On the role of the pancreatic secretory trypsin inhibitor as an inactivator of trypsin-alpha 2-macroglobulin complexes in acute pancreatitis

High levels of immunoreactive pancreatic secretory trypsin inhibitor (PSTI) were demonstrated in the serum and peritoneal exudates of patients suffering from acute pancreatitis. Trypsin-like immunoreactivity in these fluids was found in complex with alpha 1-antitrypsin and in complex with alpha 2-macroglobulin and also as a free peak correlating to free trypsin(ogen). No trypsin-PSTI complexes or PSTI were demonstrated in the macroglobulin fraction of the peritoneal exudates. Saturated and partially saturated trypsin-alpha 2-macroglobulin complexes were prepared in vitro. PSTI was able to partially inhibit the BzArgNan-cleaving activity of both types of complexes in a slow dose-dependent non-linear reaction. Equilibrium was reached in each case within 1 h, but total inhibition was not reached even with large amounts of PSTI. Partially saturated trypsin-alpha 2-macroglobulin complexes were inhibited more readily than saturated complexes. The results support the concept of PSTI acting as a strictly local inhibitor of trypsin in compartments lacking plasma protease inhibitors.     

Influence of plasma proteinase inhibitors and aprotinin on trypsin-induced bradykinin release in vitro in man

The consumption of kininogen (measured as kinin-releasable material) was studied in an experimental model in vitro. Analyses were made following the addition of increasing amounts of human cationic trypsin to human serum and plasma. The consumption of kininogen was correlated with the degree of saturation of the plasma proteinase inhibitors alpha 2-macroglobulin (alpha 2-M) and alpha 1-proteinase inhibitor (alpha 1-PI) with trypsin in the presence and absence of aprotinin (Trasylol). The level of kininogen fell dramatically when alpha 2-M was saturated to 70% in spite of 90% free alpha 1-PI. Trypsin-alpha 2-M complexes had no effect on kininogen levels. 60 mumol/l of aprotinin, i.e. approximately 3 X 10(6) KIU/l, blocked only 60% of the trypsin-induced kininogen consumption in serum, while 15 mumol/l of aprotinin blocked 100% of this consumption in plasma. With increasing concentration of aprotinin in serum, a decreasing consumption of alpha 2-M and especially of alpha 1-PI was observed on the addition of trypsin. The high aprotinin concentration needed to block trypsin-induced kininogen cleavage in human serum or plasma may explain the poor clinical effect of aprotinin to date in human acute pancreatitis.     

Calcitonin gene-related peptide can attenuate or augment pancreatic damage in caerulein-induced pancreatitis in rats.

We have recently shown that treatment with calcitonin gene-related peptide (CGRP) before and during induction of acute pancreatitis exhibits a protective effect against pancreatic damage evoked by overdose of caerulein. Studies in the stomach have shown that administration of CGRP exhibits dual action on gastric mucosa, CGRP administration before induction of gastric lesions, protects gastric mucosa against damage, whereas treatment with this peptide after development of gastric ulcer exacerbates mucosal injury. These observations prompt us to determine the influence of CGRP administrated before and after induction of pancreatitis on development and evolution of pancreatic tissue damage. METHODS: Acute pancreatitis was induced by s.c. infusion of caerulein (10 microg/kg/h) for 5 h. CGRP was administrated (10 microg/kg s.c. per dose) 30 min prior to caerulein infusion and 3 h later during caerulein infusion or at the time 1 h, 4 h and 7 h after the end of caerulein infusion. Rats were sacrificed at the time 0 h, 3 h or 9 h after cessation of caerulein administration. The pancreatic blood flow (PBF), plasma activity of amylase, plasma interleukin-1beta concentration, cell proliferation, biochemical and morphological signs of pancreatitis were examined. RESULTS: Caerulein-induced pancreatitis (CIP) led to 42% decrease in DNA synthesis, 30% inhibition of PBF, as well as, a significant increase in pancreatic weight, plasma amylase activity, plasma interleukin-1beta concentration, and development of the histological signs of pancreatic damage (edema, leukocyte infiltration and vacuolization). Treatment with CGRP prior and during induction of CIP attenuated the pancreatic damage what was manifested by partial reversion of the drop in DNA synthesis (40.9+1.7 v. 34.2+2.0 dpm/microg DNA) and PBF (83+3% v. 70+3%). Increases in pancreatic weight and plasma interleukin-1beta were reduced. Morphology showed improvement of pancreatic integrity. Administration of CGRP after induction of CIP aggravated pancreatic damage what was manifested by additional decrease in PBF and DNA synthesis. Also pancreatic weight as well as histological signs of pancreatic damage were increased. CONCLUSIONS: (1) Administration of CGRP before and during induction of pancreatitis protects pancreas against pancreatic damage. (2) Treatment with CGRP after development of CIP aggravates pancreatic damage.     

Apoptosis of phagocytic cells induced by Candida albicans and production of IL-10

Macrophages co-incubated with Candida albicans strain CR1 in vitro showed early signs of apoptosis, but evolved to necrosis after 2 h. In this study, we investigated whether strain CR1 caused apoptosis or necrosis of macrophages after its inoculation into mice peritoneal cavity, and whether this correlated with the secretion of IL-10. Peritoneal macrophages from mice that received an inoculum of C. albicans CR1 showed signs of apoptosis and necrosis from 30 min to 2 h afterwards, whereas heat-killed C. albicans did not cause those effects. IL-10 production was low during the first 6 h post-infection, when macrophages predominated in the peritoneal exudate, whereas its higher production after 24 h correlated with an increase of neutrophils in the exudate. Treatment of CR1 with pepstatin (an inhibitor of proteinases) prevented the process of apoptosis and significantly reduced IL-10 production, suggesting that the increased production of IL-10 was caused by processes occurring during the initial phase of infection, such as apoptosis, necrosis and uptake of death cells.     

Effect of combination of nitric oxide synthase and cyclooxygenase inhibitors on carrageenan-induced pleurisy in rats

In the present study, we examined the effects of L-nitroarginine methylester (L-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, indomethacin (IND), a non-selective COX inhibitor and a combination of these agents (L-NAME+IND) on carrageenan-induced pleurisy in rats. Exudate volume, albumin leakage, leukocyte influx, exudate and plasma nitrite/nitrate (NO(x)) levels and exudate PGE(2) levels increased markedly 6 h after an intrapleural injection of 2% carrageenan. First, the effects of L-NAME and IND alone were investigated. L-NAME non-significantly reduced exudate volume by 26% at 10 mg/kg (i.p.), and significantly by 45% at 30 mg/kg. IND dose-dependently decreased the exudate volume at 0.3-10 mg/kg (p.o.) and the effect reached the maximal level at 1 mg/kg (33%). Second, the effects of L-NAME (10 mg/kg, i.p.), IND (1 mg/kg, p.o.) and L-NAME+IND were examined. L-NAME and IND alone at the dose employed significantly reduced the exudate volume and albumin levels by 21-26%. L-NAME but not IND tended to reduce the increased exudate and plasma NO(x) by 18% and 19%, respectively. IND but not L-NAME significantly reduced leukocyte numbers and PGE(2) levels in the exudates by 25% and 77%, respectively. L-NAME+IND significantly reduced exudate volume, albumin leakage, leukocyte number, PGE(2) and NO(x) by 43%, 41%, 31%, 80% and 37%, respectively. The inhibitory effects of L-NAME+IND on exudate volume, albumin leakage and NO(x) levels were greater than those of L-NAME and IND alone. In conclusion, a non-selective NOS inhibitor and COX inhibitor showed anti-inflammatory effects at the early phase of carrageenan-induced pleurisy, and a combination of both inhibitors had a greater effect than each alone probably via the potentiation of NOS inhibition. The simultaneous inhibition of NOS and COX could be a useful approach in therapy for acute inflammation.     

Release of granulocyte elastase in lethal canine endotoxin shock.

The release of granulocyte elastase and its interaction with plasma protease inhibitors was studied in dogs receiving a slow infusion of a lethal dose of Escherichia coli endotoxin. During endotoxin infusion a marked decline in leucocyte counts was parallelled by a rapid increase in plasma granulocyte elastase concentrations. Maximal values were reached after 3 h, when the infusion was ended. Crossed immunoelectrophoresis with antiserum against granulocyte elastase did not reveal the presence of elastase components with the electrophoretic mobility of free elastase, but elastase-alpha1-antitrypsin complexes were detected. A gradually decreasing plasma concentration of alpha2-macroglobulin was noted during the experiments. Crossed immunoelectrophoresis, however, did not reveal any electrophoretic heterogeneity. It is concluded that the release of granulocyte proteases might be of significance for several pathophysiological changes seen in endotoxin shock.     

Changes in fatty acid composition in rat blood and organs after infusion of eicosapentaenoic acid ethyl ester.

An infusible emulsion of 10% eicosapentaenoic acid ethyl ester (EPA-EE, 99.2% pure) was prepared. Three ml of the emulsion was infused into tail veins of 20 Wistar rats weighing approx. 300 g. They were killed 1 h, 6 h, 24 h, 3 d and 7 d after the infusion, and fatty acid composition of various organs and plasma was analyzed along with that of control rats. There was no lipidosis in any organs of any rats. It was estimated that not less than 98% of infused EPA was cleared from plasma during the first hour after the infusion. EPA concentrations reached their peaks within 6 h after EPA infusion in plasma lipid fractions and in the phospholipid fraction of liver, heart, lung, kidney and spleen. The fatty acid composition of the phospholipid fraction of heart was very stable, and was not altered by EPA infusion except for a very slight increase in EPA at 1 h after the infusion (0.18% at 0 h to 0.56%). However, EPA concentrations increased markedly in the free fatty acid fraction of heart at 1 h after the infusion (0.15% at 0 h to 4.23%). Arachidonic acid concentrations decreased significantly within 24 h in the phospholipid fraction of organs except for heart. EPA emulsion might be useful for patients in whom a rapid increment in EPA in tissues is beneficial.     

Transport of GABA at the Blood-CSF Interface

Abstract: The entry of GABA into cerebrospinal fluid (CSF) was studied in dogs anesthetized with pentobarbital and relaxed with suxamethonium. GABA was administered intravenously as a priming dose and subsequent maintenance infusion to compensate for the rapid elimination of the amino acid. Steady state concentrations of GABA in CSF were reached between 10 and 60 min after injection, the rate of entry tending to decrease with increasing plasma levels. During steady state conditions CSF concentrations showed great interin-dividual differences and varied between 0.03 and 5.1% of those in plasma. Probenecid and sodium valproate considerably enhanced the CSF/plasma concentration ratio of GABA. When GABA was directly injected into the liquor space, probenecid slowed down the elimination of GABA from CSF. The results suggest a transport of GABA into and out of CSF, the outward transport being inhibited by probenecid and sodium valproate.     

Acute phase induction of mouse serum amyloid P component. Correlation with other parameters of inflammation

Hepatic mRNA levels of the mouse major acute phase proteins serum amyloid P component (SAP) and serum amyloid A component (SAA) were monitored at timed intervals after i.p. injection of thioglycollate or s.c. injection of azocasein. Both mRNA increased dramatically in response to either inflammatory stimulus. The increase in SAA mRNA levels accompanied an abrupt change in mRNA size from 650 to 750 bases. Peak SAA mRNA concentrations were observed 18 h after either stimulus; by 72 h concentrations had returned to preinflammatory levels. Peak SAP mRNA concentrations were observed 8 h after thioglycollate and 12 to 18 h after azocasein injection; by 36 h concentrations were close to preinflammatory levels. All mRNA species studied (SAP, SAA and the complement components C3, C5 and factor B) were induced more rapidly by the thioglycollate stimulus and reached higher peak concentrations. SAP mRNA levels were correlated with other parameters of inflammation: infiltration of peritoneal exudate cells (PEC) into the peritoneum after thioglycollate injection, and serum concentrations of SAP after azocasein injection. Serum SAP concentrations rose 20-fold in response to the latter stimulus by 36 h, i.e., 18 to 24 h after the peak SAP mRNA levels. The highest numbers of PEC were present 24 h after the thioglycollate stimulus, i.e. 16 h after the maximum SAP mRNA concentration, indicating the continuation of an active local inflammation many hours after one aspect of the systemic response has ceased.     

Production of antiviral and migration inhibitory activities in the peritoneum of mice after inoculation with allogenic Ehrlich ascites tumor cells.

Peritoneal inoculation of Ehrlich ascites cells into mice stimulates the appearance of migration inhibitory factor (MIF) not only in the peritoneum but also in the circulation of mice. Whereas the MIF-activity in the peritoneum reached maximum at 6 days and disappeared within 17 days, the MIF-activity of sera reached maximum levels at about 11 days after intraperitoneal inoculation of tumor cells (10(6) of EAC per mouse). In addition, an antiviral activity of peritoneal exudates was observed in the early stage (24--72 h) of tumor challenge. The time-course of appearance of both MIF and AV-inhibitor are presented. A significant decrease of MIF-activity was noted when the tumor-inoculated mice were treated with ds-RNA, antithymocyte serum and cyclophosphamide, respectively. The appearance of antiviral activity in the peritoneum of tumor-inoculated mice seems to be macrophage-dependent. Although the antiviral factor meets several criteria of interferons, further studies are required for its characterization.     

Nitrate biosynthesis in the rat. Precursor-product relationships with respect to ammonia.

The endogenous biosynthesis of nitrate in rats was investigated by using 15NH3 administered as a continuous intravenous infusion for as long as 96 h. A comparison of the enrichment of 15N in urinary nitrate after a 24 h infusion revealed that it was 36% of the enrichment of plasma NH3 and about 50% of the enrichment of plasma urea and urinary NH3. Continuous infusion of 15NH3 for 96 h showed that a plateau for the incorporation of NH3 into nitrate is reached by 24 h, whereas the enrichment of urinary NH3 and urea increase during the 96 h. After the infusion of progressively larger doses of 15NH3, the concentration of nitrate synthesized de novo increased. Although there was a significant correlation between plasma 15NH3 concentration and 15NO3- appearance, a given change in plasma NH3 concentration does not produce a direct proportional change in nitrate synthesis. Our findings indicate that NH3 is a quantitatively significant nitrogen precursor for nitrate, but that approx. 50% of nitrate nitrogen is derived from other, as yet unidentified, sources.     

Action of low-frequency ultrasound on the peritoneum, peritoneal exudate cells and the course of experimental peritonitis

The authors studied the action of low-frequency ultrasound on rat and guinea-pig peritoneal exudate cells during aseptic peritonitis, on the intact peritoneum of these animals, and on experimental peritonitis in guinea-pigs. It was shown that ultrasound "hammers in" India ink solutions and antibacterial drugs into the peritoneum and in combination with antibiotics, it increases the guinea-pig survival rate in peritonitis. Ultrasound was not found to produce a direct bactericidal effect in vivo. Exposure of peritoneal exudate to ultrasound (1 s/cm2) demonstrated an increase in chemotaxis of neutrophil leukocytes to autologic serum and appreciable phagocytic activity. A longer exposure (up to 3-5 s/cm2 or 6-8 s/cm2) resulted in the partial damage to the peritoneum. Leukocytes, mesotheliocytes and subperitoneal striated muscles were found to be especially sensitive to ultrasound.     

Adrenocortical responses to corticotropin-releasing factor in the rat

The time course of plasma corticosterone was measured in male Sprague-Dawley rats whose endogenous release of ACTH had been blocked following rapid i.v. injections of doses ranging from 0.003 to 10 micrograms corticotropin-releasing factor (CRF) per rat and during i.v. infusions at rates ranging from 0.001 to 20 ng CRF X min-1 X 100 g body weight-1. The range of the dose-response curve, following rapid injection, extends from 0.01 to 0.37 micrograms CRF, whereas it extends over a 20 000-fold range from 0.001 to 20 ng CRF X min-1 X 100 g body weight-1 during a continuous infusion. The delayed response to a small rate of CRF could be ascribed to a relatively long time of residence of CRF in the plasma which implies that a relatively long period of time is required until a minimal plasma CRF concentration is reached after the onset of a continuous infusion of CRF at a small rate. When presented with a prolonged infusion of CRF at a large rate, the pituitary secretion of ACTH is rapidly turned on at a rate which exhibits the characteristics of a prolonged secretion at a constant large magnitude.     

Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids. However, this provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (k(p-if)) or its mean residence time in interstitial fluid (MRT(if)). To determine these parameters for a pharmacologic dose of exogenous apolipoprotein A-I (apoA-I) given intravenously as apoA-I/lecithin discs, we measured apoA-I in plasma and prenodal leg lymph in five healthy men before, during, and after a 4 h infusion at 10 mg/kg/h. ApoA-I concentrations in plasma and lymph were modeled by linear compartmental models (SAAM II version 1.1), using lymph albumin to adjust for the effects of variations in lymph flow rate. k(p-if) averaged 0.75%/h (range, 0.33-1.32), and MRT(if) averaged 29.1 h (14.1-40.0). Neither parameter was correlated with the distribution volume (57-105 ml/kg) or the fractional elimination rate (1.44-2.91%/h) of apoA-I, determined by modeling plasma apoA-I concentration alone. Although used here to study the mass kinetics of apoA-I, if combined with infusion of a tracer, analysis of lymph could also expand the modeling of endogenous apolipoprotein kinetics.     

Effect of Rapid Intravenous Infusion on Serum Concentrations of Amphotericin B

The magnitude of the concentrations of amphotericin B produced in serum of patients with systemic mycoses may significantly influence the outcome of therapy with this drug. Since amphotericin B is conventionally administered in intravenous infusions lasting 4 to 6 hr, we asked whether faster infusions of this drug might yield higher serum concentrations without an increase in dose. This question was studied in three patients who received 16 infusions of this drug: eight infusions administered slowly (5 hr) and eight administered rapidly (45 min). Serum concentrations after each rapid infusion were compared with those after a slow infusion administered to the same patient. The mean serum concentration of amphotericin B 1 hr after the rapid infusions (2.02 mug/ml) was significantly higher (P < 0.001) than the mean serum concentration of amphotericin B 1 hr after the slow infusions of this drug (1.18 mug/ml). Mean serum concentrations 18 and 42 hr after rapid infusion remained slightly but not significantly higher than respective mean concentrations after slow infusions. By yielding higher initial serum concentration, rapid intravenous infusion may be therapeutically more effective than slow infusion of amphotericin B. Although rapid infusions caused no more toxicity than did slow infusions, the lack of greater toxicity with rapid infusion of amphotericin B should be further documented prior to extensive clinical application of this procedure.     

Generation of inflammatory cytokines in zymosan-induced pleurisy in rats: TNF induces IL-6 and cytokine-induced neutrophil chemoattractant (CINC) in vivo

Levels of inflammatory cytokines tumour necrosis factor (TNF), interleukin 1 (IL-1), IL-6, and cytokine-induced neutrophil chemoattractant (CINC), which is a member of the alpha-chemokine family in rats, were measured in the pleural exudates during zymosan-induced pleurisy to examine the relationship between the local production of cytokines and the inflammatory reaction. All four cytokine levels in the pleural exudate began to increase after 1-2 h, preceding the influx of neutrophils, and peaked after 4-5 h. Thereafter, these cytokine levels declined after 24 h, whereas the exudate volume still continued to increase and leukocyte number reached a plateau. Concomitant injection of actinomycin D (10 microg) with zymosan markedly suppressed the neutrophil infiltration, parallel with CINC production in the pleural exudate at 4 h. A transient elevation of IL-6 level, peaking at 5 h, and subsequent rise in the level of an acute-phase protein, T-kininogen, were also observed in the plasma. When recombinant human TNF-alpha (rhTNF-alpha) (20 000 U) was intrapleurally injected a rapid increase in pleural CINC level, followed by neutrophil infiltration, and a sharp rise in IL-6 level in the plasma, followed by an increase in T-kininogen, were demonstrated. These results suggest that CINC produced in the pleural exudate may participate in neutrophil infiltration, that IL-6 induced in the plasma stimulates T-kininogen production, and that endogenous TNF may be partly involved in the induction of CINC and IL-6 in this zymosan inflammation.     

Effects of S-propargyl-cysteine (SPRC) in caerulein-induced acute pancreatitis in mice

Hydrogen sulfide (H(2)S), a novel gaseous messenger, is synthesized endogenously from L-cysteine by two pyridoxal-5'-phosphate-dependent enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). S-propargyl-cysteine (SPRC) is a slow H(2)S releasing drug that provides cysteine, a substrate of CSE. The present study was aimed to investigate the effects of SPRC in an in vivo model of acute pancreatitis (AP) in mice. AP was induced in mice by hourly caerulein injections (50 μg/kg) for 10 hours. Mice were treated with SPRC (10 mg/kg) or vehicle (distilled water). SPRC was administered either 12 h before or 3 h before the induction of pancreatitis. Mice were sacrificed 1 h after the last caerulein injection. Blood, pancreas and lung tissues were collected and processed to measure the plasma amylase, plasma H(2)S, myeloperoxidase (MPO) activities and cytokine levels in pancreas and lung. The results revealed that significant reduction of inflammation, both in pancreas and lung was associated with SPRC given 3 h prior to the induction of AP. Furthermore, the beneficial effects of SPRC were associated with reduction of pancreatic and pulmonary pro-inflammatory cytokines and increase of anti-inflammatory cytokine. SPRC administered 12 h before AP induction did not cause significant improvement in pancreatic and lung inflammation. Plasma H(2)S concentration showed significant difference in H(2)S levels between control, vehicle and SPRC (administered 3 h before AP) treatment groups. In conclusion, these data provide evidence for protective effects of SPRC in AP possibly by virtue of its slow release of endogenous H(2)S.     

Pancreatic damage and regeneration in the course of ischemia-reperfusion induced pancreatitis in rats.

The objective of this study was to assess the biochemical and histological signs of pancreatic damage development and pancreatic recovery in the course of ischemia-reperfusion induced pancreatitis. Acute pancreatitis was induced in rats by limitation of pancreatic blood flow (PBF) in inferior splenic artery for 30 min using microvascular clips, followed by reperfusion. Rats were sacrificed at the time: 1 h, 12 h, 24 h, and 2, 3, 5, 7, 10, 14, 21 and 28 days after ischemia. PBF was measured using laser Doppler flowmeter. Plasma amylase, interleukin 1beta (IL-1beta) and interleukin 10 (IL-10) concentration, pancreatic DNA synthesis, as well as, morphological features of pancreatic damage were examined. Ischemia with reperfusion caused acute necrotizing pancreatitis followed by pancreatic regeneration. After removal of microvascular clips, PBF was reduced and the maximal fall of PBF was observed 24 h after ischemia, then PBF grew reaching the control value at 28th day. Plasma amylase activity was increased between 12th h and 3rd day with maximum at 24 h after ischemia. Also plasma IL-1beta and IL-10 were elevated with maximal value at the first and second day after ischemia, respectively. DNA synthesis was maximally reduced at the first day (by 70%) and from second day the reversion of this tendency was observed with full restoration of pancreatic DNA synthesis within four weeks. Morphological features of pancreatic tissue showed necrosis, strongly pronounced edema and leukocyte infiltration. Maximal intensity of morphological signs of pancreatic damage was observed between first and second day of reperfusion. During pancreatic regeneration between second and tenth day after ischemia the temporary appearance of chronic pancreatitis-like features such as fibrosis, acinar cell loss, formation of tubular complexes and dilatation of ducts was observed. The regeneration was completed within four weeks after pancreatitis development. We conclude that partial and temporary pancreatic ischemia followed by reperfusion causes acute necrotizing pancreatitis with subsequent regeneration within four weeks. Pancreatic repair after necrotizing pancreatitis is connected with the increase in plasma IL-10 concentration and transitory formation of tubular complexes.     

Effect of injection of adult mouse peritoneal macrophages on suppressor cell activity in neonatal mice

Injection of adult mouse peritoneal exudate cells into newborn mice results in a premature decrease of splenic suppressor cell activity in the neonates. The effect becomes apparent 4–5 days after ip injection of 10–15 × 10⁶ thioglycollate-induced peritoneal exudate cells into mice on the day of birth. The macrophage in the peritoneal exudate is the responsible cell type. The effect is not H-2 restricted or strain limited. Heat-killed peritoneal exudate cells or peritoneal cells from unstimulated donors can also decrease neonatal suppressor cell activity prematurely. Adult spleen cells, injected into neonatal mice, do not affect suppressor cell activity. The data are discussed in light of the hypothesis that macrophages control suppressor activity in neonatal mice and that an increase in the number and/or function of macrophages shortly after birth results in a decrease in the number and/or function of suppressor cells, allowing for immunological competence to emerge.     

Inhibitors of sterol synthesis. Metabolism of [2,4-3H]5 alpha-cholest-8(14-)-en-3 beta-ol-15-one after intravenous administration to a nonhuman primate

The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol synthesis with marked hypocholesterolemic activity, has been studied after the intravenous administration of a mixture of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one and [4-14C] cholesterol to a baboon. The levels of 3H in plasma which was associated with the free 15-ketosterol decreased very rapidly (T1/2 approximately 9 min) after injection of the labeled sterol. By 4 h, the level of the [3H]15-ketosterol in plasma was negligible. The rapid decrease in the levels of the free 15-ketosterol was associated with rapid formation of fatty acid esters of the 15-ketosterol. The maximum level of 3H-labeled 15-ketosteryl esters was observed at 20 min after the injection of the 15-ketosterol. Thereafter, the levels of the 15-ketosteryl esters decreased rapidly with an apparent T1/2 of approximately 3.5-4.0 h. The results also indicated rapid formation of 3H-labeled cholesterol and cholesteryl esters. Substantial formation of [3H]cholesterol was observed at 20 min after the injection of the 15-ketosterol and reached a maximum level in plasma at 2 h. The maximum levels of [3H]cholesteryl esters in plasma were observed much later. These and other findings indicated that the observed slow clearance of total 3H from plasma is a consequence of metabolism of the 15-ketosterol to cholesterol and cholesteryl esters, normal constituents of plasma whose turnover in the whole animal is known to be relatively slow.