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E Borrelli

Publications and source records attributed to E Borrelli.

At least 37 records · Page 2Linked to original sources
PubMed2000

Inhibition of CD11-CD18 complex prevents acute lung injury and reduces mortality after peritonitis in rabbits.

Acute lung injury is frequent after severe peritonitis. The aim of this study was to investigate whether inhibition of the adhesion molecule CD11-CD18 on polymorphonuclear leukocytes (PMNs) would have any beneficial effects on pulmonary function and mortality in an animal model reproducing these clinical conditions. Acute peritonitis was induced in 36 rabbits by intraperitoneal injection of zymosan (0.6 g/kg) suspended in mineral oil; 20 were pretreated with a murine-specific IgG2a anti-CD18 monoclonal antibody, 16 (controls) with nonspecific purified murine IgG (1 mg/kg). The animals were followed for 10 d, then killed for histologic examination of the lungs. Blood samples were taken on Days 0, 1, 3, 7, and 10 for red blood cell (RBC), white blood cell (WBC), and platelet counts, pH, PO(2), PCO(2), carbon dioxide content (HCO(3)(-)) measurements, and renal and liver tests. Treatment with the anti-CD18 monoclonal antibody reduced mortality by approximately 40% (p < 0.05). PO(2) was higher in these treated animals than in the control animals throughout the study (p < 0.05 on Day 1, 3, and 10). On Day 1 control animals had significant leukopenia, whereas anti-CD18-treated animals had a moderate increase of the number of circulating WBC compared with baseline values (p < 0.05 between groups). The lungs of the anti-CD18-treated animals showed minor signs of inflammation and PMN infiltration whereas controls had interstitial and intra-alveolar edema and a large number of granulocytes. Quantification of PMNs by morphometry showed that there were constantly less granulocytes in the lungs of the animals treated with the anti-CD18 antibody (p < 0.001). PMN infiltration correlated with the levels of PO(2) (p < 0.001). Lung tissue of anti-CD18-treated rabbits contained less malonyldialdehyde, a by-product of membrane lipid peroxidation by PMN oxygen radicals (950 +/- 120 versus 1,710 +/- 450 pM/mg of protein) and, conversely, more of the antioxidant alpha-tocopherol (136 +/- 22 versus 40 +/- 9 ng/mg of protein), than the control rabbits (p < 0.01). In this particular model of ARDS the monoclonal antibody against the CD11-CD18 complex had a beneficial effect, reducing PMN infiltration and oxygen radical release in the lungs, preventing alveolocapillary membrane damage, improving gas exchange and, finally, significantly reducing mortality.

Animals↗
PubMed2000

Extracorporeal blood oxygenation and ozonation (EBOO) in man. preliminary report.

Autohemotherapy with ozone has been used for four decades with encouraging results but, owing to the lack of clinical studies, it has never been adopted by orthodox medicine. Confident of the valid principles of ozone therapy, we have endeavoured to increase its therapeutic efficacy. Over a ten-year period we have developed an apparatus that makes it possible to treat large quantities of blood with ozone in extracorporeal circulation (extracorporeal blood oxygenation and ozonation EBOO). One of us volunteered to test the system and after six treatments noted the disappearance of two lipomas. This prompted us to treat a patient with Madelung disease and several patients with atherosclerotic vasculopathy. Besides showing therapeutic effects, the preliminary results indicate that EBOO is clinically valid, without side-effects and worthy of testing in various diseases.

Aged↗
PubMed2000

Heparin coating of extracorporeal circuits inhibits cytokine release from mononuclear cells during cardiac operations.

PURPOSE: To evaluate whether the production of interleukin 2 (IL 2), interleukin 6 (IL 6) and interleukin 10 (IL 10) from stimulated peripheral blood mononuclear cells (PBMC) was affected by coating extracorporeal circuits in patients undergoing cardiopulmonary bypass (CPB). In addition, postoperative clinical parameters were compared between patients with heparin-coated and uncoated CPB. DESIGN: Prospective, controlled in vivo/ex vivo study. PROCEDURE: Blood samples were drawn immediately before, at the end and 24 hours after the end of CPB using either a conventional circuit (n=10) or a heparin-coated circuit (n=10) in patients undergoing CPB. Cytokine release on the supernatants of activated PBMC was detected. Cardiopulmonary parameters were measured before CPB, at ICU admission, 3 hours and 24 hours after ICU admission in both groups of patients. Statistical difference intragroups and between groups were investigated with the analysis of variance for repeated measures. RESULTS: IL 6 and IL 10 release was significantly less (p<0.05) in the heparin-coated group. No differences in clinical parameters were observed between the two groups. CONCLUSIONS: These results suggest that with the use of heparin-coated circuits there is a lower production of IL 6 and IL 10 from isolated PBMC than with uncoated circuits.

Analysis of Variance↗
PubMed1999

Interleukin 10 production in patients undergoing cardiopulmonary bypass: evidence of inhibition of Th-1-type responses.

The cardiopulmonary bypass (CPB) procedure has long been associated with a generalized immunosuppression. To understand further the cytokine-mediated regulation of the complex physiological and immunological changes induced by CPB, the authors decided to investigate whether CPB affects the release of interleukin (IL)-10, as well as other cytokines, in correlation to the inhibition of T cell responses. Using phytohaemagglutinin (PHA) as mitogen and peripheral blood mononuclear cells (PBMC) isolated from patients undergoing CPB, we investigated whether this procedure has an effect on the secretion of different patterns of cytokines (Th1- and Th2-type) and PBMC proliferation. In all patients, CPB significantly enhances IL-10 and IL-6 production in resting and PHA-stimulated PBMC. On the other hand, IL-2 production, in response to PHA, was significantly diminished. Reduced IL-2 and enhanced IL-10 production were associated with a significant decrease in PBMC proliferation. Immunosuppression was also associated to lymphopenia, while neutrophil counts were significantly enhanced. These results show that after CPB there is a transient but clear unbalanced immune response demonstrated by a differentiated production of Th1- and Th2-type cytokines. The release of different patterns of cytokines observed after CPB may be helpful in understanding and preventing the development of infectious and immune complications in surgical procedure employing CPB.

Aged↗
PubMed1999

Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists.

The dopamine (DA) D2-like family of receptors is comprised of three subtypes, the D2, D3, and D4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than at the D2 subtype. However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D3 receptors in these in vivo effects. In order to investigate whether the DA D2 receptor is the subtype that mediates hypothermia and hypolocomotion produced by DA D2/D3 receptor agonists, we tested the effects of ip administration of the DA D2/D3 receptor agonists 7-OH-DPAT and PD 128907, on core temperature and locomotor activity in DA D2 receptor knock-out mice (homozygotes: D2(-/-) and heterozygotes: D2(+/-)), and in wild-type (D2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 (1-10 mg/kg) induced hypothermia and decreased locomotion in D2(+/+) mice, but had no effects in D2(-/-) mice; the magnitude of the hypothermic and locomotor-reducing effects of these two agonists in D2(+/+) mutants was approximately half that of D2(+/+) mice. During the first 10 min in the activity chambers, the level of spontaneous locomotor activity of D2(-/-) individuals was almost 50% below that of D2(+/+) mice; basal locomotor activity of D2(+/-) mice was between that of D2(-/-) and D2(+/+) individuals. Neither type of mutant showed spontaneous catalepsy or deficits in forelimb muscle strength (grip-strength test). These results show that the presence of DA D2 receptors is necessary for the expression of the locomotor- and core temperature-decreasing effects of DA D2/D3 receptor agonists such as 7-OH-DPAT and PD 128907.

Animals↗
PubMed1999

Absence of the dopamine D2 receptor leads to a decreased expression of GDNF and NT-4 mRNAs in restricted brain areas.

Neurotrophic factors (NTFs) control the metabolic and electrophysiological properties of dopaminergic neurons in the brain. At the level of the substantia nigra, NTFs have been proposed to control dopamine release by regulating the firing rate of dopaminergic cells. This function is normally controlled by presynaptic dopaminergic autoreceptors. Dopamine has also been proposed to regulate the expression of NTFs and their receptors in the nigrostriatal pathway. Thus, an interaction between the signalling cascades activated by NTFs and dopamine receptors might possibly influence the physiology of dopaminergic neurons. Among dopamine receptors, D2 receptors (D2R) are the most abundant on dopaminergic neurons, where they exert autoreceptor functions. To test for an interaction between the NTF and dopaminergic pathways we have analysed the expression of NTFs and their receptors in D2R-deficient (D2R -/-) mice. Our study shows that the mRNA levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 and their corresponding receptors are not modified in the dopaminergic system of D2R -/- adult mice compared with wild-type littermates. However, a marked reduction of glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4 (NT-4) mRNAs is observed in the striatum and parietal cortex of D2R -/- mice, respectively. These results implicate dopamine, acting through D2 receptors, in the local control of specific NTF expression. The down-regulation of GDNF and NT-4 expression might also contribute to the locomotor phenotype of D2R -/- mice.

Animals↗
PubMed1999

Ozonation of blood during extracorporeal circulation. I. Rationale, methodology and preliminary studies.

We investigated whether exposure of blood ex-vivo to oxygen-ozone (O2-O3) through a gas exchanger is feasible and practical. We first evaluated the classical dialysis-type technique but we soon realized that semipermeable membranes are unsuitable because they are hydrophilic and vulnerable to O3. We therefore adopted a system with hydrophobic O3-resistant hollow fibers enclosed in a polycarbonate housing with a membrane area of about 0.5 m2. First we tested the system with normal saline, determining the production of hydrogen peroxide (H2O2) at O3 concentrations from 5 to 40 microg/ml. We then evaluated critical parameters by circulating swine blood in vitro; this revealed that heparin is not an ideal anticoagulant for this system. Finally, we performed several experiments in sheep and defined optimal anticoagulant dose (sodium citrate, ACD), priming solution, volume of blood flow per min, volume and concentration of O2-O3 mixture flowing countercurrent with respect to blood and the time necessary for perfusion in vivo. The biochemical parameters showed that an O3 concentration as low as 10 microg/ml is effective; this means that gas exchange and O3 reactivity are rapid and capable of inducing biological effects. The sheep showed no adverse effects even after 50 min of extracorporeal circulation at higher O3 concentrations (20 to 40 microg/ml) but the exchanger became less effective (low pO2 values) due to progressive clogging with cells.

Animals↗
PubMed1998

Lack of autoreceptor-mediated inhibitory control of dopamine release in striatal synaptosomes of D2 receptor-deficient mice.

Mouse purified striatal synaptosomes were used to study the release of newly synthesised [3H]-dopamine ([3H]-DA) or of previously taken up [3H]-DA. Quinpirole (QP, 10 microM), a D2/D3 dopaminergic agonist, was found to reduce the release of newly synthesised [3H]-DA with a larger amplitude when 4-aminopyridine (100 microM) instead than veratridine (1 microM) or potassium (25 mM) was used to evoke DA release. Among the different D2/D3 dopaminergic agonists tested R(-)-propylnorapomorphine (NPA) and quinpirole were the most potent. These compounds reduced, in a concentration-dependent manner, the 4-aminopyridine-evoked release of [3H]-DA previously taken up by synaptosomes (50% maximal inhibition). In contrast, the D3 agonist PD-128,907 had little effect even when used at 100 nM. The QP (100 nM)-induced response was completely antagonised by sulpiride (1 microM). Strikingly, the NPA (100 nM) and PD-128,907 (100 nM)-evoked responses were completely suppressed in D2 receptor-deficient mice. This data strongly suggest that only D2 but not D3 receptors are involved in the autoreceptor-mediated inhibition of the evoked release of [3H]-DA. Interestingly, while amphetamine-induced release of [3H]-DA was not modified, a slight reduction of [3H]-DA efflux induced by the dopamine (DA) uptake inhibitor cocaine was observed in D2 receptor-deficient mice.

4-Aminopyridine↗
PubMed1998

Impaired locomotion and dopamine signaling in retinoid receptor mutant mice.

In the adult mouse, single and compound null mutations in the genes for retinoic acid receptor beta and retinoid X receptors beta and gamma resulted in locomotor defects related to dysfunction of the mesolimbic dopamine signaling pathway. Expression of the D1 and D2 receptors for dopamine was reduced in the ventral striatum of mutant mice, and the response of double null mutant mice to cocaine, which affects dopamine signaling in the mesolimbic system, was blunted. Thus, retinoid receptors are involved in the regulation of brain functions, and retinoic acid signaling defects may contribute to pathologies such as Parkinson's disease and schizophrenia.

Animals↗
PubMed1998

Absence of dopaminergic control on melanotrophs leads to Cushing's-like syndrome in mice.

Dopamine negatively regulates POMC gene expression in melanotrophs of the intermediate lobe of the pituitary gland. The dopaminergic receptor involved in this control is the dopamine D2 receptor (D2R). The principal products of the POMC gene in melanotrophs are beta-endorphin and alpha-MSH. POMC is differently processed in the corticotrophs, where it is not regulated by dopamine and it is principally processed into ACTH. Here we show that D2R-deficient mice have increased POMC expression and intermediate lobe hypertrophy. Strikingly, D2R-deficient mice have unexpected elevated ACTH levels with a corresponding increase of corticosteroids and consequent hypertrophy of the adrenal gland. This phenotype is reminiscent of Cushing's syndrome in humans. Interestingly, we show that the elevation in ACTH levels is due to an aberrant processing of POMC in melanotrophs. Indeed, we demonstrate that in addition to controlling POMC gene expression in these cells, dopamine, by modulating the expression of the convertases involved in the cleavage of the POMC prohormone, strictly regulates its processing. These results reveal a key role for dopamine in the control of POMC-derived peptides and furthermore indicate an implication of the dopaminergic system in the genesis of Cushing's syndrome.

Adrenal Glands↗
PubMed1997

Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family.

Dopamine is a neuromodulator involved in the control of key physiological functions. Dopamine-dependent signal transduction is activated through the interaction with membrane receptors of the seven-transmembrane domain G protein-coupled family. Among them, dopamine D2 receptor is highly expressed in the striatum and the pituitary gland as well as by mesencephalic dopaminergic neurons. Lack of D2 receptors in mice leads to a locomotor parkinsonian-like phenotype and to pituitary tumors. The D2 receptor promoter has characteristics of a housekeeping gene. However, the restricted expression of this gene to particular neurons and cells points to a strict regulation of its expression by cell-specific transcription factors. We demonstrate here that the D2 receptor promoter contains a functional retinoic acid response element. Furthermore, analysis of retinoic acid receptor-null mice supports our finding and shows that in these animals D2 receptor expression is reduced. This finding assigns to retinoids an important role in the control of gene expression in the central nervous system.

Animals↗
PubMed1997

Absence of opiate rewarding effects in mice lacking dopamine D2 receptors.

Dopamine receptors have been implicated in the behavioural response to drugs of abuse. These responses are mediated particularly by the mesolimbic dopaminergic pathway arising in the ventral tegmental area and projecting to the limbic system. The rewarding properties of opiates and the somatic expression of morphine abstinence have been related to changes in mesolimbic dopaminergic activity that could constitute the neural substrate for opioid addiction. These adaptive responses to repeated morphine administration have been investigated in mice with a genetic disruption of the dopaminergic D2 receptors. Although the behavioural expression of morphine withdrawal was unchanged in these mice, a total suppression of morphine rewarding properties was observed in a place-preference test. This effect is specific to the drug, as mice lacking D2 receptors behaved the same as wild-type mice when food is used as reward. We conclude that the D2 receptor plays a crucial role in the motivational component of drug addiction.

Animals↗
PubMed1997

Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors.

Dopamine D2 receptors (D2Rs) are of crucial importance in the striatal processing of motor information received from the cortex. Disruption of the D2R gene function in mice results in a severe locomotor impairment. This phenotype has analogies with Parkinson's disease symptoms. D2R-null mice were used to investigate the role of this receptor in the generation of striatal synaptic plasticity. Tetanic stimulation of corticostriatal fibers produced long-term depression (LTD) of EPSPs in slices from wild-type (WT) mice. Strikingly, recordings from D2R-null mice showed the converse: long-term potentiation (LTP). This LTP, unlike LTD, was blocked by an NMDA receptor antagonist. In magnesium-free medium, LTP was also revealed in WT mice and found to be enhanced by L-sulpiride, a D2R antagonist, whereas it was reversed into LTD by LY 17555, a D2R agonist. In D2R-null mice this modulation was lost. Thus, our study indicates that D2Rs play a key role in mechanisms underlying the direction of long-term changes in synaptic efficacy in the striatum. It also shows that an imbalance between D2R and NMDA receptor activity induces altered synaptic plasticity at corticostriatal synapses. This abnormal synaptic plasticity might cause the movement disorders observed in Parkinson's disease.

2-Amino-5-phosphonovalerate↗
PubMed1997

Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline.

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia.

Adult↗
PubMed1997

Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice.

Dopamine plays a key role in the control of motor and cognitive functions through the interaction with membrane receptors. Dopamine elicits its physiological effect by interacting with receptors that belong to the seven transmembrane domain G-protein-coupled receptors family. Pharmacological and structural analyses have allowed the division of these receptors into two classes: the D1- and D2-like receptors. The D1-like subfamily comprises D1 and D5 while the D2-like is formed by D2, D3 and D4. Dopaminergic neurons arise from the ventral tegmental area and the substantia nigra. These neurons give rise to four dopaminergic pathways: the nigrostriatal, the mesolimbic, the mesocortical and tuberoinfundibular pathways. These pathways are involved in the control of movement, learning, motivation reward and hormone synthesis and release. Dysfunction in these pathways leads to neurological, psychiatric and endocrine disorders. Indeed, degeneration of the nigrostriatal pathway leads to Parkinson's disease in humans, characterized by a strong reduction of released dopamine. Thus, a fine tuning of the firing discharge of dopaminergic neurons is a key function in the regulation of dopamine mediated activities in the central nervous system. Somatodendritic dopaminergic autoreceptors of the D2-like family are responsible for such a function. However, it is still controversial whether this function could be ascribed only to one or more members of this subfamily.

Animals↗