SVIBOR - Project code: 1-08-151

MINISTRY OF SCIENCE AND TECHNOLOGY

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Project code: 1-08-151


BIOLOGICAL RESPONSE MODIFIERS - MECHANISM OF ACTION


Main researcher: HRŠAK, IVO (16676)


Assistants
Type of research: basic
Duration from: 01/01/94.
Papers on project (total): 30
Papers on project quoted in Current Contents: 7
Institution name: Institut "Ruđer Bošković", Zagreb (98)
Department/Institute: Department of Biology and Medicine
Address: Bijenička cesta 54
City: 10000 - Zagreb, Croatia
Communication
E-mail: ihrsak@olimp.irb.hr
Summary: In the years 1994. and 1995. investigations of the mechanism of action of biological response modifiers, i.e. bacterial peptidolgycans (PGM) and met-enkephalin (MENK) have been continued. PGM and its lipophylic derivative Na-lauroil-PGM stimulate macrophageas from the spleen and RAW 264.7 cultures to release increased quantities of TNF. Metalo-derivatives of PGM (Zn-PGM and Al-PGM) as well as lipophylic derivative Na-lauroil-PGM are not effective. PGM and LPS added to the macrophages in suboptimal doses does not induce synergistic effect on TNF release. In vivo single injection of PGM changed temporarily the permeability of liver lysosomal membranes and increased the quantity of lipid peroxidation products in plasma and liver. In vitro administration of PGM modulated macrophage superoxide anion production but did not affect the activity of lysosomal membrane and enzymes. In vitro multiple injections of PGM did not cause significant changes in the examined parameters. In animals subjected to stress the intensity of lipid peroxidation and corticosterone levels in the sera could be modulated by the treatment with MENK. The in vitro effects of lipophylic and metalo PGM-derivatives on the metabolic activity of spleen macrophages in preleukemic AKR mice have been tested and the results obtained compared to the effects of native PGM. In the 1 month young mice neither PGM nor their derivatives had any effect. On the contrary, in young-adult (4 month old) mice PGM and some of its derivatives stimulated the depressed activity of mitochondrial enzymes. Stimulation of superoxide anion release by MENK is associated with an increse of diacylglycerol, translocation of protein kinase C into the membranes of treated cells and an increase of intracellular calcium. The main degradating product of MENK (TGG), suppressed superoxide anion release, and this was not associated with the increased levels of diacylglycerol. In vivo MENK affected the immune response like in the stress; NK activity and antibody production were decreased, phagocytosis enhanced and the level of corticosterone elevated. If the MENK is applied before stressing the animals, then the effects of stress could be blocked, what suggests the involvement of hypothalamo-pituitary-adrenal axis in the mechanism of opioid effects.

Keywords: peptidoglycans, met-enkephaline, second messengers, TNF, preleukemic AKR mice, lipid peroxidation, stress, lysosomes

Research goals: The aims of the investigations in this project are to get better knowledge about the mechanisms of action of biological response modifiers - peptidoglycans and met-enkephaline on the cellular and subcellular levels. In the years 1994. and 1995. the aim was to investigate whether some lypophilic and metalo-derivatives of peptidoglycan PGM have better or different effect than the native PGM, as well as whether this biological response modifiers have possible unwanted toxic side effects on metabolic functions of liver and splenic cells in physiological and stress-induced states. In the same conditions we wanted to examine the mechanism of MENK effect upon several immune functions (NK activity, phagocytosis, antibody production, blastogeneic transformation) and the level of corticosterone in the plasma of stressed mice. Also, it was planed to examine which second messenger(s) is involved in MENK induced production of superoxide anion from human neutrophils.

COOPERATION - PROJECTS


  1. Name of project: Užinak MBO-a na oslobađanje slobodnih radikala
    Name of institution: Institut "Vuk Vrhovac", Sveučilišna klinika za dijabetes, endokrinologijui metaboličke bolesti
    City: 10000 - Zagreb, Croatia
Other information about the project.
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