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M S Caplan

Publications and source records attributed to M S Caplan.

At least 37 records · Page 2Linked to original sources
PubMed1994

Endothelial cell 1-acyl-platelet-activating factor synthesis in response to anticardiolipin antibody-positive serum fractions.

Enhanced endothelial cell 1-acyl platelet-activating factor (1-acylPAF) synthesis has been identified as a consequence of anticardiolipin-antibody-positive serum exposure. While this observation suggests that PAF analogues may play a role in antibody-mediated vasculopathy, it has not been determined whether the antibodies themselves are directly responsible for stimulating 1-acylPAF production. The objective of the current study was to determine whether extracted immunoglobulins or non-immunoglobulin serum constituents are responsible for the increased endothelial cell 1-acylPAF production previously observed. Sera from six ACA-positive, non-pregnant women were precipitated with ammonium sulfate and dialyzed to extract their respective immunoglobulin fractions. IgG, A and M concentrations were measured by nephelometry before and after precipitation and enzyme immunoassay was used to quantify anticardiolipin antibody activity in both whole serum and immunoglobulin suspensions. Paired endothelial cell monolayers were incubated separately with 20% whole serum and the corresponding immunoglobulin fraction from each patient source. After ionophore A23187 stimulation, intracellular PAF production was measured by lipid extraction and radiolabeling. RadylPAF species were distinguished by zonal thin-layer chromatography. Mean radylPAF synthesis was compared between experimental conditions by paired T-test. Significantly more endothelial cell radylPAF synthesis was observed subsequent to whole serum exposure as compared to incubation with the corresponding immunoglobulin fractions (19154 +/- 1916 vs 11785 +/- 1778; dpm, mean +/- SE; p = 0.007); the majority of recovered radylPAF was the sn-1-acyl derivative. Serum samples recovered after immunoglobulin extraction, retained similar stimulatory activity for radylPAF (23045 +/- 4175 dpm) in comparison to intact whole serum (19635 +/- 1266 dpm; p = 0.25). These findings suggest that in ACA-positive serum, non-immunoglobulin constituents provide greater stimulation of 1-acylPAF synthesis than the immunoglobulins themselves.

Antibodies, Anticardiolipin↗
PubMed1994

Tumour necrosis factor and endotoxin synergistically activate intestinal phospholipase A2 in mice. Role of endogenous platelet activating factor and effect of exogenous platelet activating factor.

Previous studies have shown that: (a) platelet activating factor induces shock and intestinal injury, (b) exogenous platelet activating factor stimulates synthesis of endogenous platelet activating factor, and (c) tumour necrosis factor alpha and endotoxin synergise to induce shock and bowel injury in animals. These last two effects are largely mediated by platelet activating factor forming phospholipase A2 A2, a key enzyme for platelet activating factor synthesis, was examined in mouse intestine. It was found that tumour necrosis factor alpha and endotoxin synergise to stimulate platelet activating factor forming phospholipase A2 activity in the intestine, as well as platelet activating factor production, and these effects were blocked by pretreatment with platelet activating factor antagonists, SRI-63-441 and WEB 2086. In addition, exogenous platelet activating factor stimulates intestinal phospholipase A2 activity. These results show that tumour necrosis factor alpha and lipopolysaccharide synergistically activate the phospholipase A2 that participates in platelet activating factor formation, and this activation is largely mediated by endogenous platelet activating factor. Furthermore, platelet activating factor itself increases phospholipase A2 activity, suggesting that platelet activating factor induces its own synthesis, probably by phospholipase A2 activation.

Animals↗
PubMed1994

Altered mitochondrial redox responses in gram negative septic shock in primates.

Gram negative sepsis causes changes in oxygen supply-demand relationships. We have used a primate model of hyperdynamic gram negative sepsis produced by intravenous infusion of Escherichia coli (E. coli) to evaluate sepsis-induced alterations in mitochondrial oxidation-reduction (redox) state in muscle in vivo. The redox state of cytochrome a,a3, the terminal member of the intramitochondrial respiratory chain, was assessed in the intact forearm by near-infrared (NIR) spectroscopy. The muscle NIR data were compared to routine measures of oxygen delivery (DO2) and oxygen consumption (VO2). After E. coli infusion and fluid resuscitation, DO2 and VO2 showed minimal changes through 24 hr of sepsis. In contrast, changes in cytochrome a,a3 redox state evaluated by NIR occurred within a few hours and were progressive. Mitochondrial functional responses were correlated with structural changes observed on serial muscle biopsies. Gross morphological changes in muscle mitochondria were present in some animals as early as 12 hr, and, in most animals, by 24 hr. The morphologic changes were consistent with decreases in oxidative capacity as suggested by NIR spectroscopy. The NIR data also suggest that two mechanisms are operating to explain abnormalities in oxygen metabolism and mitochondrial function in lethal sepsis. These mechanisms include an early defect in oxygen provision to mitochondria that is followed by a progressive loss in functional cytochrome a,a3 in the muscle.

Animals↗
PubMed1994

Inflammatory mediators and intestinal injury.

Although the causes of necrotizing enterocolitis (NEC) are not well understood, there is compelling evidence to suggest that the inflammatory mediators play an important role in the pathophysiology of the disease. This article examines the role of platelet-activating factor (PAF) and other mediators on the development of NEC, and attempts to explain the association of the putative NEC risk factors with altered mediator production and subsequent intestinal injury. The authors hypothesize that PAF is a key mediator in the final common pathway leading to NEC.

Animals↗
PubMed1993

Acetylsalicylic acid inhibits anticardiolipin antibody-induced platelet-activating factor (PAF) synthesis.

Enhanced endothelial cell PAF synthesis has been identified as a consequence of anticardiolipin antibody (ACA)-positive serum exposure. We proposed this observation as a contributing factor to thrombogenesis in women with the antiphospholipid syndrome. Since acetylsalicylic acid (ASA) is an accepted therapeutic alternative in these patients, we sought to determine if ASA would attenuate endothelial cell PAF production resulting from ACA exposure. Using primary, confluent monolayers of umbilical vein endothelial cells, experiments were performed to evaluate PAF synthesis after incubation with antibody-positive serum and ASA. Total PAF and its radyl-derivatives (1-alkyl- and 1-acyl-PAF) were quantified by tritiated acetate incorporation, phospholipid extraction, thin-layer chromatography and scintillation spectroscopy. ASA consistently decreased ACA-induced PAF synthesis (No ASA, 9573 +/- 443 vs 1mmol/L ASA, 4829 +/- 838 dpm/ml; p = 0.016) and the observed reduction was dose-dependent over a range of ASA concentrations (0.1, 1, 10 and 100 mmol/L; ANOVA, p = .00015). Reduced PAF synthesis was also observed in cultures exposed to ASA and incubated with antibody-negative serum. These observations suggest that in ACA-positive women, the antithrombotic effects of ASA may relate in part, to reduced endothelial cell PAF synthesis.

Antibodies, Anticardiolipin↗
PubMed1992

Hypoxia increases stimulus-induced PAF production and release from human umbilical vein endothelial cells.

Hypoxia alters endothelial cell function and metabolism. Since PAF is synthesized by endothelial cells and capable of modulating endothelial cell responses, we investigated the effect of hypoxia on synthesis and release of PAF from endothelial cells. We found: (1) Approx. 90% of the radylPAF derivative in stimulated endothelial cells is acylPAF. (2) Acute hypoxic (15 min-1 h) priming increased ionophore- and thrombin-induced radylPAF accumulation. (3) Long-term hypoxic exposure increased radylPAF accumulation at 24 and 48 h in the presence of ionophore. (4) Bioactive PAF was released into media and hypoxia and ionophore synergistically increased PAF release. (5) Hypoxia and ionophore stimulation increased phospholipase A2 activity and decreased acetylhydrolase activity in endothelial cells. We conclude that hypoxia and ionophore increase PAF synthesis and release from endothelial cells.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1992

Amniotic fluid platelet-activating factor (PAF) is elevated in patients with tocolytic failure and preterm delivery.

Certain biological properties of PAF, including its ability to promote PGE2 synthesis and to induce myometrial contractions, support its potential role in parturition. The presence of PAF in amniotic fluid of human pregnancy appears to correlate with normal and pathologic labor. To further refine this relationship, we selected the clinical endpoints of preterm labor, tocolytic failure and preterm delivery, and evaluated amniotic fluid PAF within these groups of patients. We also measured acetylhydrolase (AH), PAF's primary degradative enzyme, to identify any correlation with the observed PAF levels. 39 specimens were collected by amniocentesis: 17 for karyotype, 6 to assess lung maturity at term and 16 in cases of preterm labor; 8 each with intact membranes and ruptured membranes at the time of sampling. PAF and AH were measured by a 3H-serotonin release bioassay and an in vitro enzyme assay using radiolabelled substrate, respectively. A 12-fold increase in PAF was found in the 3 preterm labor patients in whom tocolysis failed (delivery less than 48 hrs after treatment) compared to the 7 patients in whom labor was arrested (mean PAF = 35.0 vs 2.9 ng/ml, respectively; p = .017). Four of 8 patients with membrane rupture had preterm deliveries; their PAF levels were also elevated when compared to those that delivered at term (mean PAF = 19.7 vs 4.95 ng/ml). The 2 patients with positive amniotic fluid gram stains had the highest PAF levels in the entire cohort (30.5, 44.1 ng/ml), with low or undetectable AH. These data suggest that increased PAF production may be associated with preterm labor subsequent to tocolytic failure.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1992

Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor.

We have previously shown that intravascular platelet activating factor (PAF) causes ischemic bowel necrosis in rats morphologically similar to neonatal necrotizing enterocolitis (NEC). Because endotoxin (LPS) and hypoxia are risk factors for NEC, we studied their effect on PAF metabolism and the development of intestinal injury. Young male Sprague-Dawley rats were anesthetized with pentobarbital and divided into six experimental groups: 1) control, 2) LPS alone (2 mg/kg), 3) hypoxia alone (5% O2), 4) LPS+hypoxia, 5) WEB 2086 (PAF antagonist)+LPS+hypoxia, and 6) SRI 63-441 (PAF antagonist)+LPS+hypoxia. Evaluations included blood pressure recording, superior mesenteric artery blood flow, arterial blood gas, white blood cell count, hematocrit, plasma PAF, plasma acetylhydrolase, plasma tumor necrosis factor, intestinal perfusion, and intestinal injury at 3 h. We found that LPS+hypoxia synergistically contributed to hypotension (mean blood pressure 27 +/- 5.6% baseline versus 101 +/- 3.9% control), metabolic acidosis (pH 7.05, base deficit 24 mEq/L), hemoconcentration, decreased superior mesenteric artery blood flow (2.2 +/- 0.3 mL/min versus 5.8 +/- 0.2 mL/min control), and intestinal injury. The morbidities resulting from LPS+hypoxia were partially or completely prevented by PAF antagonists. In addition, animals treated with LPS+hypoxia had neutropenia, elevated plasma acetylhydrolase, and elevated plasma TNF. These results suggest that endogenous PAF may contribute to LPS+hypoxia-induced intestinal hypoperfusion and necrosis.

Animals↗
PubMed1991

Hypoxia, PAF, and necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an important neonatal disease with a high mortality rate. The pathophysiology is unclear but epidemiologic studies suggest that hypoxia and infection are important risk factors. In this review we discuss the effect of hypoxia and platelet-activating factor (PAF) on intestinal blood flow and intestinal necrosis, and implicate PAF as an important mediator in hypoxia-induced intestinal injury. Finally we provide evidence that PAF may be important in neonatal NEC.

Animals↗
PubMed1991

Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion.

BACKGROUND AND METHODS: The mechanism of ischemic bowel necrosis induced by platelet-activating factor is unclear. Since intestinal hypoperfusion is observed after platelet-activating factor injection, we hypothesized that mesenteric vasoconstriction is the mechanism of bowel injury. The present study investigated the effects of saline infusion on platelet activating factor-induced bowel necrosis and its mechanism. Male Sprague-Dawley rats were divided into four groups: group A consisted of sham-operated rats; group B received platelet-activating factor (1.5 micrograms/kg iv); group C received platelet-activating factor and saline (0.097 mL/min iv); group D received platelet-activating factor and WEB 2086 (platelet-activating factor antagonist). RESULTS: Saline infusion largely reversed platelet activating factor-induced hypotension, hemoconcentration, and reduction of the superior mesenteric arterial blood flow. Saline infusion also ameliorated platelet activating factor-induced bowel injury, although a mild-to-moderate degree of necrosis still developed focally. In addition, saline prevented the platelet activating factor-induced increase in intestinal platelet-activating factor production. Saline also prevented the increase in intestine leukocyte number, as estimated by myeloperoxidase activity. CONCLUSIONS: Saline infusion is an effective treatment for platelet activating factor-induced shock and intestinal necrosis. However, focal bowel injury is still observed, suggesting that other factors besides hemodynamic changes contribute to the development of tissue injury. We also showed that, in vivo, platelet-activating factor stimulates its own synthesis via a positive feedback loop, which could be blocked by intravascular volume expansion with saline.

Animals↗
PubMed1990

Hypoxia causes ischemic bowel necrosis in rats: the role of platelet-activating factor (PAF-acether).

We have previously shown that injection of platelet-activating factor causes necrotizing enterocolitis in the rat and that platelet-activating factor is an endogenous mediator in lipopolysaccharide-induced bowel necrosis. Because hypoxia is a known predisposing factor for neonatal necrotizing enterocolitis, we investigated the effect of hypoxia on platelet-activating factor formation and intestinal necrosis. Young male Sprague-Dawley rats were made severely hypoxic by placing them in a 100% N2 chamber for 2 minutes; moderate hypoxia was accomplished using 10% O2 for 15 or 30 minutes. To evaluate the role of platelet-activating factor on intestinal perfusion and injury, two platelet-activating factor antagonists, SRI 63-441 and WEB 2086, were injected 10 minutes before the hypoxic exposure. We found that plasma platelet-activating factor levels were significantly elevated after 2 minutes of severe hypoxia (13.8 +/- 2.9 ng/mL vs. control 2.1 +/- 0.8 ng/mL) and after 30 minutes of moderate hypoxia (41.1 +/- 11.7 ng/mL). This increase in platelet-activating factor level was not caused by decreased degradation, because neither plasma nor intestinal platelet-activating factor acetylhydrolase was decreased in the hypoxic rats. (Intestinal acetylhydrolase activity was actually increased). Intestinal perfusion was markedly decreased at 30 minutes in hypoxic animals. In contrast, all platelet-activating factor antagonist-treated animals had normal intestinal perfusion. Histological examination of affected bowel from hypoxic animals showed early intestinal necrosis which was completely prevented by pretreatment with SRI 63-441 and WEB 2086. Because 30 minutes of hypoxia also resulted in metabolic acidosis, we further investigated if acidosis alone could induce platelet-activating factor release and bowel injury. We found that acidosis alone resulted in moderate increase of plasma platelet-activating factor but did not produce bowel injury. We conclude that platelet-activating factor plays a central role in mediating hypoxia-induced intestinal necrosis. Acidosis may enhance the effect of hypoxia on platelet-activating factor production.

Animals↗
PubMed1990

Role of platelet activating factor and tumor necrosis factor-alpha in neonatal necrotizing enterocolitis.

Because previous investigations have suggested that platelet activating factor and tumor necrosis factor-alpha (TNF-alpha) are important mediators of experimental necrotizing enterocolitis in the rat, we measured platelet activating factor, acetylhydrolase (the platelet activating factor breakdown enzyme), and TNF-alpha in the plasma of 12 human neonates with necrotizing enterocolitis and eight age-matched control subjects with similar gestational ages, postnatal ages, and weights. Almost all patients with necrotizing enterocolitis had elevated plasma platelet activating factor values (18.1 +/- 3.6 ng/ml vs. 3.1 +/- 0.9 ng/ml in control subjects, p less than 0.01). Plasma acetylhydrolase activity was lower in patients than in control subjects (10.6 +/- 0.7 nmol/ml/min vs 23.0 +/- 1.4 nmol/ml/min, p less than 0.01). Plasma TNF-alpha concentration was significantly elevated in patients with necrotizing enterocolitis (136 +/- 75 U/ml vs 1.5 +/- 0.8 U/ml, p less than 0.05), although the individual variation was high. There was no correlation between individual TNF-alpha and platelet activating factor levels. We conclude that platelet activating factor and TNF-alpha are elevated in patients with necrotizing enterocolitis and that suppressed platelet activating factor degradation contributes to the increased platelet activating factor levels; platelet activating factor and TNF-alpha may contribute to the pathophysiology of necrotizing enterocolitis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1990

Circulating plasma platelet activating factor in persistent pulmonary hypertension of the newborn.

Platelet activating factor (PAF) is an endogenous phospholipid mediator that causes pulmonary hypertension and thrombocytopenia in experimental animal models. To investigate circulating PAF in persistent pulmonary hypertension of the newborn (PPHN), we studied PAF and its degradative enzyme, acetylhydrolase. Thirteen neonates with PPHN, diagnosed by routine clinical methods including echocardiography, were compared to six age-matched control patients with respiratory distress. Overall, plasma PAF levels were elevated in patients with PPHN compared to control patients (20.1 +/- 3.9 versus 1.6 +/- 0.7 ng/ml, p less than 0.01). In addition, plasma PAF concentrations in patients with PPHN correlated with the severity of disease as defined by the delta AaPO2 (r = 0.65, p = 0.015). In three patients with elevated PAF levels, as the clinical status improved, the plasma PAF values decreased. Acetylhydrolase activity was similar in both groups (3.96 +/- 0.90 versus 3.78 +/- 1.44 nmol/ml/min, p = NS). We conclude that PAF production is increased in PPHN and that abnormal production of PAF may be associated with pulmonary hypertension.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1989

Favorable outcome of neonatal aortic thrombosis and renovascular hypertension.

Fifteen children with renovascular hypertension as a result of aortic thrombosis were followed for a mean of 26 months (range 5 to 58 months) to determine outcome. As neonates, all patients had hypertension and elevated plasma renin activity. Of 11 patients studied with radionuclide renography and scintigraphy, 10 had abnormal renal blood flow; three had complete absence of unilateral perfusion. On follow-up examination all children were normotensive; five children ages 5 to 24 months required antihypertensive medication. Of 15 children, 14 had normal statural growth; all had normal serum creatinine, plasma renin activity, and calculated glomerular filtration rate values. Patients with complete absence of renal perfusion unilaterally remained functionally anephric; children with less severe perfusion deficits had improved perfusion as shown by radionuclide renography and scintigraphy. We believe that many patients with aortic thrombosis and renovascular hypertension who have had aggressive antihypertensive therapy in the neonatal period will have good renal function and increased perfusion to the affected kidney 2 years later.

Aortic Diseases↗