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Biomedical subjects

W Hsueh

Publications and source records attributed to W Hsueh.

At least 91 records · Page 5Linked to original sources
PubMed1987

LTB4 production and lysosomal enzyme release by rat alveolar macrophages: effects of phagocytosis, receptor binding, and ionophore stimulation.

We have previously shown that the predominant lipoxygenase product of arachidonic acid metabolism in rabbit alveolar macrophages is leukotriene (LT) B4. LTB4 was not detectable in normal unstimulated rabbit macrophages, but its production was increased following calcium ionophore A23187 stimulation, especially after in vivo activation of the immune system. In the present study, we describe that (a) rat alveolar macrophages produced LTB4 in response to natural, biological stimuli such as binding of Fc receptors and complement receptors, as well as zymosan phagocytosis and ionophore stimulation. In contrast, binding of lectin receptors such as concanavalin A and phytohemagglutinin failed to elicit significant increase of LTB4. (b) The predominant LT that was produced was LTB4 regardless of the type of stimulus. This pattern is similar to that of rabbit lung macrophages, but rat alveolar macrophages released higher quantities of LTB4, which can be easily quantitated by high-performance liquid chromatography (HPLC). (c) Phorbol myristate acetate by itself was a weak agonist for LTB4 release. Yet, in combination with a low dose of calcium ionophore A23187 it resulted in LTB4 production. (d) There was a general correlation between release of LTB4 and lysosomal enzymes. In other words, the stimulus that is effective for eliciting enzyme release was usually also effective in causing LTB4 production. (e) A considerable proportion of the LTB4 produced was retained intracellularly. This phenomenon was especially pronounced when zymosan was used as stimulus. (f) Despite the parallelism between LTB4 production and lysosomal enzyme release, the former probably does not regulate the latter. The time courses of their release are dissimilar, and nordihydroguaiaretic acid fails to inhibit lysosomal enzyme release by a dose markedly inhibiting LTB release. (g) Contrary to rabbit lung macrophages rat lung macrophages showed a predominance of lipoxygenase pathway over cyclooxygenase pathway following zymosan ingestion. However, macrophages from both species produced mainly cyclooxygenase products in response to exogenous arachidonic acid.

Animals↗
PubMed1987

Bilateral renal dysplasia with features of nephroblastomatosis.

We report a case of bilateral renal dysplasia with "cystic nephroblastomatosis" in a 29-week-old white female infant. The patient presented with bulging flanks, anuria, and respiratory distress. She survived for 1 1/2 days. Both kidneys were markedly enlarged by a diffuse cystic malformation. Microscopically, there was no demarcation between cortex and medulla. Numerous cysts and partially differentiated metanephric blastema cells were seen throughout the cortex and medulla. In addition, dysplastic tissues including cartilage occurred in the medulla. No evidence of Wilm's tumor was found. To our knowledge, this unique form of renal pathology has not been previously reported.

Anuria↗
PubMed1987

Effect of aspirin on experimental diabetic nephropathy.

The decline in glomerular filtration rate (GFR) in long-term diabetes in humans and animals in preceded by a period of hyperfiltration that may be responsible for it. The mediators of the increase in glomerular filtration are unknown, but recent studies suggest a prominent role for prostaglandins. To test the hypothesis that prostaglandins mediate early hyperfiltration and contribute to the progression of diabetic nephropathy, we examined the effects of long-term aspirin (ASA) treatment on whole kidney GFR and renal prostaglandin E2 (PGE2) synthesis in control and diabetic rats 8 days and 16 weeks after streptozocin administration. The rats were divided into four groups, control, control with ASA (C/ASA), diabetic, and diabetic with ASA (D/ASA). We found that 8 days after streptozocin treatment, PGE2 synthesis and GFR were increased in diabetic rats. ASA treatment inhibited renal prostaglandin synthesis and prevented the GFR increase. ASA given to control rats reduced PGE2 synthesis without changing GFR. In the 16-week study diabetic rats had lower GFR and increased renal PGE2 synthesis. Diabetic rats also had thickened glomerular basement membrane compared with control rats. By contrast GFR did not fall and thickening of the glomerular basement membrane did not occur in diabetic rats receiving ASA. ASA had no effect on GFR or glomerular basement membrane in normal rats but decreased renal PGE2 synthesis. The data demonstrate that aspirin prevents early hyperfiltration and prevents the fall in GFR and glomerular basement membrane thickening that occurs over time in diabetic rats. Inhibition of PGE2 synthesis by aspirin, or some other effect of aspirin, may be responsible for the protection observed.

Animals↗
PubMed1986

Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism.

Hyporeninemic hypoaldosteronism is an important cause of hyperkalemia and is characterized by low renin secretion. We found that prostacyclin, a potent vasodilator and renin secretagogue, was markedly reduced--as reflected by its stable urinary metabolite 6-keto-prostaglandin F1 alpha--in seven patients with hyporeninemic hypoaldosteronism as compared with seven matched controls with renal insufficiency and as compared with 12 normal volunteers (mean +/- SE, 42 +/- 7 vs. 185 +/- 37 and 164 +/- 20 ng per gram of creatinine, respectively; P less than 0.001). In contrast, renal prostaglandin E2 excretion was similar in all three groups. A low-dose infusion of calcium or norepinephrine (known stimulants of prostacyclin) increased renal prostacyclin release in normal subjects and controls with renal insufficiency. Neither agonist, however, increased the low basal prostacyclin excretion in the patients (49.6 +/- 11 [basal] vs. 62 +/- 20 [norepinephrine] and 47.5 +/- 16 [calcium]; P greater than 0.8). To evaluate the functional importance of the altered prostacyclin production, we studied the responses of renal blood flow and blood pressure to the calcium infusion. The calcium infusion did not alter blood pressure or renal blood flow in the normal subjects or the controls with renal insufficiency. In contrast, the same dose of calcium in the patients with hyporeninemic hypoaldosteronism produced a rise in mean blood pressure (from 91 +/- 6 to 104 +/- 8 mm Hg, P less than 0.05) and a fall in renal blood flow (from 673 +/- 58 to 560 +/- 42 ml per minute per 1.73 m2, P less than 0.05). These results indicate that a deficiency of prostacyclin could explain the low active-renin concentration and altered vasomotor tone seen in hyporeninemic hypoaldosteronism.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Platelet activating factor-induced ischemic bowel necrosis: the effect of PAF antagonists.

We have reported a model of ischemic bowel necrosis produced in the rat by injecting platelet activating factor (PAF) or PAF with bacterial endotoxin (LPS) into the mesenteric vasculature. In the present study, we examined the protecting effects of three PAF antagonists, i.e. (R,S)-3-[2-[(2-octadecylaminocarbonyloxymethyltetrahydro-2-fura nylmethoxy) -hydroxyphosphinyloxy]-ethyl]-thiazolium hydroxide inner salt 4-oxide (SRI 63-072), (+/-)-3-[4-[3-octadecylaminocarbonyloxy-2-methoxy)-propoxy]-butyl] -thiazolium bromide (SRI 63-119) and 1-O-hexadecyl-2RS-O-ethyl-3-O -(7-thiazolinoheptyl)-glycerol-methanesulfonate (ONO-6240), on PAF-induced bowel necrosis. The antagonists were injected into the vein 10 min before PAF. Two microgram of PAF or 20 micrograms LPS with 1 microgram of PAF were injected into the aorta above the renal arteries. The parameters assessed included blood pressure, hematocrit, white blood cell count, extent of bowel perfusion and microscopic changes of the bowel. We found that SRI 63-072 (3 mg/kg), SRI 63-119 (3 mg/kg) and ONO-6240 (2 mg/kg) significantly improved the initial hypotension, hemoconcentration and leukopenia caused by PAF. All three drugs also corrected the sustained hypotension and hypoperfusion and gross lesions of the bowel, although microscopic examination still revealed focal mild lesions. SRI 63-072 was also active at a much lower dose (0.3 mg/kg).

Animals↗
PubMed1986

Neurohumoral consequences of vasodilator therapy with hydralazine and nifedipine in severe congestive heart failure.

We evaluated the effects of intravenous hydralazine (5 to 30 mg) and oral nifedipine (20 to 80 mg) on plasma catecholamines, renin, and aldosterone in 18 patients with severe chronic heart failure. Both drugs resulted in a significant decrease in systemic vascular resistance and mean systemic blood pressure, and led to an increase in cardiac output. Baseline plasma norepinephrine concentration was elevated in most patients; however, augmentation of cardiac output with both drugs did not decrease the values of this hormone (from 870 +/- 128 to 946 +/- 161 pg/ml with hydralazine and from 1088 +/- 260 to 1106 +/- 187 pg/ml with nifedipine). Plasma epinephrine level was also elevated at baseline and did not change significantly following nifedipine therapy (164 +/- 44 vs 199 +/- 54 pg/ml), but increased in most patients following the administration of hydralazine (from 105 +/- 45 to 153 +/- 27 pg/ml, p less than 0.01). The renin-aldosterone system was activated in our patients and also demonstrated a different response to both drugs. Hydralazine therapy did not change either the plasma renin concentration (30 +/- 7 vs 28 +/- 7 ng/ml/hr) or the aldosterone level (24 +/- 7 vs 22 +/- 5 ng/dl). In contrast, nifedipine increased the plasma renin concentration (22 +/- 7 to 29 +/- 8 ng/ml/hr, p less than 0.05). This change did not correlate with changes in systemic blood pressure (r = 0.03) and was probably the result of previously shown calcium blockade-mediated stimulation of renin release from the juxtaglomerular cells of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Effects of sulindac and ibuprofen in patients with cirrhosis and ascites. An explanation for the renal-sparing effect of sulindac.

Nonsteroidal antiinflammatory drugs impair renal function in susceptible patients with cirrhosis and ascites. A new antiinflammatory drug, sulindac, is reported not to affect renal function. To evaluate its renal-sparing mechanism, sulindac was administered for 5 days and ibuprofen for 1 day to 10 patients and paraaminohippurate and inulin clearances, serum and urine eicosanoids, and serum and urine sulindac metabolites were monitored. Ibuprofen reduced renal clearances in the 5 subjects with greatest sodium retention, whereas sulindac had no effect. Plasma concentration of the active sulfide metabolite was markedly increased in liver patients, and this concentration correlated with the inhibition of serum thromboxane (r = 0.75, p = 0.01). The percent inhibition of serum thromboxane with sulindac administration correlated with the inhibition of urinary eicosanoids (r = 0.68-0.81, all p less than 0.02). Ibuprofen was generally a more potent inhibitor of serum and urine eicosanoids. Thus, a major factor in the renal-sparing effect of sulindac appears to be its less potent inhibition of renal and extrarenal cyclooxygenase systems.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Release of leukotriene C4 by isolated, perfused rat small intestine in response to platelet-activating factor.

We reported a rat model of necrotizing enterocolitis by injecting platelet-activating factor (PAF) into the mesenteric vascular bed, and suggested that leukotrienes (LT) are secondary mediators. The present study, using isolated, buffer-perfused rat small intestine, shows: Isolated, perfused small intestine synthesizes LTs in response to PAF. Leukotriene C4 (LTC4) was the predominant LT released. The initial vasoconstriction after PAF injection was due to a transient release of LTC4 since FPL 55712 pretreatment abolished the vasoconstriction. The sustained rise in perfusion pressure was also blocked by FPL 55712, which suggests that other vasoconstrictors released are regulated by LTs. The vasoconstrictor(s) responsible for sustained rise in perfusion pressure is unknown, but is not thromboxane. Most of the LT was released from intestinal tissue rather than mesenteric arteries. Vasodilating prostaglandins (PGs) were also released, probably secondary to LTs. The complex interaction of these lipid mediators (PAF, LTs, and PGs) and their subtle balance may affect the course of the disease.

Animals↗
PubMed1986

Platelet-activating factor-induced ischemic bowel necrosis. An investigation of secondary mediators in its pathogenesis.

The authors have previously reported a model of ischemic bowel necrosis produced in the rat by synthetic platelet-activating factor (PAF) or a combination of PAF and bacterial endotoxin. Because rat platelets are refractory to PAF and thromboemboli were not found in the mesenteric or intestinal microvasculature, they suspected that secondary mediators were involved in the pathogenesis of bowel necrosis. They have found the following lipoxygenase products of arachidonic acid, especially leukotrienes (LT), probably played an important role in the pathogenesis of bowel necrosis, because diethylcarbamazine (an inhibitor for LTA synthesis) and FPL55712 (LT antagonist) ameliorated, and at times completely prevented, the lesions. NDGA (a nonspecific lipoxygenase inhibitor) was less effective, probably because of its additional effect on cyclooxygenase inhibition. Verapamil, a calcium channel blocker, ameliorated the disease. Thromboxane A2, a potent vasoconstrictor, was probably not responsible for the ischemia of the gastrointestinal tract. This is suggested by the ineffectiveness of OKY-046 in preventing bowel necrosis. Prostaglandin (PG) E1 infusion often prevented the bowel necrosis, which suggested beneficial effects of vasodilating PGs, probably released as a defense mechanisms. Indomethacin aggravated the disease, probably by inhibiting PG release and shifting the metabolic pathway toward the lipoxygenase pathway. Antihistamine and antiserotonin had no effect, which suggested that these mediators were not involved in the pathogenesis of bowel necrosis. Shock produced by PAF was probably not the only cause of bowel necrosis, because reversal of the hypotension did not always prevent the development of bowel necrosis. Hemoconcentration (increased vasopermeability) and leukopenia induced by PAF did not correlate with the development or severity of bowel necrosis.

Alprostadil↗
PubMed1985

The biosynthesis of leukotriene B4, the predominant lipoxygenase product in rabbit alveolar macrophages, is enhanced during immune activation.

Rabbit alveolar macrophages synthesize prostaglandins in response to various stimuli. We have previously shown that prostaglandin production was decreased in immunologically activated (live Bacillus Calmette-Guérin (BCG)-injected) animals. (Hsueh, W., Lamb, R. and Gonzalez-Crussi, F. (1982) Biochim. Biophys. Acta 710, 406-414). In the present study, we examined the lipoxygenase products of alveolar macrophages from normal and immunologically activated rabbits injected intravenously with live BCG or complete Freund's adjuvant. We found: unstimulated lung macrophages produced no detectable leukotrienes; the predominant lipoxygenase product upon stimulation was leukotriene B4; alveolar macrophages did not significantly degrade leukotriene B4 into its 20-hydroxy derivative, and the total degradation of leukotriene B4 during 90 min of incubation was minimal; the production of leukotriene B4 reached the peak at 30 min after A23187 stimulation, while zymosan caused a much slower and smaller release; following stimulation, immunologically activated lung macrophages produced more leukotriene B4 than resident macrophages. It is possible that the increased leukotriene B4 production in immunologically activated lung macrophages was related to the immunoregulatory function of this substance, such as enhancing cytotoxicity, interferon production and proliferation of suppressor-cytotoxic T cells.

Animals↗
PubMed1985

Ventriculocholecystic shunt. A mortality report.

Ventriculocholecystic shunts are not commonly used for the treatment of hydrocephalus. We present a case of a child who underwent such a procedure and died of unusual complications. This case represents a unique juxtaposition of uncommon neurosurgical entities and complications including acquired communicating hydrocephalus, bilious ventriculitis secondary to a ventriculocholecystic shunt, and pulmonary edema. The unusual features of this case are discussed and emphasis is placed on the pathophysiologic findings.

Cerebrospinal Fluid Shunts↗
PubMed1985

Isometric exercise in patients with chronic advanced heart failure: hemodynamic and neurohumoral evaluation.

We evaluated the hemodynamic effects of isometric exercise in 53 patients with congestive heart failure (CHF) and compared them with those found in 10 normal subjects. In both groups, isometric exercise increased heart rate and blood pressure. Systemic resistance increased in patients with CHF (1862 +/- 520 vs 2126 +/- 642 dyne-sec-cm-5; p less than .001) but not in normal subjects (1359 +/- 268 vs 1380 +/- 252 dyne-sec-cm-5). Cardiac index and stroke volume index increased mildly but not significantly in the normal subjects (2.8 +/- 0.5 vs 3.1 +/- 0.7 liters/min/m2 and 46 +/- 8 vs 47 +/- 7 ml/m2) and showed a significant fall in the patients with CHF (2.1 +/- 0.6 to 1.9 +/- 0.6 liters/min/m2, p less than .01 and 23 +/- 7 vs 20 +/- 7 ml/m2, p less than .01). Mean pulmonary arterial wedge pressure increased in patients with CHF from 26 +/- 7 to 30 +/- 8 mm Hg (p less than .001). Although no significant change was found in mean value for stroke work index (21 +/- 9 vs 20 +/- 9 g-m/m2), the individual changes were variable, with marked decrease (greater than 15%) in 17 of the patients. This hemodynamic deterioration could not be predicted from resting hemodynamics, left ventricular ejection fraction, or functional classification. Isometric exercise resulted in no significant change in circulatory catecholamine levels or plasma renin concentration in our 10 normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Therapeutic effect of calcium channel blockade in primary aldosteronism.

To determine the potential therapeutic effect of calcium entry blockade in primary aldosteronism, 10 patients (5 adenoma and 5 hyperplasia) documented by endocrine testing and/or surgery were given nifedipine (20 mg, sublingually) in the afternoon. In all patients, nifedipine acutely lowered systolic and diastolic blood pressure to normal for up to 6 h. Plasma cortisol and potassium did not change in the acute study. The basal plasma renin concentration was suppressed and was not altered by nifedipine. However, nifedipine reduced aldosterone within 120 min [22 +/- 5 (+/- SE) to 10 +/- 2 ng/dl; P less than 0.02], including the 5 patients with adenomas (22 +/- 3 to 10 +/- 3; P less than 0.02). In a 4-week study, nifedipine controlled blood pressure (134 +/- 5 mm Hg systolic and 85 +/- 3 mm Hg diastolic) and normalized serum K+ (3.0 +/- 0.1 to 3.7 +/- 0.1 meq/liter; P less than 0.01) while reducing plasma aldosterone levels (46 +/- 8 to 20 +/- 3; P less than 0.02). These results suggest that Ca+2 channel blockers may provide a new medical therapy, both controlling blood pressure and reducing aldosterone levels, for patients with primary aldosteronism.

Adenoma↗
PubMed1985

Rabbit lymphocyte factors modulate prostaglandin biosynthesis in alveolar macrophages.

We have previously shown that alveolar macrophages from BCG-infected rabbits release less prostaglandins (PG) and arachidonic acid than normal resident macrophages. In order to investigate the possible role of lymphocytes in modulating PG secretory activity of macrophages, we added the supernatant of spleen lymphocyte culture to alveolar macrophages prelabelled with [14C] arachidonic acid, and subsequently quantitated the release of PGs and arachidonic acid by macrophages. It was found that lymphocytes stimulated by phytohaemagglutinin (PHA) released soluble factors which inhibited arachidonic acid release and PG synthesis by macrophages. This inhibition was not seen with either supernatant of lymphocytes cultured without PHA, or when PHA was added at the end of lymphocyte incubation. The inhibitor factors were pronase-sensitive and exhibited molecular weight heterogeneity. Production of these could be enhanced by indomethacin treatment. These lymphokines might play a regulatory role in the suppression of macrophage PG synthesis in cell-mediated immunity.

Animals↗
PubMed1984

Identification of C3b as the major serum protein that stimulates prostaglandin and thromboxane synthesis by macrophages.

We have previously reported that heterologous, homologous and autologous sera, all stimulated rabbit alveolar macrophages to synthesize prostaglandins (PG). Gel permeation chromatography of serum showed multiple fractions possessing this stimulatory activity, with the major one at 150-160K daltons. In the present study, we have shown that: (a) Fresh rabbit serum stimulated PG release by macrophages. (b) Serum depleted of C3 and C5 lost its stimulatory activity. (c) Trypsinized serum, sera activated by aggregated IgG and zymosan, partially purified C3, C5 and the C3, C5 preparation or purified C3 activated by zymosan, all stimulated PG release by macrophages with the following order of potency: activated C3, C5 = activated C3 = zymosan-activated serum greater than trypsinized serum = aggregated IgG-activated serum greater than partially purified C3, C5 = serum. PGE2 was the predominant PG synthesized by stimulated macrophages. However, thromboxane (TX) production seemed to be more selectively enhanced i.e., increase in TX production was more pronounced than the increase in PGE release. To further identify the active complement component, we blocked the C3b receptor (C3 b R) by preincubating macrophages with anti-C3bR, and showed that subsequent treatment with activated C3 and C5 failed to elicit any PG release. This pretreatment with anti-C3bR had no inhibitory effect on subsequent zymosan stimulation of PG release. Thus we concluded that C3b was the major serum protein that stimulates PG synthesis by macrophages.

Animals↗
PubMed1983

Serum and plasma stimulate prostaglandin production by alveolar macrophages.

Fetal bovine serum (FBS) stimulated rabbit alveolar macrophages to synthesize prostaglandins (PG) and release lysosomal enzymes. This stimulatory action was not entirely due to the effect of foreign protein in FBS, since rabbit serum and plasma, both homologous and autologous, also induced release of PGs and lysosomal enzymes. Rabbit serum and plasma are less effective than FBS as a stimulus for PG release, with rabbit serum being more potent than plasma at the same concentration. Bovine serum albumin elicited a dose-dependent increase of arachidonic acid release by macrophages, but not of PG production. Hence, the fatty acid "trapping" effect of albumin in serum and plasma is not responsible for the PG stimulation. The PG stimulating factors were stable at 56 degrees C for 30 min., but lost half the activity after heating at 100 degrees C for 10 min. Gel permeation chromatography of FBS showed several peaks of PG stimulating and arachidonic acid releasing activity. The molecular weight of the major one (150,000 daltons) is similar to that of immunoglobulin G. Rabbit IgG, when added to the macrophage culture, stimulated release of arachidonic acid and PGs. However, the major stimulatory effect in serum or plasma is not all due to IgG, since removal of IgG by a Protein A-agarose column did not remove the stimulatory effect of FBS and rabbit serum. The possibility of other factors, such as complement fragments, is discussed.

Animals↗
PubMed1983

Prostaglandin biosynthesis by a human macrophage-like cell line, U937.

The human macrophage-like cell line, U937, produced significant amounts of prostaglandin (PG) E2 when incubated with exogenous arachidonic acid (AA). The synthesis of PGE2 was completely inhibited by pretreatment with indomethacin (20 micrograms/ml). Another major metabolite, unidentified, which was released during incubation with AA, was not inhibited by indomethacin, but was decreased by nordihydroguaiaretic acid (NDGA) (10(-5)M) or BW755C (10(-4)M). These results confirm the presence of cyclooxygenase and perhaps lipoxygenase activities in this macrophage-like cell line. Challenge of U937 cells with zymosan, opsonized zymosan, phorbolmyristate acetate (PMA), heat-aggregated human IgG (AHG), or calcium ionophore A23187 failed to stimulate synthesis and release of either PGE2 or the above mentioned metabolite. The inability of U937 cells to release endogenous AA from cell lipid for PG synthesis constitutes an important functional difference between these cells and normal macrophages.

Arachidonic Acids↗