoxic shock remains uncertain. In the present study, the effects of a selective leukotriene (LT) D4/LTE4 antagonist, LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-YL)-butoxy]-phenyl ethanone], on endotoxin-induced sequelae in the rat were assessed. LY171883 was given as a bolus (30 mg/kg i.v.) 10 min before Salmonella enteritidis endotoxin (40 mg/kg) in ketamine-anesthetized (200 mg/kg i.m.) rats, followed by an infusion (10 mg/kg/hr) starting at 30 min postendotoxin. Carotid artery blood pressures were determined at 10 min before and at intervals up to 240 minutes postendotoxin administration. Compared to shocked vehicle controls LY171883 attenuated (analysis of variance, P less than .02) the initial (0-30 min), but not the later, endotoxin-induced hypotension. LY171883 prevented completely (analysis of variance, P less than .001) the neutropenia (0-180 min), but not the thrombocytopenia induced by endotoxin. Hemoconcentration resulting from endotoxemia was reduced by LY171883 compared to the vehicle control group (P less than .02). These data demonstrate that this LTD4/LTE4 antagonist has significant salutary actions in endotoxemia and suggest that LTs may contribute to some endotoxin-induced sequelae.

Acetophenones↗
PubMed1985

Ibuprofen, methylprednisolone, and gentamicin as conjoint therapy in septic shock.

Septic shock is associated with increased metabolism of arachidonic acid to thromboxane A2 (TxA2) and prostacyclin (PGI2). The effects of ibuprofen, methylprednisolone-sodium succinate, and gentamicin alone, or in combination on survival time and, TxA2 and PGI2 production in rats in a LD100 fecal peritonitis shock model were assessed. Plasma levels of TxA2 and PGI2 were measured by radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha, respectively. Drugs were given 30 min before induction of fecal peritonitis. Survival times in hours were as follows: fecal peritonitis = 10.5 +/- 0.4 (n = 50); ibuprofen (15 mg/kg) = 16.1 +/- 0.8 (n = 8); methylprednisolone-sodium succinate (40 mg/kg) = 17.1 +/- 0.7 (n = 22); methylprednisolone-sodium succinate (80 mg/kg) = 46.1 +/- 10.4 (n = 25) with 8% long-term survivors (survival greater than 7 days); gentamicin (4 mg/kg) = 23.8 +/- 4.4 (n = 16); methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 20.3 +/- 1.8 (n = 6); gentamicin + methylprednisolone-sodium succinate = 31.0 +/- 1.6 (n = 11); gentamicin + ibuprofen = 28.5 + 2.3 (n = 12); gentamicin + methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 46.9 +/- 5.4 (n = 8). Treatment with the combination of gentamicin + ibuprofen + methylprednisolone-sodium succinate (80 mg/kg) resulted in a mean survival time of 116 +/- 13.9 h with 26% long-term survivors. Methylprednisolone-sodium succinate (40 mg/kg) reduced (P less than 0.05) plasma iTxB2 from 995 +/- 78 (n = 16) to 714 +/- 48 (n = 18) pg/ml and i6-keto-PGF1 alpha from 4,090 +/- 334 (n = 12) to 2,009 +/- 119 (n = 17) pg/ml, 4 h post-FP. Methylprednisolone-sodium succinate (80 mg/kg) produced no further decrease in either iTxB2 or i6-keto-PGF1 alpha. Ibuprofen reduced the fecal peritonitis-induced iTxB2 and i6-keto-PGF1 alpha synthesis to nondetectable levels (less than 200 pg/ml). The latter results demonstrate that methylprednisolone-sodium succinate is less effective than ibuprofen in inhibiting arachidonic acid metabolism and suggest other salutary actions. These composite observations provide evidence that conjoint therapy with steroidal and nonsteroidal anti-inflammatory agents, and antibiotics in septic shock may be beneficial.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Exchange transfusions in rats with a perfluorated blood substitute: effect on thromboxane B2 levels during endotoxemia.

The effect of exchange transfusion with the perfluorated blood substitute (Fluosol-43) on endotoxin-induced synthesis of immunoreactive (i) thromboxane (Tx)B2, the stable metabolite of TxA2, was investigated in rats. Fluosol-43 was infused via the femoral vein with matched, incremental blood withdrawal from the carotid artery. Blood was replaced with Fluosol-43 to a final hematocrit of less than 3% in anesthetized rats maintained on 95% O2 and 5% CO2. Circulating platelet counts were reduced from 875 +/- 47 X 10(3)/mm3 in sham controls (N = 21) to 75 +/- 10 X 10(3)/mm3 in Fluosol-43 exchange transfused rats (N2 = 19, P less than 0.001). Circulating leukocytes were decreased from 105 +/- 6.3 X 10(2)/mm2 in sham controls (N = 21) to 17 +/- 1.4 X 10(2)/mm3 in the exchange transfused group (N = 19, P less than 0.001). Immunoreactive (i)TxB2 was measured in plasma or Fluosol-43 obtained from rats prior to and after injection of Salmonella enteritidis endotoxin (20 mg/kg). The iTxB2 levels at 30 minutes after endotoxin increased from 438 +/- 83 pg/ml (N = 4) to 2,895 +/- 663 pg/ml (N = 7) (P less than 0.01) in sham controls. iTxB2 also increased from 242 +/- 23 pg/ml (N = 7) to 2,213 +/- 589 pg/ml (N = 7) in the Fluosol-43 group (P less than 0.002) following endotoxin. The iTxB2 levels also remained significantly elevated (P less than 0.01) in both the sham and the Fluosol-43 groups 2 hours after endotoxin treatment. Endotoxin-stimulated iTxB2 levels at both 30 minutes and 2 hours in sham and Fluosol-43 exchange transfused rats did not vary significantly from each other. Indomethacin pretreatment (2 mg/kg) inhibited the increase in iTxB2 levels by greater than 85% in both groups (P less than 0.004). Blood and Fluosol-43 were taken from sham and exchange transfused rats and incubated ex vivo with the calcium ionophore, A23187 (10 microM). These studies demonstrated that ionophore-stimulated iTxB2 synthesis in the ex vivo Fluosol-43 samples was only 2.6% that of whole blood. Collectively these observations suggest that tissues other than blood components are potential sources of iTxB2 synthesis in endotoxin shock.

Animals↗
PubMed1985

Lack of effect of glucocorticoids upon plasma thromboxane in patients in a state of shock.

Twenty-five patients with sepsis were studied retrospectively to examine the effects of methylprednisolone on plasma thromboxane B2 levels. Although the plasma iTxB2 level was elevated in patients dying from sepsis, the use of glucocorticoids did not reduce plasma iTxB2. Aspirin, a cyclo-oxygenase inhibitor, did reduce the plasma iTxB2 value in four patients. It does not appear that glucocorticosteroids significantly affect the conversion of arachidonic acid to thromboxane in septic patients.

Aspirin↗
PubMed1984

The potential role of thromboxane and prostacyclin in endotoxic and septic shock.

The potential role of thromboxane (TxA2), a platelet aggregator and vasoconstrictor, and prostacyclin (PGI2) a platelet anti-aggregator and vasodilator, in endotoxic and septic shock was investigated. Early endotoxic shock in the rat is associated with marked elevations of plasma TxB2 (the stable metabolite of TxA2) and lesser increases in plasma 6-keto-PGF1 alpha (the stable metabolite of PGI2). Selective inhibition of TxA2 synthesis by several different chemical classes of Tx synthetase inhibitors was beneficial in endotoxic shock. In contrast, shock induced by acute intra-abdominal sepsis in the rat was characterized by high levels of plasma 6-keto-PGF1 alpha, which exceeded plasma TxA2 six- to eight fold at most time intervals studied. Tx synthetase inhibitors were not protective in this model of acute sepsis, but treatment with fatty acid cyclo-oxygenase inhibitors, an antibiotic (gentamicin), or reduction in arachidonic acid metabolism by essential fatty acid (EFA) deficiency significantly prolonged survival time. An important aspect of the latter study is that decreased arachidonic acid metabolism was an effective adjunct to antibiotic therapy. Conjoint administration of gentamicin in EFA-deficient rats or with indomethacin synergistically improved long-term survival, a result that was not evident with single treatment interventions. In addition to experimental studies, plasma TxB2 levels were measured during clinical sepsis. These studies demonstrated that plasma TxB2 levels were elevated tenfold in patients dying of septic shock compared with septic survivors or nonseptic controls. These composite experimental and clinical observations suggest that arachidonic acid metabolites play a role in the pathogenesis of endotoxic and septic shock.

Animals↗
PubMed1984

Periodic lateralized EEG abnormality in a case of Neuro-Behcet syndrome.

A thirty-six year old male with a sixteen month history of a progressive neurological disorder had Behcet's disease. His initial electroencephalogram showed periodic lateralizing epileptiform discharges (PLEDs). The electroencephalographic changes in this disorder have not been described in detail in the American literature. The review of world publications in this matter disclosed that there is no specific EEG pattern in this condition, and that electroencephalographic changes are mainly related to the side of the lesion and have no prognostic value.

Adult↗
PubMed1983

Morbidity in schistosomiasis japonica in relation to intensity of infection. A study of two rural brigades in Anhui Province, China.

Schistosomiasis japonica remains endemic in several provinces south of the Yangtze River in China because of relatively sparse populations of human beings and dense populations of snails. We studied two brigades in a rural commune in Gui-chi County, Anhui Province, to determine the prevalence, intensity, and morbidity associated with this infection before concerted control efforts were instituted. Quantitative fecal examinations, histories, and physical examinations relevant to schistosomiasis japonica were performed in 96 per cent of the available population 2 to 65 years of age. The prevalence was 26.3 per cent in Brigade A (778 persons) and 14.4 per cent in Brigade B (1532 persons). Clinical symptoms and signs were compared among uninfected persons and persons at three levels of infection as determined by fecal egg output. Some increased weakness was seen only at the heaviest levels of infection; abdominal pain was not an important symptom. Hepatomegaly was somewhat more frequent in moderate and heavy infections, but splenomegaly was rare and unrelated to intensity of infection. Neither stool consistency nor occult blood was related to the presence or intensity of infection. Approximately 50 per cent of the population had been treated for schistosomiasis japonica, 25 per cent repeatedly.

Adolescent↗
PubMed1983

Studies on the beneficial effects of aspirin in endotoxic shock. Relationship to inhibition of arachidonic acid metabolism.

Endotoxic shock is associated with increased metabolism of arachidonic acid into thromboxanes and prostaglandins. This study assessed the effects of varied doses of aspirin, an inhibitor of arachidonic acid metabolism, on Salmonella enteritidis endotoxin-induced mortality, plasma levels of arachidonate metabolites, and other pathophysiologic sequelae in Long-Evans rats. Aspirin in doses of 3.75, 15, and 30 mg/kg given 30 minutes prior to endotoxin challenge significantly (p less than 0.01) improved 24-hour survival rates from 11 percent to approximately 65 percent, but 100 mg/kg afforded no protection. Pretreatment with aspirin (15 or 100 mg/kg) 30 minutes prior to endotoxin also significantly (p less than 0.001) decreased the endotoxin-induced elevations in plasma levels of immunoreactive thromboxane B2, a stable metabolite of thromboxane A2, and immunoreactive 6-keto prostaglandin F1 alpha, a stable metabolite of prostacyclin. Aspirin doses of 15 or 100 mg/kg given 24 hours prior to challenge with endotoxin significantly improved 24-hour survival rates from 17 percent to 42 percent (p less than 0.01) and 44 percent (p less than 0.005), respectively. Pretreatment with an aspirin dose of 15 mg/kg 24 hours prior to challenge with endotoxin significantly (p less than 0.05) inhibited thrombin-induced immunoreactive thromboxane B2 synthesis in platelet-rich plasma (in vitro) and endotoxin-induced immunoreactive 6-keto-prostaglandin F1 alpha and immunoreactive thromboxane B2 synthesis by rat peritoneal macrophages. Although 24-hour pretreatment with aspirin (15 or 100 mg/kg) significantly (p less than 0.001) reduced endotoxin-induced elevations in immunoreactive thromboxane B2, only the 100 mg/kg dose significantly lowered plasma levels of immunoreactive 6-keto prostaglandin F1 alpha. These observations are consistent with the notion that the beneficial effects of aspirin seen in experimental endotoxic shock may be mediated, in part, via inhibition of arachidonic acid metabolism.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat.

1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (less than 200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875 +/- 90 pg/ml (n = 9), iPGE was 1670 +/- 271 (n = 9) and i6-keto-PGF1 alpha was 1191 +/- 209 pg/ml (n = 10). By 4 h plasma iTXB2 was 1743 +/- 328 pg/ml (n = 5), iPGE was 2589 +/- 494 pg/ml (n = 9) and i6-keto-PGF1 alpha was 4251 +/- 984 pg/ml (n = 10). UK 37248 pretreatment resulted in a significant (P less than 0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193 +/- 28 pg/ml (n = 5) and 421 +/- 57 pg/ml (n = 5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGF1 alpha at 30 min and 4 h to 360 +/- 75 pg/ml (n = 10) (P less than 0.005) and 1920 +/- 513 pg/ml (n = 10) (P less than 0.05), respectively, iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210 +/- 370 pg/ml (n = 9) or 4 h 3529 +/- 1093 pg/ml (n = 13) after endotoxin compared to the vehicle-treated rats. 3 UK 37248 significantly (P less than 0.05) reduced the endotoxin mortality rate at 24 h from 69% (n = 13) to 30% (n = 13), UK 37248 also reduced splanchnic infarction from 90% (n = 20) to 6% (n = 16). 4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.

6-Ketoprostaglandin F1 alpha↗