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Biomedical subjects

I L Bonta

Publications and source records attributed to I L Bonta.

At least 55 records · Page 3Linked to original sources
PubMed1990

Atriopeptins and nitroprusside provoke opposite changes in cGMP and cAMP levels in human macrophages.

Atrial natriuretic factor (ANF, 10(-7) M) and, even more potently, sodium nitroprusside (SNP, 10(-5)-10(-3) M) stimulated cGMP formation in human peritoneal macrophages. This suggests that the two forms of guanylate cyclase, the particulate form stimulated by ANF and the soluble form activated by SNP, coexist in this cell type. A fall in cAMP levels in parallel with the rise of cGMP levels provoked by ANF and SNP was noticed that was amplified by an increase in the concentration of the phosphodiesterase inhibitor, IBMX. Our finding that ANF, contrary to its action in other tissues, was unable to exert direct inhibitory effects on the adenylate cyclase activity in isolated macrophage membranes, together with the observation that SNP was able to mimic the effect of ANF on cAMP levels indicates that the cAMP-lowering effect of ANF is most likely mediated through the cGMP signal.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Adenyl cyclase activity in human alveolar macrophages.

The inflammatory mediators PGE2, DC-PGI2 and histamine as well as the beta-adrenergic drugs isoprenaline and salbutamol increase intracellular cyclic AMP-concentrations whereas Platelet Activating Factor does not induce any change in adenyl cyclase activity of normal human alveolar macrophages. Functional H2-histaminergic and beta 2-adrenergic receptor-subtypes are coupled to macrophage adenyl cyclase.

Adenylyl Cyclases↗
PubMed1990

Activated human granulocytes contract isolated human airways.

Human granulocytes activated with serum treated zymosan (0.2 mg/ml) contract isolated human airways. The magnitude of the contraction depends on the number of granulocytes and the proportion of eosinophils among the granulocytes. The contraction is blocked by a leukotriene C4/D4 (LTC4/D4) receptor antagonist and by inhibition of lipoxygenase. This suggests that eosinophils rather than neutrophils are implicated in this response, which seems to be caused by LTC4/D4.

Bronchi↗
PubMed1990

Additive effect of epithelial denudation and low levels of inflammatory mediators on the sensitivity of isolated human airways to methacholine.

The presence of low concentrations of histamine or the stable thromboxane analogue U46619 and the removal of the epithelium separately and addictively increase the sensitivity of isolated human airways to methacholine. This raises the possibility that these factors play a role in the pathogenesis of bronchial hyperresponsiveness to inhaled methacholine in asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Macrophage function during the development of adjuvant disease.

Using rat peritoneal macrophages and blood monocytes we examined the relationship of developing adjuvant disease (AD) with the expression of class I and II antigens, release of interleukin-1 (IL-1) and production of prostaglandin E2 (PGE2). We observed that class I and II antigens initially decreased; class II remained low throughout, whereas class I returned to normal. PGE2 and IL-1 gradually increased. Treatment in vivo with the NSAID Na-diclofenac lowered PGE2 and IL-1 release and partly reversed the observed reduction of class I and II antigens. Also, exposure of the cells in vitro to lipopolysaccharide increased class I antigen expression.

Animals↗
PubMed1990

Interactions between inflammatory mediators in expression of antitumor cytostatic activity of macrophages.

Antitumor properties and participation in inflammatory events are important characteristics of activated macrophages. We show here that both antitumor cytostatic function of macrophages and participation of these cells at inflammatory sites are controlled by two main groups of mediators: cytokines (IL-1, TNF alpha) and eicosanoids (prostanoids and leukotrienes). These two groups of mediators represent a complex system of mutual interactions in regulation of their production and activities. Multiple sets of experiments with murine macrophages are discussed in favor of the views that PGE2 and lipoxygenase products oppose each other's actions, and that the regulating role of PGE2 in the secretions of cytokines are of pivotal importance in antitumor cytostasis of macrophages in vitro. Such observations can be extended to a situation ex vivo, showing that human macrophages harvested from inflammatory sites have markedly augmented cytostatic expression. It thus appears that the antitumor cytostatic function of macrophages is related to the production of inflammatory mediators by these cells. Accordingly, it might be that occurrence of inflammation in tumor-bearing individuals plays a role in the promotion of antitumor activity of macrophages.

Arachidonic Acid↗
PubMed1990

Leukotriene C4 is an essential 5-lipoxygenase intermediate in A23187-induced macrophage cytostatic activity against P815 tumor cells.

Resident peritoneal macrophages incubated with 3.5 x 10(-7) M Calcium ionophore A23187 in tumor cell growth medium (TGM) release large amounts of leukotriene (LT)E4 and an unidentified 5-lipoxygenase product, whereas A23187-stimulated macrophages produce in serum free medium LTD4, predominately. LTC4 and 3H-LTC4 incubated for 20 min at 37 degree C in serum containing TGM, convert into LTE4 and 3H-LTE4, respectively. Thus, LTC4 released from A23187-stimulated macrophages is an intermediate in TGM which rapidly converts into LTE4, probably because of the presence of gamma-glutamyl transpeptidase and cystenylglycinase in TGM. Macrophages express antitumor cytostatic activity towards P815 cells (49-53%) in a cocultured ratio (macrophage: tumor cell) 2:1 when stimulated with 3.5 x 10(-7) M A23187 in TGM. The 5-lipoxygenase inhibitor AA861 reverses the cytostatic activity by 42-58% and it inhibits also the formation of A23187-induced 5-lipoxygenase products from macrophages. Restoration of 38% macrophage- antitumor cytostatic activity by exogenous LTC4 (10(-8) M) indicates that LTC4 is an essential 5-lipoxygenase intermediate in the pathway of required signals underlying A23187-induced macrophage antitumor cytostatic activity. Macrophages not stimulated by A23187 do not express cytostatic activity in the presence of LTC4. This implies that besides LTC4, increased cytosolic [Ca2+] is required for A23187 induction of macrophage cytostatic activity.

Animals↗
PubMed1990

Macrophage cytokines render WEHI-3B tumor cells susceptible to cytostasis by prostaglandins.

The growth of the murine myelomonocytic leukemia tumor, WEHI-3B, has been shown to be inhibited by a two-step treatment: first, incubation for one hour with either interleukin-1 (human recombinant IL-1 alpha or tumor necrosis factor (human recombinant TNF-alpha); second, subsequent exposure to prostaglandins. Preincubation with IL-1 rendered the tumor cells more susceptible to subsequent treatment with either prostaglandin E2 or to the stable synthetic analogue of prostacyclin DC-PGI2. Preincubation with TNF-alpha rendered the tumor cells more susceptible to further treatment with PGE2 but not with DC-PGI2. Preconditioning of the tumour cells with either IL-1 alpha or TNF alpha did not affect cytostasis by subsequent culture of tumor cells in presence of either one of the cytokines. It is concluded that the interactions between macrophage cytokines and prostaglandins in enhancement of antitumor activity might imply first binding or induction of certain modifications in the tumor cells by the cytokines which render the cells more susceptible to exposure to prostaglandins.

Antineoplastic Agents↗
PubMed1990

The effect of acute feeding of carnitine, acetyl carnitine and propionyl carnitine on basal and A23187-stimulated eicosanoid release from rat carrageenan-elicited peritoneal macrophages.

Little is known about the ability of carnitine to modulate cell functions. As carnitine plays an important role in lipid metabolism we investigated the acute effect of L-carnitine, L-acetyl carnitine and L-propionyl carnitine (300 mg/kg per d; 4 d) on the basal and calcium-ionophore (A23187)-stimulated release of arachidonic acid metabolites from rat carrageenan-elicited peritoneal macrophages. A decrease in the number of peritoneal carrageenan-elicited macrophages was observed after feeding all three compounds. The basal release of prostaglandin E2, 6 keto-prostaglandin F1 alpha and leukotriene B4 was stimulated by all treatments. In contrast, thromboxane B2 production was diminished by feeding carnitine and acetyl carnitine. A23187-stimulated synthesis of 6 keto-prostaglandin F1 alpha and leukotriene B4 was further enhanced by all three compounds. Acetyl carnitine and propionyl carnitine also enhanced thromboxane B2 synthesis. However, no effects on prostaglandin E2 formation were detected. The 6 keto-prostaglandin F1 alpha:thromboxane B2 ratio, calculated from the basal and A23187-stimulated values, was increased by carnitine treatment. In the presence of A23187 there was also an increase in the 6 keto-prostaglandin F1 alpha:leukotriene B4 ratio. We conclude that carnitine, and possibly some of its derivatives, could modify the macrophage component of an inflammation in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Endotoxin-stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin-1 beta in vitro during infectious peritonitis.

Interleukin-1 (IL-1) release by peritoneal macrophages obtained from patients on continuous ambulatory peritoneal dialysis (CAPD) was studied in nine patients during an infection-free period and eight patients during an infectious peritonitis, using an ELISA for IL-1 beta. Without exogenous stimulation with LPS, peritoneal macrophages from infected and uninfected patients released the same amounts of IL-1 beta, 183 +/- 40 pg ml-1 24 h-1) per 10(6) cells (means +/- SEM) and 251 +/- 96 pg ml-1, respectively. However, in response to a dose of 5 micrograms ml-1 of LPS, peritoneal macrophages released significantly more (P less than 0.005) IL-1 beta during peritonitis (6579 +/- 2793 pg ml-1 24 h-1 per 10(6) cells) compared with the infection-free period (1040 +/- 182 pg ml-1). These findings show that after microbial invasion of the peritoneal cavity, peritoneal macrophages are primed in vivo to release an increased amount of IL-1 beta in vitro after subsequent exogenous stimulation with LPS, indicating that peritoneal macrophage activation for IL-1 beta secretion occurs in steps.

Adult↗
PubMed1990

Effects of changes in osmolarity on isolated human airways.

The effects of hypo- and hyperosmolarity on the function of isolated human airways were studied. Changes in osmolarity induced an increasing bronchoconstriction that was proportional to the magnitude of the change in osmolarity. Hypertonicity-induced airway narrowing resulted when buffer was made hypertonic with sodium chloride or mannitol but not with urea. The airways showed no tachyphylaxis to repetitive exposure to hypo- and hypertonic buffer of 200 and 600 mosM, respectively. The bronchoconstriction was not secondary to stimulation of H1 or leukotriene C4/D4 receptors or the release of prostaglandins in the preparation. The bronchoconstriction in hypotonic buffer was totally dependent on extracellular calcium, whereas in hypertonic buffer the bronchoconstriction seemed partially dependent on intracellular calcium release. Isoprenaline prevented the bronchoconstriction in hyper- or hypotonic buffer of 450 and 250 mosM but not in buffer of 600 and 150 mosM. It is concluded that hypo- and hypertonic buffers lead to bronchoconstriction via different mechanisms, which relate to influx of extracellular calcium in hyposmolar buffer and probably to release of calcium from intracellular stores in hypertonic buffer. In strongly hypertonic buffer, part of the bronchoconstriction may be due to osmotic shrinkage. The relevance of our data for the mechanism of bronchoconstriction after inhalation of hypo- or hypertonic saline depends on whether changes in osmolarity around the airway smooth muscle occur in asthmatics but not in normal subjects, and this has not yet been established.

Adult↗
PubMed1990

Effects of inflammatory mediators on the responsiveness of isolated human airways to methacholine.

Several studies have suggested that in asthmatics the quantities of inflammatory mediators such as histamine, thromboxane A2 (TxA2), prostaglandin D2 (PGD2), prostaglandin F2 alpha (PGF2 alpha), and leukotriene C4 (LTC4) that are present in the airway lumen are related to the degree of bronchial responsiveness to inhaled methacholine (MCh). Therefore, we studied the effect of these mediators on the cholinergic responsiveness of isolated human airway segments. Lung tissue collected at thoracotomy from 30 patients was studied. Dose-response curves to MCh were obtained from bronchial segments before, during, and after incubation with either a subthreshold or a threshold concentration of histamine (10(-10) or 10(-8) M), the stable TxA2 analogue U46619 (10(-11) or 10(-9) M), PGD2 (5 x 10(-9) or 5 x 10(-7) M), PGF2 alpha (10(-9) or 10(-7) M), or LTC4 (10(-11) or 10(-9) M). With the exception of LTC4, the presence of any of these mediators at either concentration increased the sensitivity to MCh by a factor of 1.1 to 2 (p less than 0.05, ANOVA). This increase did not depend on the dose of the mediator (p greater than 0.05, ANOVA). These data indicate that mediator-induced muscle hypersensitivity can explain a small part of the leftward shift of the dose-response curve to inhaled MCh as observed in asthma.

Aged↗
PubMed1990

Peritoneal macrophages from patients on CAPD show an increased capacity to secrete interleukin-1 beta during peritonitis.

The in vitro release of interleukin-1 beta (IL-1 beta) by peritoneal macrophages from CAPD patients was studied during 16 infection free periods (16 patients) and 13 episodes of peritonitis (10 patients) using an ELISA. Without exogeneous stimulation with LPS, peritoneal macrophages released the same amounts of IL-1 beta. irrespective if they were obtained during an infection free period (473 +/- 92 pg/ml 24h, means +/- SEM) or during peritonitis (324 +/- 125 pg/ml). However, in response to a dose of 5 micrograms/ml of LPS, peritoneal macrophages released significantly more (p less than 0.005) IL-1 beta during peritonitis (6155 +/- 1743 pg/ml). These findings show that during peritonitis, peritoneal macrophages are primed in vivo to release more IL-1 beta in vitro after stimulation with LPS, indicating that activation of peritoneal macrophages for IL-1 beta secretion occurs stepwise.

Bacterial Infections↗
PubMed1989

Antigen challenge modifies the cyclic AMP response of inflammatory mediators and beta-adrenergic drugs in alveolar macrophages.

Adenylate cyclase activity was determined in alveolar macrophages (AMs) obtained from bronchoalveolar lavage (BAL) fluids of naive and antigen-challenged guinea pigs. After the anaphylactic reaction in ovalbumin-sensitized guinea pigs, the basal levels of cyclic AMP in AMs were significantly increased compared to the levels in naive AMS (1.87 +/- 0.22 versus 5.26 +/- 0.45 pmol cyclic AMP/5.10(6) cells). Prostaglandin E2 (PGE2), prostacyclin (DC-PGI2), histamine, isoprenaline and salbutamol stimulated adenylate cyclase activity more effectively in AMs obtained from sensitized guinea pigs after the booster injection compared to AMs obtained from non-treated animals. Moreover, DC-PGI2 and histamine, which were hardly able to induce a rise in cyclic AMP levels in naive AMs, become effective activators in AMs obtained after antigen challenge (100 and 60% increase in the response, respectively). Using selective receptor ligands, we have shown that beta 2-adrenoceptors and H2-subtype histamine receptors are functionally coupled to macrophage adenylate cyclase activity. The present data indicate that sensitization does not affect the configuration of the receptor on the outer membrane (no change in affinity constants), but affects other parts of the transmembrane signal system leading to the intracellular production of cyclic AMP (e.g. regulatory binding proteins or increases in the number of receptors).

Adrenergic beta-Agonists↗
PubMed1989

Prostaglandin E2 enhances, and leukotriene C4 inhibits, interleukin-1 inhibition of WEHI-3B cell growth.

Human recombinant interleukin-1 (HrIL-1) inhibited WEHI-3B cell growth in a dose-related manner (10-10,000 U/ml). Prostaglandin E2 at high concentrations (1000 ng/ml) also inhibited cell growth. When added together, HrIL-1 and prostaglandin E2 inhibited WEHI-3B growth in a synergistic manner (HrIL-1 concentrations of 10-10,000 U/ml and prostaglandin E2 concentrations of 10-1000 ng/ml). In contrast to the effects of the cyclooxygenase metabolite of arachidonic acid leukotriene C4, a lipoxygenase metabolite, reversed the cytostatic action of HrIL-1.

Adjuvants, Immunologic↗