Biomedical subjects

G Fantuzzi

Publications and source records attributed to G Fantuzzi.

At least 73 records · Page 4Linked to original sources

PubMed1995

Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation.

The role of the glucocorticoid receptor (GR) in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/- mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.

Adrenal Cortex↗

PubMed1995

Ciliary neurotrophic factor (CNTF) induces serum amyloid A, hypoglycaemia and anorexia, and potentiates IL-1 induced corticosterone and IL-6 production in mice.

Ciliary neurotrophic factor (CNTF) supports the survival of ciliary ganglion neurons and was shown to induce the synthesis of acute-phase proteins and fever. We studied the effect of CNTF, alone or in association with IL-1, on levels of corticosterone (CS), glucose, serum amyloid A (SAA), and IL-6. We also compared the effect of CNTF with that of IL-6, since the gp130 receptor subunit for CNTF is shared with that of IL-6. A single intravenous injection of CNTF induced hypoglycaemia and SAA and potentiated IL-1-induced CS and IL-6. Chronic CNTF, but not IL-6, resulted in decreased food intake and body weight up to days 6-7. After this time, body weight and food intake recovered even if CNTF treatment was continued, indicating that a phenomenon of tolerance occurred. Finally, CNTF (unlike IL-1) was not toxic in adrenalectomized mice. Therefore the similarities of CNTF activities with those of other cytokines, particularly IL-6, might go beyond the activation of the same receptor-signal transduction pathway of IL-6.

Animals↗

PubMed1995

The upregulating effect of dexamethasone on tumor necrosis factor production is mediated by a nitric oxide-producing cytochrome P450.

Dexamethasone (DEX) is a well-known inhibitor of tumor necrosis factor (TNF) production when given shortly before lipopolysaccharide (LPS). However, DEX (10 mg/kg, ip) potentiates TNF production when administered 24-48 hr before LPS (16 micrograms/kg, ip). We have found that this is probably due to DEX induction of cytochrome P450 3A, which is known to produce nitric oxide (NO). The upregulating effect of DEX on TNF production is associated with increased NO production. Both the upregulation of NO and of TNF production by DEX are inhibited by co-administration of the P450 3A inhibitor troleandomycin (TAO, 40 mg/kg, ip). These data suggest that P450 3A-generated NO might be involved in TNF induction.

Animals↗

PubMed1995

Independent down-regulation of central and peripheral tumor necrosis factor production as a result of lipopolysaccharide tolerance in mice.

Lipopolysaccharide (LPS) induces a variety of central and peripheral effects that are largely mediated by cytokines, including tumor necrosis factor (TNF). Peripheral (intravenous [i.v.]) administration of LPS (2.5 micrograms per mouse) induced TNF levels in the serum and spleen but not in the brain, while central (intracerebroventricular [i.c.v.]) administration of LPS induced TNF production both in the brain and in the periphery. Mice challenged with LPS after LPS pretreatment (35 micrograms per mouse, intraperitoneally, as a single dose on day -3 or as a 4-day treatment on days -5 to -2) were unresponsive in terms of induction of serum TNF. When peripherally LPS-tolerant mice (where LPS pretreatment was given intraperitoneally) were challenged with an i.c.v. dose of LPS, brain (but not serum) TNF was still produced, meaning that the LPS-tolerant state was confined to the periphery. However, if LPS pretreatment was given i.c.v. (35 micrograms, as a single dose), the brain, like the periphery, became LPS tolerant in terms of TNF production. We investigated how tolerance to LPS affected two of its actions, decrease in food intake and induction of serum corticosterone (CS). After an i.v. challenge in peripherally LPS-tolerant mice, no decrease in food intake was observed, but this response was still elicited by an i.c.v. challenge. LPS tolerance reduced the CS response to i.v. and i.c.v. challenge. These results suggest that LPS-induced decrease in food intake might be a fully central effect, while the increase of serum CS might be due to both central and peripheral actions.

Animals↗

PubMed1995

Chlorpromazine inhibits tumour necrosis factor synthesis and cytotoxicity in vitro.

Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysaccharide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-alpha (TNF-alpha) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-alpha action by assessing TNF-alpha cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1-100 microM) inhibited TNF-alpha production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10-25 microM) also inhibited TNF-alpha activity: in fact it reduced the cytotoxicity of TNF-alpha on L929 cells (EC50 was increased four times) and could provide protection even as a post-treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-alpha or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-alpha signalling pathways.

Apoptosis↗

PubMed1994

Indoor exposure to perchloroethylene (PCE) in individuals living with dry-cleaning workers.

Perchloroethylene (PCE) is the most widely used solvent in dry-cleaning; it is toxic to the liver, kidney and central nervous system and may be a human carcinogen. PCE levels in the ambient air of dry-cleaners' homes were measured, and samples of end-exhaled air (alveolar air) from subjects who were not themselves occupationally exposed, but who were members of the household of dry-cleaners were compared with samples from the general population. Thirty apartments were visited housing dry-cleaners and their families, and located well away from the dry-cleaning premises. Indoor air samples and alveolar air samples were collected contemporaneously from the dry-cleaners (36) and members of their household (34). The same sampling procedure was followed in 25 private homes where samples of alveolar air were collected from 41 subjects who were not occupationally exposed and who acted as control group. All the samples were analysed by direct-injection gas-chromatography. PCE levels in dry-cleaners' homes proved to be significantly higher than in control houses (geometric means: 265 vs. 2 micrograms/m3, P < 0.001). PCE levels in the alveolar air exhaled by dry-cleaners, their family members and control subjects were statistically different (geometric means: 5140, 225 and 3 micrograms/m3, respectively; P < 0.001). PCE is a ubiquitous substance in indoor air, but is present at higher concentrations in apartments where dry-cleaners and their families live. Biological monitoring of PCE in alveolar air confirms that family members of dry-cleaners are more exposed than the general population.

Adult↗

PubMed1994

Defective inflammatory response in interleukin 6-deficient mice.

Systemic and localized inflammation elicit a number of host responses which include fever, cachexia, hypoglycemia, and major changes in the concentration of liver plasma proteins. Interleukin 6 (IL-6) is considered an important mediator of the inflammatory response, together with IL-1 and tumor necrosis factor alpha (TNF-alpha). The purpose of this study was to unequivocally determine the role of IL-6 in these phenomena making use of IL-6-deficient mice that we have recently generated by gene targeting. We report here that in the absence of IL-6, mice are unable to mount a normal inflammatory response to localized tissue damage generated by turpentine injection. The induction of acute phase proteins is dramatically reduced, mice do not lose body weight and only suffer from mild anorexia and hypoglycemia. In contrast, when systemic inflammation is elicited through the injection of bacterial lipopolysaccharide (LPS), these parameters are altered to the same extent both in wild-type and IL-6-deficient mice, demonstrating that under these conditions IL-6 function is dispensable. Moreover, we show that LPS-treated IL-6-deficient mice produce three times more TNF-alpha than wild-type controls, suggesting that increased TNF-alpha production might be one of the compensatory mechanisms through which a normal response to LPS is achieved in the absence of IL-6. We also show that corticosterone is normally induced in IL-6-deficient mice, demonstrating that IL-6 is not required for the activation of the hypothalamic-pituitary-adrenal axis. Our results reinforce the idea that different patterns of cytokines are involved in systemic and localized tissue damage, and identify IL-6 as an essential mediator of the inflammatory response to localized inflammation.

Acute-Phase Reaction↗

PubMed1994

Perchloroethylene exposure can induce colour vision loss.

We evaluated colour vision in 35 dry-cleaners exposed to perchloroethylene (PCE) and in a paired number of controls matched for sex, age, alcohol consumption and cigarette smoking. A subclinical colour vision loss, mainly in the blue-yellow range, was present in dry-cleaners. This effect was related to PCE exposure levels, and appeared at environmental concentrations of the solvent well below the current exposure limits for exposed workers. The results suggest that PCE exposure, even at low environmental levels, can induce a dose-related impairment of colour vision.

Adult↗

PubMed1994

Trace elements in saliva and dental caries in young adults.

The results of a study on Zn, Cu, Ca and Mg content in whole saliva and supernatant of young adults in relation to caries prevalence are reported. A total of 225 university students were selected for the study on the basis of voluntary participation. The salivary electrolytes showed a high intersubjective variability and females had significantly lower levels than males. In whole saliva, the trace elements were highly correlated, whereas the correlations were weaker in the supernatant. The ratio supernatant/whole saliva varied between subjects and according to the examined electrolytes. No association could be found between the measured trace elements and DMFT. When we analysed the relation with recent caries experience in the subgroup of subjects undergoing oral examinations for at least 1 year, we found evidence that the Zn/Cu molar ratios in whole saliva were significantly decreased in subjects with more than three decayed teeth compared with those with no caries (1.54 vs. 1.11, P < 0.05). No significant association was found when supernatant was analysed. We conclude that the electrolytes' levels in whole saliva might be more adequate than the levels in supernatant to evaluate the relationship with caries.

Adolescent↗

PubMed1994

Differential effect of glucocorticoids on tumour necrosis factor production in mice: up-regulation by early pretreatment with dexamethasone.

Glucocorticoids (GC) are well known inhibitors of tumour necrosis factor (TNF) production. We investigated the role of endogenous GC in the regulation of TNF production in mice treated with lipopolysaccharide (LPS) using a pretreatment with dexamethasone (DEX) to down-regulate the hypothalamus-pituitary-adrenal axis (HPA). Short-term DEX pretreatment (up to 12 h before LPS) inhibited TNF production, but earlier (24-48 h) pretreatments potentiated it. This up-regulating effect was not observed in adrenalectomized mice or when GC synthesis was inhibited with cyanoketone (CK). This effect could not be explained only by the suppression of LPS-induced corticosterone (CS) levels induced by DEX, since a 48-h pretreatment potentiated TNF production without affecting LPS-induced CS levels. On the other hand, mice chronically pretreated with DEX were still responsive to its inhibitory effect on TNF production, thus ruling out the possibility of a decreased responsiveness to GC.

Adrenalectomy↗

PubMed1994

Depression of liver metabolism and induction of cytokine release by diphtheria and tetanus toxoids and pertussis vaccines: role of Bordetella pertussis cells in toxicity.

A 24-h pretreatment of mice with diphtheria and tetanus toxoids and whole-cell pertussis vaccines depressed liver cytochrome P-450 and therefore prolonged hexobarbital-induced sleeping time in mice. The depression of liver drug metabolism by a cellular vaccine containing a mutated pertussis toxin was less marked than that induced by the wild-type vaccines, indicating that the mutated vaccine might have lower toxicity in this regard. The wild-type vaccines decreased microsomal P-450 levels by 50%, while the mutated whole-cell vaccine had a less marked effect (a decrease of 30%), paralleling the results obtained in sleeping time experiments. Furthermore, an acellular mutated vaccine did not affect liver drug metabolism, indicating a role of the whole bacterial cell in this side effect. All the cellular vaccines studied induced high serum interleukin-6 levels; on the other hand, the acellular mutated vaccine induced very low interleukin-6 levels, indicating that the whole bacterial cell is also important for interleukin-6 induction. All vaccines studied were very poor tumor necrosis factor inducers.

Animals↗

PubMed1994

Cytokines in acute myocardial infarction: selective increase in circulating tumor necrosis factor, its soluble receptor, and interleukin-1 receptor antagonist.

Cytokines play a pathogenetic role in a variety of infective and inflammatory diseases. In the present study, we had two objectives: (a) to define the kinetics of tumor necrosis factor (TNF) in plasma after acute myocardial infarction (AMI) in patients treated with early thrombolysis, and (b) to measure other cytokines, interleukin-1 (IL-1) and TNF receptor antagonists, in plasma. TNF-alpha, but not IL-1 beta or IL-8, was present in plasma of 6 of 7 patients with severe AMI (Killip class 3 or 4). No TNF (< 50 pg/ml) was detected in a group of 11 patients with uncomplicated myocardial infarction (Killip class 1) or in control patients without AMI. Soluble TNF receptor type I and IL-1 receptor antagonist (IL-1Ra) were also significantly increased in the group with severe AMI compared with those with uncomplicated AMI. Circulating TNF is increased only in AMI complicated by heart failure at hospital admission. This finding may have diagnostic and therapeutic relevance.

Aged↗

PubMed1994

Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice.

We have previously shown that chlorpromazine (CPZ) inhibits tumour necrosis factor (TNF) production and protects against endotoxic shock in mice. In this paper we investigated the effect of pretreatment with CPZ, 4 mg/kg i.p. 30 min before, compared with dexamethasone (DEX; 3 mg/kg) on the induction of other endotoxin (lipopolysaccharide; LPS)-induced cytokines in the serum of mice, i.e. interleukin-1 alpha (IL-1 alpha), IL-6 and IL-10, and TNF. We also studied the effect of CPZ on serum and spleen-associated TNF. Both DEX and CPZ inhibited TNF production, whereas induction of IL-1 and IL-6 was inhibited by DEX but not by CPZ. DEX did not affect IL-10, while CPZ potentiated its induction. CPZ also inhibited spleen-associated TNF induction in LPS-treated mice, suggesting an effect on the synthesis of TNF. CPZ inhibited TNF induction by Gram-positive bacteria (heat-killed Staphylococcus epidermidis) and by anti-CD3 monoclonal antibodies. Intraperitoneal administration of CPZ also inhibited the induction of brain-associated TNF induced by intra-cerebroventricular injection of LPS. Therefore, CPZ is a more specific inhibitor of TNF production than DEX; in particular, CPZ increased the induction of IL-10, which is a 'protective' cytokine known to inhibit LPS toxicity and TNF production. CPZ inhibited TNF production in vivo, irrespective of the TNF stimulus used to induce TNF. Finally, CPZ did not induce the 'rebound' effect of DEX that, when given 24 hr before LPS, potentiates TNF production, but it did inhibit TNF production after 24 hr.

Animals↗

PubMed1993

Inhibitors of cytochrome P450 suppress tumor necrosis factor production.

We tested the effect of different inhibitors of cytochrome P450 on tumor necrosis factor (TNF) production. Metyrapone and SKF525A (100 and 50 mg/kg, ip, respectively) suppressed serum TNF induced by cotreatment with endotoxin (LPS), (2.5 micrograms/mouse). Inhibition was independent of endogenous corticosteroids since it was also observed in adrenalectomized mice. In vitro production of TNF by endotoxin-stimulated human monocytes was also inhibited by metyrapone and SKF525A. Since lipoxygenase (LO) inhibitors also block TNF production and metyrapone was reported to inhibit LO, we suggest that inhibition by metyrapone and SKF525A might be due to inhibition of either LO or a cytochrome P450 implicated in the oxidation of endogenous substrates involved in the inflammatory response.

Animals↗

PubMed1993

The pneumotoxicant paraquat induces IL-8 mRNA in human mononuclear cells and pulmonary epithelial cells.

Paraquat (PQ) is a herbicide which is highly pneumotoxic by generating reactive oxygen intermediates (ROI). Pro-inflammatory cytokines, particularly IL-1 and TNF, have been implicated in some ROI-mediated pathologies, including bleomycin toxicity and ischaemia/reperfusion injury. We have studied the effect of PQ on the expression of the neutrophil chemotactic cytokine, IL-8, by human peripheral blood mononuclear cells (PBMC). While almost no IL-8 mRNA was detected in unstimulated cells, PQ (100 microM) induced high mRNA expression with a maximum at 24 h of incubation. While PQ did stimulate the appearance of IL-8 mRNA, no significant production of IL-8 protein was detected. However, PQ potentiated the production of IL-8 in the presence of 1 ng/ml of endotoxin (lipopolysaccharide, LPS). This was paralleled by an increased production of chemotactic activity for neutrophils, indicating that the IL-8 was actually bioactive. Stimulation of IL-8 mRNA by PQ was suppressed by IL-4 and by free radical scavengers (dimethylsulfoxide, mannitol). Increased IL-8 expression by PQ was also observed in the human pulmonary epithelial cell line A549 indicating that the effect of PQ was not specific for PBMC. These findings suggest that IL-8 might be involved in the pulmonary effects of PQ and that its production might be stimulated following an oxidative insult, and might clarify the pathogenetic mechanisms of adult respiratory distress syndrome (ARDS) or oxidant-induced pulmonary fibrosis.

Antioxidants↗

PubMed1993

Differential regulation of cytokine production in lipopolysaccharide tolerance in mice.

We investigated the pattern of down-regulation of cytokine production in endotoxin (lipopolysaccharide [LPS]) tolerance. A 4-day treatment with LPS (35 micrograms per mouse) was followed by a challenge on day 6 with one more injection of LPS. Circulating tumor necrosis factor (TNF) and interleukin-6 (IL-6) could not be induced (> 99% inhibition) by LPS in LPS-tolerant mice; colony-stimulating factor (CSF) was also down-regulated by more than 95%, whereas interferon (IFN) and IL-1 syntheses were only partially inhibited. To study the mechanism of cytokine down-regulation in tolerance, we attempted to reverse the tolerant state by pretreatment with phorbol 12-myristate 13-acetate (PMA) (4 micrograms per mouse) 10 min before the LPS challenge. PMA completely restored IL-6 production and partially that of CSF. PMA had no effect on IFN production and inhibited the induction of IL-1. TNF production was also not restored by PMA. To investigate the role of endogenously produced cytokines in the development of LPS tolerance, we administered IL-6, TNF, or IL-1 alpha, using the same treatment schedule as that for LPS. Whereas IL-6 had no effect, IL-1 alpha or TNF induced partial tolerance to LPS in terms of inhibition of LPS-stimulated TNF and IL-6 production. However, a full LPS-tolerant state could not be induced by administration of recombinant cytokines, suggesting the existence of additional mechanisms, such as a loss of LPS receptors or changes in release of soluble binding proteins.

Animals↗

PubMed1993

Early down-regulation of TNF production by LPS tolerance in human monocytes: comparison with IL-1 beta, IL-6, and IL-8.

We studied the effect of a 4-hr preexposure to LPS on the ability of human monocytes to respond to a subsequent stimulation with LPS in terms of cytokine production. LPS-preexposed monocytes did not produce TNF on LPS restimulation, but they retained the ability to produce IL-1 beta, IL-6, and IL-8. LPS-tolerant monocytes were still capable of producing TNF when restimulated with zymosan. Down-regulation of TNF by LPS tolerance was also evident at the mRNA level. To investigate the possible mechanisms underlying this phenomenon, we also studied the effect of LPS preexposure on membrane CD14, which was suggested to be an LPS receptor, and on intracellular cAMP, an inhibitor of TNF production. LPS induced a 50% decrease in CD14 expression. On the other hand, the increase in cAMP levels by LPS was not affected by preexposure to LPS. In conclusion, (a) TNF is more rapidly down-regulated than IL-1 beta, IL-6, and IL-8 during LPS tolerance in vitro; (b) early LPS tolerance is associated with decreased CD14, which might partially explain the decreased LPS response; and (c) a feedback mechanism controlling TNF synthesis, cAMP elevation, is not down-regulated in LPS tolerance.

Antigens, CD↗

PubMed1993

Relationship between low lead exposure and somatic growth in adolescents.

The possible effects of moderate lead exposure on human growth and development are not well defined. This study was carried out in order to evaluate the relationship between somatic growth and lead exposure. 418 subjects (202 males and 216 females) aged 11-13 years in good health and living in an area of the northern region of Italy were submitted to the following determinations: blood lead levels (PbB), serum concentrations of gonadotropins (LH, FSH) and sex-steroid hormones (DHA-S, T, E2) and anthropometric measurements (stature and weight). The mean blood levels were 85.39 and 70.08 micrograms/1, respectively, for males and females. Significant and negative relationships were found between blood lead levels and stature in 13 years old males and 12 years old females (p = 0.009 and p = 0.006, respectively). Negative relationships between lead in blood and LH and FSH were found only in males with lead levels higher than 90 micrograms/1. Our findings seem to suggest that even for low lead exposure this metal may affect stature growth and gonadotropins levels.

Adolescent↗