Granulocyte colony-stimulating factor crosses the placenta and stimulates fetal rat granulopoiesis

We studied the effect of recombinant human granulocyte colony- stimulating factor (rhG-CSF) administration to pregnant rats upon fetal and neonatal myelopoiesis. Pregnant rats were treated with rhG-CSF twice daily for 2, 4, and 6 days before parturition. rhG-CSF crossed the placenta and reached peak fetal serum concentrations 4 hours after administration. Peak fetal serum levels were 1,000-fold lower than levels detected in the dam. Hematopoietic effects of rhG-CSF were assessed by cytologic analysis of the newborn blood, spleen, bone marrow, thymus, and liver. White blood cell counts were increased twofold to fourfold in newborns. This increase was due to circulating numbers of polymorphonuclear cells (PMN). rhG-CSF induced a myeloid hyperplasia in the newborn marrow consisting of immature and mature myeloid cells in the day-2 and day-4 treated pups. Bone marrow of pups treated for 6 days contained mostly hyper-segmented PMN with little or no increase in myeloid precursors. An increase in the number of postmitotic (PMN, bands, and metamyelocytes) and mitotic (promyeloblasts, myeloblasts, and metamyeloblasts) myeloid cells in the spleen of neonates was observed. No change was detected in splenic lymphocytes or monocytes. No effect of rhG-CSF was noted in the newborn liver or thymus. These results demonstrate that maternally administered rhG-CSF crosses the placenta and specifically induces bone marrow and spleen myelopoiesis in the fetus and neonate. The significant myelopoietic effects of rhG-CSF at low concentrations in the fetus suggest an exquisite degree of developmental sensitivity to this cytokine and may provide enhanced defense mechanisms to the neonate.     

Apolipoprotein C-II deficiency syndrome. Clinical features, lipoprotein characterization, lipase activity, and correction of hypertriglyceridemia after apolipoprotein C-II administration in two affected patients.

Two patients (brother and sister, 41 and 39 yr of age, respectively) have been shown to have marked elevation of plasma triglycerides and chylomicrons, decreased low density lipoproteins (LDL) and high density lipoproteins (HDL), a type I lipoprotein phenotype, and a deficiency of plasma apolipoprotein C-II (apo C-II). The male patient had a history of recurrent bouts of abdominal pain often accompanied by eruptive xanthomas. The female subject, identified by family screening, was asymptomatic. Hepatosplenomegaly was present in both subjects. Analytical and zonal ultracentrifugation revealed a marked increase in triglyceride-rich lipoproteins including chylomicrons and very low density lipoproteins, a reduction in LDL, and the presence of virtually only the HDL3 subfraction. LDL were heterogeneous with the major subfraction of a higher hydrated density than that observed in plasma lipoproteins of normal subjects. Apo C-II levels, quantitated by radioimmunoassay, were 0.13 mg/dl and 0.12 mg/dl, in the male and female proband, respectively. A variant of apo C-II (apo C-IIPadova) with lower apparent molecular weight and more acidic isoelectric point was identified in both probands by two-dimensional gel electrophoresis. The marked hypertriglyceridemia and elevation of triglyceride-rich lipoproteins were corrected by the infusion of normal plasma or the injection of a biologically active synthesized 44-79 amino acid residue peptide fragment of apo C-II. The reduction in plasma triglycerides after the injection of the synthetic apo C-II peptide persisted for 13-20 d. These results definitively established that the dyslipoproteinemia in this syndrome is due to a deficiency of normal apo C-II. A possible therapeutic role for replacement therapy of apo C-II by synthetic or recombinant apo C-II in those patients with severe hypertriglyceridemia and recurrent pancreatitis may be possible in the future.     

Chylomicron-retinyl palmitate clearance in type I hyperlipidemic families.

Our primary aim was to determine the extent to which intraplasmic retinyl palmitate (RP) transfers to other lipoprotein particles when chylomicron remnants are not produced and/or the plasma RP residence time is increased. The study was conducted on three familial type I hyperlipoproteinemic patients, four lipoprotein lipase (LpL)-deficient heterozygotes, and three controls on a metabolic research unit. To each subject, a fat load was administered containing 16% of total daily calories in type I patients, 40% in heterozygotes and controls, plus 60,000 U/m2 vitamin A. Triglyceride (TG) and RP levels were evaluated in chylomicron and nonchylomicron fractions. Delay in the clearance of chylomicron fraction RP and the marked deficiency in nonchylomicron-RP (presumed lack of remnant production) in all three type I patients suggests that RP does not demonstrate significant intraplasmic transfer from chylomicrons to existent apolipoprotein B100 particles. In contrast to noncoincident TG and RP peaking in the normal subject, heterozygotes were found to demonstrate coincident plasma TG and RP curves, which is consistent with a common catabolic pathway for both TG and RP and inconsistent with intraplasmic RP transfer. This corroborates reports on compromised chylomicron clearance in heterozygotes. We conclude that RP is an appropriate representative marker for intestinally derived particles in LpL-deficient or partially deficient individuals.