PubMed Health⌕ Search

Biomedical subjects

M Perretti

Publications and source records attributed to M Perretti.

At least 127 records · Page 7Linked to original sources
PubMed1992

Anti-inflammatory effect of tuftsin and its retro-inverso analogue in rat adjuvant arthritis.

Tuftsin, an immunostimulating tetrapeptide derived from immunoglobulin heavy chain, and its retro-inverso analogue have been tested in rat adjuvant arthritis. The secondary lesion of rats injected with Freund's adjuvant was significantly inhibited by both the natural and retro-inverso tuftsin administered orally. The retro-inverso analogue was at least tenfold more potent than the parent molecule, suggesting an increased stability to degradation, because of its molecular modification. The anti-inflammatory effect of tuftsin may be due to its ability to modulate macrophage function.

Animals↗
PubMed1992

Reduction of aspirin-induced gastric damage in rats by interleukin-1 beta: possible involvement of endogenous corticosteroids.

Administration of interleukin-1 (IL-1; 0.01-3 microgram/kg) by either i.p. or intragastric routes to rats reduced aspirin-induced gastric damage. These effects of IL-1 were not subject to desensitization by its pretreatment and were obtained without modification of the acute anti-inflammatory efficacy of aspirin. Gastroprotection could be effected without major modification of gastric tissue to form prostaglandins I2 or E2. A dose-related decrease of the acidic gastric fluid secretion induced by aspirin was observed with i.p. administered IL-1 was found to reduce gastric fluid volume only at the highest dose tested, although this was not associated with increased gastroprotection. By using adrenalectomized rats the gastric damage induced by aspirin was increased approximately 3-fold. IL-1 treatment, albeit with higher dosage, again reduced lesion formation. Treatment of adrenalectomized rats with dexamethasone and IL-1 synergistically reduced the gastric damage caused by aspirin. In normal rats these treatments caused only an additive reduction of lesion formation although the presence of endogenous glucocorticoid in these animals may mask any effects of the exogenously administered dexamethasone. The glucocorticoid-receptor antagonist, RU 38486, also potentiated aspirin-induced gastric damage and reduced the gastroprotective efficacy of IL-1 without modifying its effect on gastric fluid volume. The data indicate that gastroprotective actions of IL-1 are unlikely to be related upon effects on prostaglandin synthesis or gastric secretion. Endogenous glucocorticoids appear to have a modulatory role in controlling the severity of gastric damage evoked by aspirin and may potentiate the protective actions of IL-1.

Adrenalectomy↗
PubMed1991

Alpha-melanocyte-stimulating hormone reduces interleukin-1 beta effects on rat stomach preparations possibly through interference with a type I receptor.

Contractions elicited by CaCl2 on isolated rat stomach strip preparations have been reported to be potentiated by interleukin-1 beta (IL-1 beta). We have investigated whether this effect can be reduced by the putative IL-1 beta antagonist, alpha-melanocyte-stimulating hormone (alpha MSH). Additionally, the effects of alpha MSH on the specific binding of IL-1 beta to B- and T-cells have been investigated to further clarify its inhibitory activities. Both alpha MSH and its carboxyl terminal tripeptide concentration dependently reduced the potentiation of CaCl2-induced contractions caused by IL-1 beta but not those caused by leukotriene D4, the parent molecule being approximately 250 times more active. Additionally, both peptides potently and selectively reduced 125I-IL-1 beta binding to the T-cell sub-clone EL4-6.1 but not to the B-cell sub-clone 1H7. The results indicate that IL-1 beta effects on rat stomach may be mediated through a type-I (80 kDa) IL-1 beta receptor.

Animals↗
PubMed1991

5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation.

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2H)pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a, which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)-induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a-m and the other pyridazinones 5-9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a, tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E2 (PGE2) production and interleukin-1 activity. Structure-activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.

Amrinone↗
PubMed1991

Immunostimulation by a partially modified retro-inverso-tuftsin analogue containing Thr1 psi[NHCO](R,S)Lys2 modification.

The tuftsin retro-inverso analogue H-Thr psi[NHCO](R,S)Lys-Pro-Arg-OH was synthesized through a novel procedure for the high-yield incorporation of isolated retro-inverso bonds into peptide chains and the use of the new Meldrum's acid derivative (CH3)2C(OCO)2CH(CH2)4NHCOCF3 followed by its efficient coupling in solution to trimethylsilylated H-D-Thr(t-Bu)NH2. Closely related peptide impurities were eliminated both from the crude final peptide and the fully protected tetrapeptide amide precursor via ion-exchange and reversed-phase displacement chromatography, respectively. The tuftsin retro-inverso analogue proved to be completely resistant to enzymatic degradation in vitro, either against isolated aminopeptidases or human plasma proteolytic enzymes. When administered either orally or intravenously, it was significantly more active than normal tuftsin in increasing the number of specific antibody secreting cells in spleen of mice immunized with sheep erythrocytes. Furthermore, the analogue exerted an enhanced stimulatory effect on the cytotoxic activity of splenocytes against YAC-1 tumor cells. Finally, retro-inverso-tuftsin was about 10-fold more potent than the native peptide in reducing rat adjuvant arthritis. The resistance of the retro-inverso analogue to peptidases might explain the increased in vivo activities and allows its further immunopharmacological characterization.

Adjuvants, Immunologic↗
PubMed1991

A novel anti-inflammatory peptide from human lipocortin 5.

1. A novel anti-inflammatory peptide (residues 204-212) of human recombinant lipocortin 5 (hrLC5) found on the high similarity region with uteroglobin is described. 2. Peptide 204-212 dose-dependently inhibited the contractions of rat isolated stomach strips elicited by porcine pancreatic phospholipase A2 (PLA2). Contractions caused by arachidonic acid (AA), prostaglandin E2 (PGE2) and 5-hydroxytryptamine were not affected. No direct enzyme inhibition was observed in a radiochemical assay. 3. PGE2 release by both human fibroblasts and rat macrophages was reduced by peptide 204-212 in a dose-dependent manner. 4. The development of carrageenin-induced oedema in rats was significantly inhibited by the local administration of peptide 204-212. 5. The pattern and potency of the biological effects of peptide 204-212 are similar to those of antiflammin 2, a lipocortin 1-derived peptide. 6. It is suggested that peptide 204-212 may represent the active site responsible for the anti-inflammatory properties of lipocortin 5.

Amino Acid Sequence↗
PubMed1991

Persistent effects of interleukin-1 on smooth muscle preparations from adrenalectomized rats: implications for increased phospholipase-A2 activity via stimulation of 5-lipoxygenase.

Human recombinant interleukin-1 beta (hrIL-1 beta) potentiated CaCl2-induced contractions of isolated stomach strip preparations from adrenalectomized rats (ADXSS). Associated with this effect were increased prostaglandin E2 and peptidyl leukotriene (LT) synthesis. Unlike preparations from normal rat stomach strips or sham-operated animals, tissue responses and eicosanoid production of ADXSS failed to return to pre-hrIL-1 beta control levels after washout of the interleukin, these effects being abrogated by the lipoxygenase inhibitor nordihydroguaiaretic acid. Additionally, the LTD4 antagonist FPL55712 also prevented the increase in contraction and prostaglandin E2 synthesis caused by hrIL-1 beta without decreasing peptidyl LT synthesis. In separate experiments, hrIL-1 beta failed to increase the recovery of arachidonic acid-induced contractions after aspirin pretreatment in both ADXSS and rat stomach strips. The data indicate that the effects caused by hrIL-1 beta on ADXSS are possibly the result of an exacerbated phospholipase A2 activity particularly inasmuch as increases in cellular cyclooxygenase synthesis are unlikely in this experimental system. It appears likely that a peptidyl LT is involved in this process. Elevation of phospholipase A2 activity by interleukin-1 like drugs may be an important factor limiting the use of these agents as adjuvants particularly in patients with low blood glucocorticoid levels.

Adrenalectomy↗
PubMed1991

Evidence that interleukin-1 and lipoxygenase metabolites mediate the lethal effect of complete Freund's adjuvant in adrenalectomized rats.

Injection of complete Freund's adjuvant (CFA) into the right hind paw of adrenalectomized (ADX) rats caused a lethal effect, maximal after 3 days. Treatment of animals with polyclonal sera raised against either murine recombinant (mr) IL-1 alpha or mrIL-1 beta gave significant protection, suggesting the involvement of this cytokine in the observed lethality. Death was also caused by the intravenous injection of human recombinant (hr) IL-1 beta in ADX rats. No lethality was induced by either CFA or hrIL-1 beta in sham-operated (SHO) rats. The administration of dexamethasone or the dural cyclooxygenase/lipoxygenase inhibitor BW 755c significantly protected against the lethality induced by both CFA and hrIL-1 beta. The cyclooxygenase inhibitors, indomethacin and acetylsalicyclic acid, were ineffective. WEB 2086, a PAF-acether receptor antagonist, gave partial but not significant protection. These results suggest that activation of arachidonic acid metabolism is involved in the observed lethality, with lipoxygenase metabolites as possible final effectors. These experimental models of lethalities may be useful for the in vivo evaluation of drugs interfering with the synthesis and/or biological effects of IL-1.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1990

Investigation of rat mast cell degranulation using flow cytometry.

Mast cells degranulation has been assessed by flow cytometry (FACS) taking advantage of the changes in the light scattering properties of mast cells stimulated by secretagogues. In turn, these changes are based on the modification of size, shape, and granule content of the cells before and after stimulation. With FACS, it is possible to work with almost pure mast cell populations (greater than 99%). Moreover, responses to compound 48/80 are carried out in real time and on the same cell sample that acts as internal control. This technique is very sensitive as shown by the ED50 of compound 48/80 (0.051 micrograms/mL) compared to its ED50 on histamine release (0.131 micrograms/mL). The well-known inhibitory effect of disodium cromoglycate against compound 48/80 was clearly observed using FACS. Furthermore, FACS allowed to distinguish between specific degranulating effects and cytotoxicity. Among the secretagogues used, only the degranulation induced by phospholipase A2 was inhibited by in vivo treatment with dexamethasone. It is suggested that the inhibitory effect is due to induction of phospholipase A2-inhibitory proteins (lipocortins).

Animals↗
PubMed1989

The release of interleukin-1-like activity by macrophages in two models of immunological inflammation in the rat.

Interleukin-1 (IL-1) is a putative mediator of inflammation released by activated macrophages in vitro. The IL-1 release by rat macrophages collected either from exudates in pertussis-induced air pouches or from the peritoneum during adjuvant arthritis has been investigated. In air pouch inflammation LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at day 6 after challenge. This enhanced IL-1 release parallels the extent of mononuclear cell migration in the inflammatory lesion. In adjuvant arthritis LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at days 16 and 23 after adjuvant injection. The secondary inflammation in arthritic rats was statistically significant at days 16 to 28. These results indicate that during immunological inflammation macrophages either from the inflamed area or from a non-inflamed region release more IL-1 than control cells. This release parallels the extent of the inflammation and may be important in its pathogenesis.

Air↗
PubMed1989

The effect of adrenalectomy on interleukin-1 release in vitro and in vivo.

1 Peritoneal macrophages (M phi) collected from adrenalectomized (ADX) rats released more interleukin-1 (IL-1) activity and prostaglandin E2 (PGE2) than macrophages from sham-operated (SHO) rats. 2 The increase in IL-1 activity in the supernatants was confirmed by the increase of the cell-associated 33 kD IL-1 alpha precursor in ADX macrophages stimulated by lipopolysaccharide (LPS). 3 After the injection of Complete Freund's Adjuvant (CFA) to induce adjuvant arthritis, 60% of the ADX rats died, while no deaths occurred in the SHO group. 4 The in vivo administration of dexamethasone inhibited both IL-1 and PGE2 release by macrophages as well as protecting ADX animals from CFA-induced death. Indomethacin and BW 755C partially protected the animals from this lethal effect. 5 These results suggest that adrenalectomy induces an increased release of IL-1 both in vitro and in vivo, and are consistent with a feedback mechanism between IL-1 and glucocorticoid hormones.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Induction and quail liver diamine oxidase (histaminase). Part I: Interference of spermidine synthase on the diamine oxidase activity assay using putrescine as substrate.

Treatment with Aroclor 1254 produces a decrease of diamine oxidase (DAO) activity in quail liver microsomes evaluated on deamination of 14C-putrescine and of histamine. The inhibition observed with the 14C-putrescine assay has peculiar behavior; it increase with the increase of 14C-putrescine concentrations until it produces values of extracted radioactivity which are less than the blanks which do not contain proteins. This effect is reserved by dicyclohexylammonium, an inhibitor of spermidine synthase (SPDS). This paper shows that SPDS rapidly decreases the putrescine concentration during the assay of DAO in tissues, particularly when SPDS is increased by induction with Arocolor.

Amine Oxidase (Copper-Containing)↗
PubMed1988

Induction and quail liver diamine oxidase (histaminase). Part II: Different responses to the inducers.

In quail liver microsomes the metabolism of histamine is prevalently sustained by diaminoxidase (DAO). Treatment with phenobarbital (PB) and clofibrate (CF) does not modify DAO activity, while that with Aroclor 1254 (PCB) and beta-naphtoflavone (BNF) significantly decreases it. The decrease of DAO activity produced by these substances is not dependent on their direct inhibition of the enzyme. DAO decrease might represent a further possibility to discriminate among different inducers; moreover, it implies that histamine metabolism might be decreased, in quail liver, by some classes of inducers.

Amine Oxidase (Copper-Containing)↗
PubMed1986

Diamine oxidase activity in Japanese quail liver induced with aroclor 1254.

Male adult quails were treated with a single intraperitoneal dose of Aroclor 1254 mg/kg. The animals showed increases in hepatic weight and benzopyrene hydroxylase activity which were continuous up to 168 h after the treatment. At 96 h after treatment the activity of diamine oxidase (DAO) in the microsomal fraction was significantly decreased whereas that of spermidine synthase seemed to increase.

Amine Oxidase (Copper-Containing)↗