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Biomedical subjects

J M Lipton

Publications and source records attributed to J M Lipton.

At least 73 records · Page 4Linked to original sources
PubMed1994

The neuropeptide alpha-melanocyte-stimulating hormone inhibits experimental arthritis in rats.

alpha-Melanocyte-stimulating hormone (alpha-MSH) modulates inflammatory processes in models of acute inflammation and in models of sepsis/septic shock/adult respiratory-distress syndrome (ARDS). Because this neuropeptide inhibits actions of cytokines and other mediators of imflammation that are also believed to underlie aspects of chronic inflammation, tests were performed to compare the effects of repeated administration of the peptide with those of prednisolone and saline on the development of adjuvant arthritis in rats. alpha-MSH (50 micrograms), injected i.p. twice daily, markedly inhibited the clinical and histological signs of experimental arthritis and moderated the weight loss observed in control animals. Prednisolone (100 mg/kg), given twice per day, prevented development of arthritis but caused marked and progressive weight loss. The results confirm the potent anti-inflammatory influence of alpha-MSH, in this case in a model of chronic inflammation that has immune components.

Animals↗
PubMed1994

Plasma concentration of cytokine antagonists in patients with HIV infection.

There is increasing evidence that cytokines contribute to the immunopathogenesis of human immunodeficiency virus (HIV) infection. It may be, therefore, that compensatory rises in circulating cytokine antagonists also occur in HIV infection and that such changes mark disease progression. To test this idea, plasma concentrations of the cytokine antagonists alpha-melanocyte-stimulating hormone (alpha-MSH), interleukin-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor (sTNFr) were measured in patients of different Centers for Disease Control (CDC) categories of HIV infection and in seronegative controls. Plasma levels of all these cytokine antagonists were higher in HIV-infected patients. IL-1ra and sTNFr concentrations were correlated with indicators of disease activity: positively with plasma neopterin and negatively with CD4+ T lymphocyte counts. alpha-MSH and sTNF r were greater in CDC groups III and IV, whereas IL-1ra was elevated only in the latter group. Because cytokines activate the hypothalamic-pituitary-adrenal axis and adrenal steroids inhibit cytokine production, we measured circulating adrenocorticotropic hormone (ACTH) and cortisol in HIV-infected patients and investigated relations among these hormones, cytokine antagonists, and markers of disease progression. It appears that these physiological modulators of cytokine activity are not closely linked to sTNFr, IL-1ra and alpha-MSH: there were no significant correlations between plasma concentrations of ACTH or cortisol and those of cytokine antagonists, nor were there correlations between hormones and markers of disease progression such as neopterin or CD4+ T cell counts. It is notable that severe adrenal insufficiency was extremely rare (3%) in HIV-infected patients; it was confined to the AIDS group and was consistently secondary to ACTH deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1994

Central neurogenic antiinflammatory action of alpha-MSH: modulation of peripheral inflammation induced by cytokines and other mediators of inflammation.

The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) has potent antipyretic and antiinflammatory properties. When administered systemically, the naturally occurring molecule and its COOH-terminal tripeptide sequence inhibit inflammation induced by peripherally applied irritants and intradermal injections of mediators of inflammation such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha). We recently found that alpha-MSH can act solely within the brain to inhibit inflammation caused by a general irritant applied to the skin. This activity appears to be shared with salicylate drugs and the combined observations suggest the existence of descending neurogenic antiinflammatory signals capable of modulating inflammation in peripheral tissues. To improve our knowledge of the scope of this action of the peptide, alpha-MSH was injected into the cerebral ventricles (i.c.v.) of mice that had received intradermal injections in the ear of mediators of inflammation: IL-1 beta, IL-8, leukotriene B4, and platelet-activating factor. The centrally administered peptide inhibited the actions of all of these proinflammatory agents as determined from comparisons with measures of ear edema over time in control animals; this indicates that the central peptide can alter inflammation induced in the periphery by major mediators of inflammation. In tests confined to IL-1 beta, central administration of alpha-MSH(11-13) was also effective. These findings support the concept of a descending neurogenic antiinflammatory influence promoted by an action of alpha-MSH within the brain, an inhibitory influence that is not restricted to modulation of just one or a limited set of the mediators of inflammation.

Animals↗
PubMed1994

Antiinflammatory influences of alpha-MSH molecules: central neurogenic and peripheral actions.

alpha-Melanocyte-stimulating hormone (alpha-MSH1-13) and its COOH-terminal tripeptide alpha-MSH11-13 (Lys Pro Val) inhibit inflammation when administered systemically. Recent evidence indicates that alpha-MSH1-13 can likewise inhibit inflammation in the skin solely via an action within the brain. Because of the potential importance of this discovery to understanding the control of inflammation and because alpha-MSH molecules might be useful for treatment of inflammation, experiments were performed to learn more about the mechanisms of action of these peptides. In tests on inflammation induced in the mouse ear by intradermal injections of recombinant human interleukin-1 beta, alpha-MSH1-1-13 administered intracerebroventricularly effectively reduced inflammation. This effect of centrally administered alpha-MSH1-13 was inhibited by systemic injection of the nonspecific beta-adrenergic receptor blocker propranolol and by administration of a specific beta 2-adrenergic receptor antagonist; the effect was not altered by blockade of cholinergic, alpha-adrenergic, or beta 1-adrenergic receptors. In mice with inflammation induced in a hind paw and with the spinal cord transected, the antiinflammatory effect of centrally administered alpha-MSH1-13 was prevented, indicating that intact descending neuronal pathways are required for the antiinflammatory influence of the central peptide. Systemic injection of alpha-MSH1-13 in animals with spinal cord transection had a smaller and later antiinflammatory effect, which suggests that the molecule also has an action, albeit lesser, in the periphery. However, alpha-MSH11-13 injected intraperitoneally had marked antiinflammatory activity in animals with spinal cord transection.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Treatment of Diamond-Blackfan anemia with recombinant human interleukin-3.

This report describes the response of eighteen Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin-3 (rhIL-3). rhIL-3 was administered subcutaneously once daily on an escalating dose schedule (0.5 to 10 micrograms/kg/d). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximum rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion-independent, while two were steroid-independent and transfusion-dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. rhIL-3 administered at 5 to 10 micrograms/kg/d was associated with an increase in total white blood cell count, secondary to increases in neutrophils, eosinophils, and lymphocytes. Patients experienced a dose-dependent elevation in absolute eosinophils across the entire dose range. Two of the responding patients remain on maintenance rhIL-3, without diminution of effect at 244 and 370 + days. rhIL-3 was discontinued in the other two responders, because of the development of deep venous thrombi.

Adolescent↗
PubMed1993

Successful treatment of Diamond-Blackfan anemia with interleukin 3.

This report describes the response of 18 Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin 3 (rhIL-3). rhIL-3 was administered s.c. once daily on an escalating dose schedule (0.5-10 micrograms/kg/day). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximal rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion-independent, while two were steroid-independent and transfusion-dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. Two of the responding patients remain on maintenance rhIL-3 without diminution of effect at 490 and 855+ days. rhIL-3 was discontinued in the other two responders because of the development of deep venous thrombi.

Animals↗
PubMed1993

Proopiomelanocortin-derived peptides and cytokines: relations in patients with acquired immunodeficiency syndrome.

alpha-Melanocyte-stimulating hormone (alpha-MSH), adrenocorticotrophic hormone (ACTH), beta-endorphin, cortisol, and the cytokines interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF alpha) were measured in 80 AIDS patients (group IV CDC) and in healthy hospital personnel. The average plasma alpha-MSH was significantly greater in AIDS patients than in control subjects; no significant differences between groups were observed in the average concentrations of ACTH, cortisol, and beta-endorphin; plasma cytokines were likewise similar in the two groups. Plasma concentrations of alpha-MSH and ACTH were inversely related in AIDS patients and a similar inverse relation between alpha-MSH and IL-6 was also observed in these patients. There were positive relations among elevated circulating ACTH, cortisol, IL-6, and high fever in AIDS patients with severe concomitant disease. Plasma alpha-MSH concentrations within a specific range correlated positively with 6 month survival. Because cytokines can stimulate HIV expression in certain cell types and they are believed to have a role in disease progression in HIV-infected patients, it may be that a potent endogenous modulator of cytokine action such as alpha-MSH is crucial to survival in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Inhibition of IL-1 beta-induced peripheral inflammation by peripheral and central administration of analogs of the neuropeptide alpha-MSH.

Interleukin-1 (IL-1) is a proinflammatory cytokine, alpha-MSH(1-13) molecules inhibit inflammation induced by cytokines, other mediators of inflammation, and by peripheral irritants. D-valine substitution in the antiinflammatory/antipyretic message sequence [alpha-MSH(11-13), Lys-Pro-Val] of alpha-MSH(1-13) increases the activity of the tripeptide. Our aim was to learn if D-valine substitution also enhances the antiinflammatory activity of the entire alpha-MSH(1-13) molecule and to determine if an antipyretic D-valine-substituted alpha-MSH(8-13) molecule is also antiinflammatory. Intraperitoneal injection of alpha-MSH(1-13) and of (D-Val13)alpha-MSH(1-13) caused dose-related suppression of ear edema induced in mice by intradermal injection of IL-1 beta; the two molecules were equipotent. (D-Val13)alpha-MSH(8-13) likewise inhibited inflammation, but the potency was less than that of the larger molecules. Intracerebroventricular injections of (D-Val13)alpha-MSH(1-13) and of the unsubstituted molecule were equipotent in reducing inflammation; the (D-Val13)alpha-MSH(8-13) molecule was less effective. The results support the idea that the alpha-MSH(1-13) molecule inhibits inflammation and suggest that the L-conformation of alpha-MSH(1-13) is maximally effective with regard to its antiinflammatory activity. The results with alpha-MSH(8-13) are consistent with previous findings of lesser antihost response activity of alpha-MSH fragments that contain the COOH-terminal tripeptide Lys-Pro-Val.

Animals↗
PubMed1993

Perioperative measurements of interleukin-6 and alpha-melanocyte-stimulating hormone in cardiac transplant patients.

Interleukin-6 (IL-6) and alpha-melanocyte-stimulating hormone (alpha MSH) are important modulators of the immunologic response to tissue injury and antigenic challenge. Serial changes in the plasma concentrations of these two peptides were measured in 12 patients undergoing heart transplantation. Tissue concentrations of IL-6 in atrial samples from both donor and recipient hearts were also compared. Plasma IL-6 concentration remained stable prior to cardiopulmonary bypass (CPB), initially decreased with the onset of CPB, and then increased significantly over control values at the end of CPB (180 +/- 40 v 53 +/- 60 pg/mL). Plasma IL-6 remained elevated for at least 60 minutes after CPB, and then it returned to control values by 24 hours postoperatively (67 +/- 9 pg/mL). Examination of IL-6 changes after CPB in 10 additional patients undergoing nontransplant cardiac surgery with CPB revealed a similar elevation in IL-6 at 60 minutes after CPB (290 +/- 76 pg/mL). However, IL-6 in the nontransplant group remained significantly elevated at 24 hours (138 +/- 42 pg/mL). These combined results suggest that CPB causes a marked increase in IL-6, and that implantation of a new heart in transplant patients does not augment this increase. The return of IL-6 to control values by 24 hours in the patients who have had transplants suggests that immunosuppression has an appreciable effect on IL-6 at this time. In contrast to IL-6, plasma alpha MSH never increased above control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Lack of effect of corticosteroids in W/Wv and S1/S1d mice: these strains are not a model for steroid-responsive Diamond-Blackfan anemia.

W/Wv and S1/S1d mice with macrocytic anemias are a potential model for human inherited pure red cell anemia, called Diamond-Blackfan anemia (DBA). The W mutation involves the gene for c-kit, and the S1 mutation the gene for the kit ligand, called mast cell growth factor, steel factor, or stem cell factor. Since many children with DBA respond to treatment with corticosteroids, we administered steroids to these genetically anemic mice, to determine whether they might provide a model for the human disease. There was no improvement in the murine anemia, consistent with other evidence suggesting that mutations in kit or steel may not be involved in Diamond-Blackfan anemia.

Adrenal Cortex Hormones↗
PubMed1992

Alpha-MSH peptides inhibit acute inflammation induced in mice by rIL-1 beta, rIL-6, rTNF-alpha and endogenous pyrogen but not that caused by LTB4, PAF and rIL-8.

The neuropeptide alpha-melanocyte stimulating hormone [alpha-MSH(1-13)] occurs in the pituitary, brain, skin and other tissues and receptors for this molecule are likewise widespread. In previous research, this tridecapeptide, which shares its amino acid sequence with ACTH(1-13), was shown to have both potent antipyretic activity and a role in the endogenous control of the febrile response. alpha-MSH(1-13) and its COOH-terminal tripeptide were subsequently found to inhibit inflammation induced by general stimuli such as topical application of an irritant. The aim in the present experiments was to determine if these peptides can inhibit acute inflammatory responses induced in mice by injection of individual cytokines, endogenous pyrogen (EP), a natural cytokine mixture, and other mediators of inflammation. Inflammation induced in the mouse ear by rIL-1 beta, rIL-6 or rTNF-alpha was inhibited by alpha-MSH and a D-valine-substituted analog of alpha-MSH(11-13) whereas substantial doses of alpha-MSH(1-13) did not alter inflammation induced by LTB4, PAF and IL-8. Both peptides inhibited edema caused in the mouse paw by local injection of EP. The results indicate that alpha-MSH molecules antagonize the actions of certain cytokine mediators of inflammation, consistent with previous observations of anti-cytokine activity of these peptides. Failure to inhibit edema caused by LTB4, PAF and IL-8 suggests that, in inflammation induced by general stimuli, such as EP, the peptides act prior to the release of these mediators of the inflammatory response. Because of the anticytokine/anti-inflammatory actions of the alpha-MSH molecules they may be useful in understanding the cytokine network and for treatment of inflammatory diseases.

Animals↗
PubMed1992

Changes in plasma atrial natriuretic peptide concentration during heart transplantation.

Examination of changes in plasma atrial natriuretic peptide (ANP) concentrations during heart transplantation may provide important information about factors influencing plasma ANP in patients with severe heart failure. Serial changes in plasma ANP during heart transplantation, and atrial content of ANP in native and donor atria, were measured in 12 patients. Preoperative plasma ANP was elevated in all patients (387 +/- 77 pg/mL), whereas atrial content of ANP in native atria was reduced (0.36 +/- 0.082 micrograms/mg protein). Preoperative plasma ANP did not correlate with hemodynamics, but was negatively correlated with creatinine clearance (r = -0.76, P < .01). Intraoperative plasma ANP prior to transplantation was strongly correlated with intraoperative plasma ANP after transplantation (r = 0.84, P < .001). Although postoperative plasma ANP was reduced from preoperative plasma ANP by 75%, these two measurements were also significantly correlated (r = 0.70, P < .02). Postoperative plasma ANP was not correlated with hemodynamics, but was negatively correlated with both creatinine clearance (r = -0.65, P < .05) and content of ANP in the native atria (r = -0.75, P < .01). Multiple linear regression analysis suggested that up to 85% of the variability of early postoperative plasma ANP could be accounted for by the variability in these latter two parameters. The decrease in native atrial ANP content, in the context of elevated plasma ANP concentration, is consistent with prior animal studies suggesting that severe heart failure induces cellular adaptations favoring accelerated ANP synthesis and secretion (with resultant reduction in tissue content).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Allogenic bone marrow transplantation in severe Gaucher disease.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.

Bone Marrow Transplantation↗