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Biomedical subjects

P Sirois

Publications and source records attributed to P Sirois.

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

Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats.

The gene expression and levels of endothelins (ETs) are increased in various animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodynamic and haematological disturbances, organ injury and circulatory failure in ENDO. Previous studies using ET(A)- and/or ET(B)-receptor antagonists exacerbated the effects of LPS in anaesthetized and conscious rats. We investigated the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mixed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-induced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injection, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. In addition, progressive liver dysfunction, characterized by increases in plasma bilirubin and alanine transferase, became even more apparent (higher than in those injected with LPS). Plasma creatinine and blood urea were similar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-induced deleterious effects.

Acid-Base Equilibrium↗
PubMed1999

Involvement of bradykinin B1 and B2 receptors in pulmonary leukocyte accumulation induced by Sephadex beads in guinea pigs.

The effects of selected bradykinin receptor antagonists on leukocyte infiltration into the lungs were studied in a model of guinea pig lung inflammation induced by the intravenous injection of Sephadex beads. The bradykinin B1 receptor antagonist, [Leu8]desArg9-BK (40 mg kg(-1) 24 h(-1)) and the bradykinin B2 receptor antagonist, DArg[Hyp3,Thi5,DTic7,Oic8]BK (code name HOE 140; 4 mg kg(-1) 24 h(-1)), administered intravenously by osmotic pumps, significantly reduced eosinophil counts by 33% and 42% in bronchoalveolar fluid, respectively. HOE 140 decreased neutrophil counts by 35%. LysLys[Hyp3,Igl5,D-Igl7,Oic8]desArg9BK+ ++ (code name B 9858), a newly described bradykinin B1 receptor antagonist, administered intraperitoneally (1 mg kg(-1)), decreased eosinophil and neutrophil counts by 45% in bronchoalveolar fluid. D-Arg[Hyp3,Igl5,D-Igl7,Oic8]BK (code name B 9430), a non-selective bradykinin B1/B2 receptor antagonist, also administered intraperitoneally (1 mg kg(-1)), decreased eosinophil and macrophage counts by 62% and 80% in bronchoalveolar fluid. These results suggest that bradykinin B1 and B2 receptors are involved in leukocyte recruitment in our model of lung inflammation.

Animals↗
PubMed1999

Evidence for the activation of blood complement in Sephadex beads-induced lung inflammation in guinea pigs.

OBJECTIVE AND DESIGN: This study evaluated the complement activation in guinea pigs that were given an intravenous injection of Sephadex and its correlation with markers of the development of inflammation. MATERIALS AND METHODS: Dunkin Hartley guinea pigs (250-300 g) were used. Whole blood was collected by heart puncture in a sodium citrate solution (0.315 g/ml) for complement measurements. Complement activation was measured using a colorimetric haemolytic assay. Bronchoalveolar lavages (BAL) were performed to monitor cell infiltration and inflammation was monitored by measurements of eosinophil peroxidase (EPO), histamine, beta-glucuronidase, albumin and total proteins in the BAL fluid. TREATMENT: Guinea pigs were pre-treated with aprotinin (40000 IKU/kg) 30 min before they were given an intravenous injection of Sephadex beads (24 mg/kg). Carboxymethyl (CM)-Sephadex (24 mg/kg) was administered alone. RESULTS: Sephadex beads activated the complement system in vitro (14.12+/-2.29 U/ml) and in vivo (9.95+/-0.08 U/ml) reaching a peak 6 h after the injection. This activation was accompanied by other characteristic features of inflammation such as leukocyte infiltration and activation. Both CM-Sephadex and aprotinin reduced the blood complement activation and eosinophil infiltration/activation observed. CONCLUSIONS: Our results strongly suggest that complement is involved in the cascade of events leading to the inflammatory state observed in guinea pig following the intravenous injection of Sephadex beads.

Animals↗
PubMed1999

Selective inflammatory response induced by intratracheal and intravenous administration of poly-L-arginine in guinea pig lungs.

Major basic protein (MBP) is a cationic protein found in eosinophil granules that was postulated to participate in the pathogenesis of bronchial asthma. Recently, it has been demonstrated that MBP level in serum or bronchoalveolar lavage (BAL) fluid was correlated with bronchial hyperresponsiveness (BHR) in asthmatics. A number a studies have established that MBP actions could be mimicked by synthetic polycations as poly-L-arginine. In this study, we investigated the effects of intratracheal and intravenous administration of poly-L-arginine on lung inflammatory response development. The intratracheal injection of poly-L-arginine at the doses of 1, 10, 100 nmol/animal increased the number of eosinophils (up to 3.2 fold) and neutrophils (up to 12 fold) in BAL fluid. Eosinophil and neutrophil infiltration was reversed by 88% and 67% respectively following low molecular weight heparin treatment (500 microg/animal). The intravenous injection of increasing doses of poly-L-arginine (1, 10, 100, 500 nmol/animal) increased the number of eosinophils (up to 2.7 fold) but not neutrophil infiltration in guinea pig lungs. Eosinophil infiltration was reversed by 87% following low molecular weight heparin treatment (1.5 mg/animal). Intratracheal treatment with poly-L-arginine (100 nmol/animal) produced an important increase of beta-glucuronidase, histamine, eosinophil peroxidase (EPO) and albumin levels in BAL fluid, whereas the intravenous treatment (500 nmol/animal) did not. These results show that the route of administration of poly-L-arginine greatly influences its effect on inflammatory cell recruitment since both administration routes elicited eosinophil migration but only the intratracheal route stimulated the migration of neutrophils. Moreover, poly-L-arginine appeared to induce other inflammatory responses since it increased beta-glucuronidase, histamine, EPO and albumin levels in BAL fluid following intratracheal treatment. These results also showed that low molecular weight heparin significantly blocks the inflammatory responses elicited by poly-L-arginine.

Animals↗
PubMed1999

Early bronchial hyperresponsiveness following injection of sephadex beads in the guinea pig: involvement of platelet activating factor and thromboxane A2.

The effects of an intravenous injection (i.v.) of Sephadex beads (20 mg kg(-1)) were examined on bronchial responsiveness to ACh (1-200 microg kg(-1) i.v.) as well as on cell accumulation in guinea-pig lung. Bronchial hyperreactivity to ACh, measured as increase in pulmonary insufflation pressure (PIP), was observed 3 h following the i.v. injection of Sephadex beads. However, no significant increase in bronchial reactivity to ACh was measured at 6 and 12 h following Sephadex injection. A second later increase in bronchial hyperresponsiveness was observed at 24 h. Bronchoalveolar lavage performed at 3 h following Sephadex treatment showed that there was no significant increase in total or differential cell number. At 6 h and 12 h, a significant increase in total cell counts was observed. At 24 h, a greater than 5-fold increase in cell number was observed and was related to a marked eosinophil, neutrophil and macrophage infiltration. A platelet-activating factor (PAF) antagonist, CV-3988 (10 mg kg(-1) i.v.), and a thromboxane A2 (TxA2) antagonist, L655,240 (10 mg kg(-1) i.v.), significantly attenuated the Sephadex-induced bronchial hyperresponsiveness to ACh observed at 3 h. The results show that an i.v. injection of Sephadex beads in guinea pigs can induce an early bronchial hyperresponsiveness to ACh that is mediated by the release of both PAF and TxA2 and is independent of airway cell infiltration.

Acetylcholine↗
PubMed1999

A rat model presenting eosinophilia in the airways, lung eosinophil activation, and pulmonary hyperreactivity.

The aim of this study was to examine antigen-induced lung cell migration, eosinophil activation, and pulmonary reactivity of Wistar rats exposed to a new sensitization technique. The animals were sensitized with a single subcutaneous implant of a fragment of heat coagulated hen egg white and challenged 21 days later with an intratracheal injection of heat-aggregated ovalbumin (EWI). For comparison, another group of rats were sensitized by an intraperitoneal injection of ovalbumin in alum as adjuvant, with one booster on day 14 and challenge on day 21 post immunization (OVA/AL). Twenty-four hours after antigen challenge, the EWI group presented a higher number of eosinophils in the bronchoalveolar lavage (BAL) (4.85 +/- 1.43 x 10(6)) than the OVA/AL group (0.2 +/- 0.06 x 10(6)) or the control group, where the level of eosinophils were essentially undetectable. Levels of eosinophil peroxidase activity were increased in the cell-free BAL and homogenates of lung tissue in the EWI group (12.10 +/- 2.97 mg/mL and 36.14 +/- 7.21 ng/mg, respectively), but not in the OVA/AL group (4.83 +/- 1.4 ng/mL and 11.95 +/- 2.54 ng/mg, respectively), as compared with controls (5.16 +/- 1.65 ng/mL and 12.13 +/- 1.74 ng/mg, respectively). Thromboxane B2 levels were also increased in the BAL of EWI group (2.89 +/- 0.54 ng/mL) but not the OVA/AL group (1.13 +/- 0.23 ng/mL) as compared with controls (1.14 +/- 0.19 ng/mL). In contrast, the levels of prostaglandin E2 in the BAL were increased in both groups (456.4 +/- 11.8 pg/mL in the EWI group and 303.5 +/- 31.7 pg/mL in the OVA/AL group) as compared with controls (205.7 +/- 29.7 ng/mL). Moreover, only the EWI group developed increased pulmonary reactivity to serotonin (around two-fold), 24 hours after antigen challenge. The extent of lung eosinophil migration and activation and the pulmonary hyperreactivity induced by this novel sensitization procedure without adjuvants represents a significant improvement over existing experimental models of asthma.

Animals↗
PubMed1999

Technology evaluation: ISIS-3521.

It is well known that the PKC family of enzymes is involved in the propagation of intracellular signals and is implicated in cancers, inflammatory processes, cardiovascular and endocrinological diseases. Relatively low isozyme specificity has largely limited the clinical use of PKC antagonists. The members of the PKC family differ from each other at the mRNA level and the selectivity of antisense compounds is distinguished by this feature. According to ISIS Pharmaceuticals Inc antisense compounds are highly selective inhibitors even within a family of closely-related genes [321211]. The use of these compounds could be invaluable as tools to discover the mechanisms and roles of specific PKC isozyme in normal and diseased tissues and could provide the information for better cancer treatments [226799]. The isozyme of PKC-alpha is believed to play an important role in the proliferation of several types of cancer cells [234471-323703]. Recently, ISIS Pharmaceuticals received a patent US-05885970, covering the antisense technique targeting human PKC-alpha for cancer therapy (US-0588970). In the past few years, several effective antisense oligonucleotides (AS ONs) targeting murine and human PKC-alpha isozymes have been developed and a series of positive results have been obtained in cell culture and in nude mice cancer transplantation [327453]. Phase I clinical trials have shown that relatively high doses were well tolerated with no obvious side-effects [226799]. Whether these AS ONs are beneficial to patients suffering from cancer, either alone or in combination with other chemotherapy drugs is still under evaluation in a clinical setting.

Animals↗
PubMed1998

Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat.

BACKGROUND: Endothelin A (ETA) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 days after infarction. Whether starting them earlier would have a more or less beneficial effect is uncertain. METHODS AND RESULTS: Rats surviving an acute myocardial infarction (MI) for 24 hours (n=403) were assigned to saline or the ETA receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect on survival, with 46% of LU rats and 47% of saline-treated rats with large MI surviving to the end of the study. LU treatment led to scar thinning, further left ventricular (LV) dilatation, an increase in LV end-diastolic pressure, and an increase in wet lung weight (P<0.05). Despite this detrimental effect on LV function, LU led to a significant decrease in RV systolic (50+/-2 to 44+/-2 mm Hg, P<0.05 vs saline) and right atrial pressures. LU treatment also prevented the increase in pulmonary ET-1 found in saline-treated rats with large MI but did not modify the increase in cardiac ET-1 in hearts with large MI. CONCLUSIONS: The early use of the ETA receptor antagonists LU 127043 or its active enantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a decrease in RV systolic and right atrial pressures and a decrease in pulmonary but not cardiac ET-1 levels. It would thus appear that the early use of ETA receptor antagonists after infarction may be detrimental.

Animals↗
PubMed1998

Effects of dual endothelin-converting enzyme/neutral endopeptidase inhibitors, CGS 26303 and CGS 26393, on lipopolysaccharide or interleukin-1 beta-stimulated release of endothelin from guinea pig tracheal epithelial cells.

A number of studies using endothelin (ET) receptor antagonists support the participation of ETs in a variety of cardiovascular, renal, and other disorders. It has also been established that a number of cytokines, which are released in such diseases, modulate the expression and production of ETs and thus activate the ET system. This effect may represent one pathway by which these inflammatory mediators operate. By regulating endothelin-converting enzyme (ECE) activities, and thus ET synthesis, one can potentiate or attenuate the production of ETs and the receptor affinity/density in such pathologic conditions. Here, the stimulated (lipopolysaccharide or interleukin-1 beta) production of ET-1 from guinea pig tracheal epithelial cells was abolished by CGS 26303 or CGS 26393, two ECE/neutral endopeptidase (NEP) inhibitors, but was unaffected by CGS 24592, a specific NEP inhibitor. Therefore, such dual, and eventually selective ECE inhibitors are effective agents to prevent the stimulated production of ETs.

Animals↗
PubMed1997

Phosphoramidon and thiorphan suppress the generation of endothelin (ET) from exogenous big-endothelin by guinea pig Clara cells.

The formation of endothelins (ET) from exogenous big-ET-1, -2 and -3 was investigated in cultured guinea pig Clara cells. When Clara cells were incubated with 10(-9) or 10(-8) M human big-ET-1 (1-38), the release of ET was 69.9 +/- 7.6 and 221.6 +/- 25 fmol/ml respectively, after 1 h incubation period. Treatment of Clara cells with 1 mM phosphoramidon strongly suppressed (80%) the conversion of big-ET-1 to ET-1 during 1, 2 and 6 h incubation periods. Treatment of Clara cells with thiorphan (1 mM), an inhibitor of neutral endopeptidase, decreased by 44 and 26% the levels of immunoreactive endothelin (ir-ET) in the cell supernatant respectively, after 1 and 2 h incubation periods. When Clara cells were incubated with 10(-8) M human big-ET-2 (1-38), the release of ir-ET was 287.6 +/- 8.9 fmol/ml after a 1 h incubation period. Phosphoramidon and thiorphan (1 mM) reduced the amount of ir-ET generated from exogenous human big-ET-2 (10(-8) M) by 69 and 56%, respectively. When Clara cells were incubated with 10(-8) M human big-ET-3 (1-41), the release of ET was not increased after a 1 h incubation period. Our results suggest that guinea pig Clara cells convert exogenous big-ET-1 and -2 but not big-ET-3 into ET-1 and ET-2, respectively, through metalloproteinases sensitive to both phosphoramidon and thiorphan.

Animals↗
PubMed1997

Myocardial alpha1-adrenoceptor: inotropic effect and physiologic and pathologic implications.

Alpha1-adrenergic receptors have been found in myocardium of all mammalian species. Although the exact underlying mechanisms have not been conclusively determined, it would appear that the myocardial effects of alpha1-adrenoceptors may vary in importance according to the pathophysiologic process involved. In physiological conditions, this receptor system plays a role in cardiac growth, cardiac contraction, and has both an antiarrhythmic function as well as a role in cardiac adaptation to various situations. This system is also involved in some pathological processes such as ischemia/reperfusion, ischemic preconditioning, and cardiac hypertrophy. The role of alpha1-adrenoceptors in heart failure is somewhat controversial. Experimental evidence suggests that myocardial alpha1-adrenoceptors can have either beneficial or deleterious effects on the heart. It thus seems possible that the development of agents specific to certain subtypes of alpha1-adrenoceptor and a better understanding of their role in pathophysiologic states could be clinically relevant.

Animals↗
PubMed1997

Repression of the 5-lipoxygenase gene by c-myb overexpression in differentiated HL-60 cells.

This paper reports on the involvement of c-MYB in the regulation of 5-lipoxygenase gene expression during differentiation of human HL-60 cells. We demonstrate that c-MYB binds the 5-lipoxygenase promoter in undifferentiated cells but not in DMSO-differentiated cells. Also, we show that overexpression of c-myb cDNA in differentiated HL-60 cells represses the 5-lipoxygenase gene expression.

Arachidonate 5-Lipoxygenase↗