Long-term function of teleost fish principal islets (Brockmann bodies) after transplantation under the renal capsule in diabetic nude mice.
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Animals↗
Biomedical subjects
J R Wright
Publications and source records attributed to J R Wright.
The anti-diabetogenic effect of essential fatty acid deficiency in multiple low-dose streptozotocin-treated mice persists if essential fatty acid repletion occurs outside of a brief window of susceptibility.
We have previously shown that essential fatty acid deficiency prevents diabetes mellitus and ameliorates insulitis in multiple low-dose streptozotocin-treated male CD-1 mice and that repletion with 99% pure methyl linoleate 3 days after the last injection causes diabetes. In the present study, we examined whether repletion of low-dose streptozotocin-treated deficient mice will cause diabetes whenever repletion occurs. Essential fatty acid deficiency was induced by dietary manipulation and was confirmed biochemically. Groups of deficient mice were repleted 6 h, 1 week, 2 weeks, 4 weeks and 8 weeks after the last low-dose streptozotocin treatment; the incidence of diabetes (i.e., non-fasting plasma glucose levels greater than 11.2 mmol/l) and group mean plasma glucose levels were 93% (19.4 mmol/l), 37% (14.8 mmol/l), 40% (13.7 mmol/l), 20% (9.0 mmol/l), and 8% (7.8 mmol/l) respectively. The incidence and mean glucose levels for low-dose streptozotocin-induced control chow-fed and non-repleted essential fatty acid deficient CD-1 mice were 100% (30.2 mmol/l) and 0% (4.2 mmol/l). The incidence and severity of insulitis also decreased with increasing repletion intervals. These results demonstrate a brief window of susceptibility of less than 8 weeks duration during which repletion will initiate an autoimmune response directed at low-dose streptozotocin-induced Beta-cell neoantigens in low-dose streptozotocin-treated essential fatty acid deficient mice.
Animals↗
Regulation of pulmonary surfactant secretion and clearance.
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Animals↗
Donor essential fatty acid deficiency does not prolong heterotopic cardiac allograft survival in rats.
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Animals↗
Clearance and recycling of pulmonary surfactant.
In a steady state the rate of secretion of pulmonary surfactant lipids and proteins into the alveolar airspace must be balanced by the rate of removal. Several potential pathways for clearance have been identified including uptake by alveolar type II cells, which also synthesize and secrete surfactant components, uptake by other epithelial cells, and internalization by alveolar macrophages. A small amount of surfactant moves up the airways and through the epithelium-endothelium barrier into the blood. Some of the surfactant lipids and proteins that are cleared from the alveolar airspace appear to be "recycled" in that they appear in the lamellar body, a surfactant secretory granule found in the type II cell. Some surfactant lipids are degraded, probably intracellularly, and the degradation products are reutilized to synthesize new lipids. Several factors have been shown to affect internalization by the type II cell and/or alveolar clearance including the surfactant proteins, lipids, and known stimuli of surfactant secretion. Surfactant proteins may be involved in regulating pool size by modulating both secretion rates and uptake rates, possibly by a receptor-mediated process, although such receptors have not yet been identified or isolated. Clearance of surfactant lipids from the alveolar airspace is more rapid than clearance from the whole lung, and these two processes may be regulated by different factors. Elucidation of the factors that fine tune the balance between synthesis, secretion, and clearance of the lipid and protein components of surfactant awaits further investigation.
Animals↗
Diazoluminomelanin: a synthetic luminescent biopolymer.
The purpose of this work was to synthesize a water-soluble derivative of 5-amino-2, 3-dihydro-1, 4-phthalazinedione (luminol) that generated sustained high level luminescence under physiologic conditions without the necessity of a catalyst. The derivative was made by a diazotization reaction with luminol and 3-amino-L-tyrosine. The resulting orange-brown anionic polymer has been given the trivial name of diazoluminomelanin (DALM). It was water soluble above and insoluble at or below pH 5.0. DALM luminesced when treated with hydrogen peroxide without the presence of a catalyst at pHs ranging from 6.5 to 12.0. Microgram quantities produced high levels of chemiluminescence for longer than 52 hr. Dried polymer generated a long-term stable electron spin resonance spectrum. The long-term chemiluminescence of DALM at pH 6.8-7.4 makes it a potentially useful reagent for detecting free radicals and peroxides in cellular and biochemical preparations.
Chemical Phenomena↗
Synthesis and possible applications of biotin-linked copper clusters.
The trifunctional aziridine XAMA-7 (CAS 57116-45-7) has been used to form crosslinks between a deep red-violet copper cluster of the type Cu(I)8Cu(II)6pen12Cl5- (pen=penicillamine) and molecules with biological activity such as d-biotin and proteins. A complex containing biotin, bovine serum albumin and the copper cluster displayed activity toward affinity columns of avidin on Agarose, and the red-violet pigment was immobilized on the gel. This interaction was completely blocked in gels which had been pretreated with d-biotin carboxylic acid. The free and biologically active versions of the cluster have some potential for biomedical applications. For example, the short-lived positron emitter 64Cu (suitable for positron tomography) may be carried in the cluster's structure. The cluster is paramagnetic, but it is a relatively weak effector of water proton spin-lattice relaxation. Other members of this structural group of inorganic compounds may have better magnetic properties, and the crosslinking reaction with aziridines appears to be generally applicable to the group.
Aziridines↗
Serum lipids and lipoproteins in continuous or cyclic medroxyprogesterone acetate treatment in postmenopausal women treated with conjugated estrogens.
This study evaluates effects on serum lipids of continuous or sequential progestogens for hormonal replacement in women. Subjects received either a cyclic regimen of replacement (0.625 mg/d of conjugated equine estrogens (Es) for 25 days/month and 10 mg medroxyprogesterone acetate [MPA] for the last 13 days of E) or 0.625 mg/d E along with either 5 or 10 mg MPA (Provera, Upjohn Company, Kalamazoo, MI). Study parameters were measured over a 24-week period. No differences in total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins I and II, sex hormone-binding globulin, or serum MPA levels were noted between the sequential and 5 mg continuous group. The 10 mg MPA group did not have an increase in HDL or decrease in low-density lipoprotein as did the other groups.
Adult↗
Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis.
C1q, a subunit of the first component (C1) of the classical complement pathway, and the pulmonary surfactant protein SP-A are structurally homologous molecules, each having an extended collagen-like domain contiguous with a non-collagenous domain. It is the collagen-like region of C1q that binds to mononuclear phagocytes and mediates the enhancement of phagocytosis of opsonized particles by these cells. Because SP-A enhances the endocytosis of phospholipids by alveolar type II cells and alveolar macrophages, we examined whether these two molecules were functionally interchangeable. The phagocytosis of sheep erythrocytes opsonized with IgG or with IgM and complement was enhanced by the adherence of monocytes or macrophages, respectively, to SP-A. The enhanced response was dependent on the concentration of SP-A used for coating the surfaces, similar to that seen when monocytes were adhered to C1q-coated surfaces. Both the percentage of cells ingesting the opsonized targets and the number of targets ingested per cell increased with increasing concentrations of SP-A. No such enhancement was seen with cells adhered to albumin, iron-saturated transferrin, or uncoated surfaces. However, SP-A did not substitute for C1q in the formation of hemolytically active C1. C1q did not stimulate lipid uptake by alveolar type II cells or alveolar macrophages and had only a slight inhibitory effect on the binding of SP-A to alveolar type II cells. Thus, these results suggested that a function which requires interactions of both the collagenous and the non-collagenous regions (i.e. initiation of the classic complement cascade) could not be mimicked by a protein sharing structural macromolecular similarity but lacking sequence homology in the non-collagen-like region. However, SP-A could substitute for C1q in stimulating a function previously shown to be mediated by the collagen-like domains of the C1q molecule.
Cells, Cultured↗
Sulfinpyrazone prolongs survival and decreases platelet uptake of heart allografts.
The purpose of this study was to evaluate the potential benefit of the platelet active drug sulfinpyrazone (SPZ) on uptake of indium-III-oxine (111In)-labeled platelets and survival of rat heart allografts. Lewis rats bearing ACI heterotopic heart transplants were treated with SPZ in high, intermediate, or low doses. In 111-labeled platelet uptake was measured 5 days postoperatively and calculated as a ratio between the transplanted and native hearts. Left and right ventricles were measured separately. SPZ given in doses of 400 and 200 mg/kg daily significantly decreased platelet uptake in the graft and reduced the ratio of uptake between transplanted and native hearts (P less than 0.05). In animals treated with SPZ 100 mg/kg/day platelet uptake was not significantly less than that of the nontreated control animals. Survival of allografts was determined by daily palpation and compared to vehicle-treated controls. Mean graft survival was prolonged for animals treated with 100 mg/kg and 200 mg/kg daily, i.e., 19.0 +/- 3.02 and 11.42 +/- 1.97 days, respectively. Animals administered 400 mg/kg did not have longer graft survival than controls (6.63 +/- 0.66 versus 6.31 +/- 0.18 days). Most animals in the 400 mg/kg group died as a result of adverse side effects of the drug. We conclude that SPZ in low to intermediate doses prolongs allografted heart survival. The enhanced survival in the lower dose group may in part be due to mechanisms other than platelet adhesiveness.
Animals↗
Uptake of perfusion imaging agents by transplanted hearts: an experimental study in rats.
There is a need for a reliable noninvasive marker of rejection in transplanted hearts. Endomyocardial biopsy is now the universally accepted diagnostic method of choice, but the invasiveness of the procedure and the limited size of the sample obtained makes this method far from ideal. As coronary blood flow may be expected to decrease during acute rejection, there has been interest in thallium-201 chloride (T1), a perfusion marker, as an imaging agent for diagnosing cardiac rejection. Hexakis(t-butylisonitrile)-technetium (Tc-TBI) is a representative of a new class of radiopharmaceuticals proposed as perfusion markers. We have compared the uptake of these imaging agents in a rat model of cardiac transplantation. Uptake of Tc-TBI as well as of T1 was significantly lower in rejecting than in nonrejecting hearts. This change was found in both left (LV) and right (RV) ventricles. Allografts in animals treated with cyclosporine (CyA) showed less severe rejection and higher uptakes of both imaging agents as compared to unmodified rejection. Our results suggest that perfusion imaging with these radionuclides is a potentially useful approach to the problem of detecting allograft rejection.
Animals↗
Lung surfactant apoprotein SP-A (26-36 kDa) binds with high affinity to isolated alveolar type II cells.
Pulmonary surfactant is synthesized and secreted by alveolar type II cells. These cells recycle surfactant lipids by an internalization process that is enhanced in vitro by the surfactant proteins with molecular masses of 26-36 kDa (SP-A). SP-A also inhibits the secretion of lipid by type II cells. These results suggest that SP-A may play a role in feedback regulation of surfactant pool size and are consistent with the hypothesis that the type II cell surface has receptors for SP-A. The goal of this study is to characterize the binding of radioiodinated SP-A to isolated rat type II cells. Binding of SP-A to type II cells at 4 degrees C has a K1/2 of approximately 5 X 10(-10) M, is saturable, and is inhibited by excess unlabeled SP-A. Binding is dependent on calcium and is reduced by heat treatment of SP-A. The binding of a proteolytic fragment of SP-A that is produced by collagenase treatment is reduced by excess unlabeled SP-A. The binding of the fragment to macrophages and lung fibroblasts is not inhibited by excess unlabeled SP-A. Trypsinization of the type II cell surface reduces the binding of both intact SP-A and the collagenase-resistant fragment. These results show that SP-A binds to type II cells with high affinity and suggest that these cells have receptors that recognize the carboxyl-terminal domain of SP-A.
Animals↗
Cellular uptake and processing of surfactant lipids and apoprotein SP-A by rat lung.
The intracellular pathways and the kinetics of metabolism of surfactant apoprotein and lipid, which may be recycled from the alveolar space, are largely unknown. We used a lipid-apoprotein complex made from liposomes of pure lipids in a ratio found in mammalian pulmonary surfactant plus surfactant apoprotein (SP-A, Mr = 26,000-36,000) to test some possible relationships in the recycling of these major surfactant components between intrapulmonary compartments. After intratracheal instillation of 80 microliters of an apoprotein-liposome mixture with separate radiolabels in the lipid and the apoprotein, rats were killed at times from 8 min to 4 h later. The lungs were lavaged with saline, and subcellular fractions were isolated on discontinuous sucrose density gradients. Both the [14C]lipid radiolabel and the 125I-apoprotein radiolabel demonstrated a time-dependent increase in radioactivity recovered in a lamellar body-enriched fraction. Uptake of the radiolabels into other subcellular fractions did not exhibit a clear-cut time dependence; more of the protein than the lipid radiolabel was found in the Golgi-rich and microsomal fractions. We conclude that both the lipid and apoprotein portions of lung surfactant are taken up by lung cells and are incorporated into secretory granules of the cells.
1,2-Dipalmitoylphosphatidylcholine↗
Surfactant secretion and clearance in the newborn.
Pregnant rabbits (30 days) were injected intravenously with [3H]choline 8 h before delivery. The fetuses were delivered, and lung lavage and lamellar body phospholipids (PL) were analyzed. Some newborns also received radioactively labeled surfactant intratracheally on delivery and were permitted to breathe. With time, intratracheal label decreased in lavage and appeared in the lamellar body fraction, and intravenous label accumulated in both pools. Using a tracer analysis for non-steady state, we calculated surfactant secretion and clearance rates for the newborn period. Before birth, both rates rose slightly from 1.8 micrograms PL.g body wt-1.h-1 at 6 h before birth to 7.3 at birth. Immediately after birth, secretion rate rose to 37.7 micrograms PL.g body wt-1.h-1. Between 1.5 and 2 h after birth it fell to a minimum of 1.8 micrograms PL.g body wt-1.h-1 and then rose slowly to 6.0 at 12 h. After birth, clearance rate increased less than secretion rate (maximum 24.7 micrograms PL.g body wt-1.h-1 shortly after birth) then followed the same pattern but did not balance secretion rate in the 1st day.
Animals↗
Oxygen free-radical scavengers and immune destruction of murine islets in allograft rejection and multiple low-dose streptozocin-induced insulitis.
We examined the effects of desferrioxamine (DFX), a potent inhibitor of the formation of oxygen-derived hydroxyl radicals, and nicotinamide (NIC), a poly(ADP-ribose) synthetase inhibitor and a weak free-radical scavenger, on two models of immune destruction of murine islets [i.e., allograft rejection and multiple low-dose streptozocin (STZ)-induced insulitis]. Freshly isolated or low-temperature-cultured BALB/cJ islets were transplanted beneath the kidney capsules of C57BL/6J recipients. The recipients were treated with NIC alone (500 mg.kg-1.day-1), DFX alone (4.2 mg/day x 14 days), or NIC + DFX. Only recipients treated with NIC + DFX, receiving cultured islets, showed a mean graft survival time significantly longer than control mice receiving freshly isolated or cultured islets. Control CD-1 mice treated with multiple low doses of STZ developed insulitis and diabetes. Treatment with NIC alone, DFX alone, or NIC + DFX decreased the severity of hyperglycemia relative to the controls. Treatment with DFX alone was more effective than NIC alone or NIC + DFX. Only the group treated with DFX alone had a lower incidence of diabetes (mean plasma glucose level greater than 200 mg/dl) than the controls after 4 wk. Histologically, islets from control mice showed severe insulitis, islet destruction, and absence of stainable insulin, whereas islets from DFX-treated mice showed only mild peri-insulitis and a relative preservation of beta-cell granulation. Our study showed that NIC and DFX partially protect islets from immune destruction in allograft rejection and in low-dose STZ-induced insulitis. Apparently, hydroxyl radicals play important roles in both of these models.
Animals↗
Induction of Ia antigen expression on murine islet parenchymal cells does not diminish islet allograft survival.
Aberrant Ia antigen expression has been implicated in the pathogenesis of type 1 diabetes. Ia antigen expression was induced on isolated B10.BR murine islet parenchymal cells by culturing them for 5 days with lymphokine supernatants containing interferon-gamma (IFN-gamma) or with recombinant murine IFN-gamma + recombinant tumor necrosis factor. Ia positivity was confirmed by indirect immunofluorescence. Islets cultured for 5 days without cytokines were Ia-negative. Purified B10.BR islets allografted into the portal veins of C57BL/6J mice do not reject, which allowed the authors to determine whether aberrant expression of Ia on parenchymal cells has a deleterious effect on allograft survival. Ia-positive or Ia-negative islets were transplanted via the portal vein into diabetic C57BL/6J mice. All mice remained normoglycemic until they were killed at 30 to 60 days. Well-granulated islet allografts were identified histologically in all mice. The experiment was repeated using Balb/cJ mice as donors. Purified Balb/cJ islets are rapidly rejected by C57BL/6J mice. Induction of Ia expression on Balb/cJ islets significantly improved allograft survival. These findings indicate that Ia-positive islet cells do not induce rejection in these allograft models but may actually have a protective effect.
Animals↗
Silica prevents the induction of diabetes with complete Freund's adjuvant and low-dose streptozotocin in rats.
Three weekly intraperitoneal injections of complete Freund's adjuvant (CFA) and, one day later, 25 mg/kg of STZ have been reported to cause a gradual onset of autoimmune diabetes. We have previously reported that the onset of diabetes in this model occurs too rapidly to be due to a specific immune reaction and that other compounds that activate macrophages also potentiate low-dose STZ in rats. We have proposed that mediators released from activated macrophages may enhance the cytotoxic effect of STZ. In the present study, we have observed that intraperitoneal injections of silica, a macrophage toxin, markedly decrease the incidence and severity of diabetes induced with CFA and low-dose STZ.
Animals↗
Pulmonary surfactant metabolism.
Recent work suggests that surfactant undergoes a complex sequence of metabolic events during its life cycle in the alveolar airspace. The composition, turnover, and metabolism of surfactant, and the possible "control points" in its metabolic pathway that might be compromised in disease states are discussed.
Humans↗