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Biomedical subjects

C Bonne

Publications and source records attributed to C Bonne.

At least 37 records · Page 2Linked to original sources
PubMed1993

Superoxide and nitric oxide cooperation in hypoxia/reoxygenation-induced neuron injury.

Oxygen-derived free radicals are implicated in hypoxia- and reoxygenation-related brain injury. In addition, excitatory amino acid neurotransmitters seem to be involved in this neurotoxicity and could act through the L-arginine/nitric oxide (NO) synthase pathway. In the present study we have used rat forebrain neurons in culture submitted to hypoxia/reoxygenation to investigate the relative role of free radicals, glutamate, and nitric oxide in hypoxic neuronal injury. Hypoxia (5 h) followed by reoxygenation (0-24 h) induced cell damage assessed by lacticodehydrogenase release into culture medium. Superoxide dismutase (SOD, 500 U/mL), D-L-2-amino-5-phosphonovaleric acid (100 microM), a glutamate receptor antagonist, and NG-nitro-L-arginine (100 microM), an NO synthase inhibitor, protected the neurons. The effect of NG-nitro-L-arginine was reversed by adding L-arginine (10 mM) in the culture medium, and hemoglobin, which scavenges NO, also afforded protection. Hypoxia (5 h) provoked glutamate release from neurons, and this effect was inhibited by SOD. Exogenous glutamate (1-100 microM) induced lacticodehydrogenase release, and this effect was inhibited by glutamate antagonism, NO synthase inhibition, or superoxide radical scavenging. These data are consistent with the following sequence of events in hypoxia-related neurotoxicity: free radical formation, glutamate release, and activation of NO synthase leading to superoxide and NO cooperative toxicity.

Animals↗
PubMed1992

Hypoxia/reoxygenation stimulates endothelial cells to promote interleukin-1 and interleukin-6 production. Effects of free radical scavengers.

Vascular endothelium produces and/or interferes with various cytokines. Previous studies have demonstrated interactions of these inflammatory and immunological mediators with oxygen-derived free radicals. The present work examines the relationship between hypoxia/reoxygenation (H/R) and cytokine production by cultured endothelial cells. Human umbilical vein endothelial cell (HUVEC) monolayers were incubated for 24 h in normoxia or submitted to 5 h hypoxia/19 h reoxygenation. Then, interleukin-1 (IL-1) alpha and beta, and interleukin-6 (IL-6), were measured in culture supernatants by specific enzyme immunoassays and bioassays, respectively. Under these conditions, the spontaneous production of IL-1 and IL-6, detected in normoxic HUVEC, greatly increased after H/R treatment. The observed enhancement was cycloheximide-sensitive and, consequently, reflected a de novo protein synthesis. Superoxide dismutase and glutathione peroxidase prevented H/R-induced IL-1 and IL-6 increase. These results constitute the first demonstration that H/R stimulates HUVEC to promote IL-1 and IL-6 production and strongly suggest a role for oxygen-derived free radicals in the cytokine synthesis.

Cell Hypoxia↗
PubMed1992

Synthesis and contractile activity of new pseudopeptido and thioaromatic analogues of leukotriene D4.

Seven new pseudopeptido and thioaromatic leukotriene analogues were synthesized and their agonist-antagonist and binding activities investigated. The synthesis led to the pleasing observation that the analogue in which the cysteinyl-glycine moiety was replaced by a 6-mercapto-3-(E)-hexenoic acid, not only exhibited potent affinity (guinea-pig lung parenchyma, IC50: 5 x 10(-9) M) but also showed 30% of the LTD4 agonist activity (guinea-pig ileum, ED 50: 2.7 x 10(-9)) giving very important key information on LTD4 geometry to the receptor. This compound was the first stable new pseudopeptido-leukotriene with such agonist activity and should contribute to the understanding of the metabolism of leukotriene D4. In addition, inversion of chirality at C5 and C6 carbon atoms of the leukotriene chain or replacement of the cysteinyl-glycine moiety by a thioaromatic acid led to new weak antagonists of the LTD4.

Animals↗
PubMed1992

Hypoxia/reoxygenation stimulates endothelium to promote neutrophil adhesion.

An in vitro model was designed to study the role of ischemia/reperfusion and endothelium-derived oxygen free radicals on neutrophil adhesion, with particular interest in the endothelial adhesion molecules involved. Human umbilical vein endothelial cells were submitted to 5 h hypoxia followed by various times (20 min to 24 h) of reoxygenation. Human resting neutrophils were added to monolayers for the last 15 min of reoxygenation. Adherence was evaluated by myeloperoxidase assay. Under these conditions, we found an increased adhesion of neutrophils with two peaks after 20 min and 4 h reoxygenation. This was correlated with the respective expression of the preformed granule membrane protein 140 (GMP-140) and of the de novo synthesized endothelial leukocyte adhesion molecule 1 (ELAM-1) on endothelial surface. Superoxide dismutase and/or catalase, or oxypurinol added to cultures before hypoxia efficiently prevented neutrophil adhesion. These results underline the crucial role played by endothelial oxy radicals at reoxygenation in adhesion of leukocytes, which could lead to an amplification of the oxidative stress injury. The protection offered by free radical scavengers emphasizes the potential therapeutic use of antioxidants in postischemic vascular disorders.

Adult↗
PubMed1992

Alterations of energetic metabolite levels by free radicals during optic nerve ischemia.

An experimental model of optic nerve ischemia was designed in the rabbit to determine early biochemical alterations, i.e.--changes of high energy phosphate metabolites (ATP and phosphocreatine)--in occlusive and peri-occlusive areas. Vascular occlusion provoked a rapid fall of ATP and phosphocreatine in the optic nerve. Free radicals scavengers, superoxide dismutase plus catalase or dimethylthiourea were able to counteract the drop of phosphate metabolites in the peri-occlusive area. These results show that hypoxia leads to oxygen-derived free radical generation which can be responsible for cell damage and emphasize the role of free radicals in the pathogenesis of ocular diseases related to vascular dysfunction.

Adenosine Triphosphate↗
PubMed1992

Beneficial effects of a retinoic acid analog, CBS-211 A, on an experimental model of keratoconjunctivitis sicca.

We report the effects of CBS-211 A, a synthetic retinoic acid analog, on a previously described experimental model of keratoconjunctivitis sicca (KCS) in the rabbit. A 9-week topical treatment with 0.02% CBS-211 A in aqueous vehicle significantly increased the conjunctival goblet cell density (P less than 0.01, impression cytology counting), stopped the evolution of the corneo-conjunctival surface alteration (P less than 0.05, rose bengal test), and restored a basically normal mucosecretory product quality in goblet cells (lectin histochemistry) compared to vehicle treatment. The results assess the efficacy of this compound in reversing KCS pathology in a relevant model different from general vitamin A deficiency models, and strongly support the rationale for using such a well-tolerated retinoid in dry eye treatment.

Administration, Topical↗
PubMed1991

Hypoxia/reoxygenation alters endothelial prostacyclin synthesis--protection by superoxide dismutase.

An in vitro model was designed to study the role of ischemia/reperfusion and oxygen free radicals on vascular prostacyclin (PGI2) synthesis and protection provided by superoxide dismutase (SOD). Cultured bovine aortic endothelial cells (BAEC) were subjected to various times of hypoxia (30 min to 5 h) followed by 30 min reoxygenation. An increase or a decrease in PGI2 synthesis capacity was then observed according to the duration of hypoxia. Inhibition of PGI2 synthesis after 5 h hypoxia/30 min reoxygenation was accompanied by a rise in lipoperoxidation products and a slight cytotoxicity. Superoxide anion could be implicated in these cellular alterations as SOD efficiently prevented these effects. Incubation of normoxic or H/R-treated BAEC with SOD led to an increase in cellular SOD activity as compared to controls. This increase, inhibited by incubation at 4 degrees C but not by addition of cycloheximide, strongly suggested endocytosis of SOD. This study emphasizes the role of endothelium as a source and target of free radicals and provides a new insight into the mechanism of protection by SOD in ischemia-related vascular pathology.

Animals↗
PubMed1990

LPS-stimulated bovine aortic endothelial cells produce IL-1 and IL-6 like activities.

Vascular endothelium is known to closely interact with leukocytes and immunocompetent cells. We report here that cultured bovine aortic endothelial cells (BAEC) synthesize both interleukin 1 (IL-1) and interleukin 6 (IL-6) like activities in response to bacterial lipopolysaccharide stimulation. Our results agree with previous data obtained from human venous endothelia and support the concept that IL-1 and IL-6 synthesis are properties common to endothelial cells from different vascular beds. The IL-1 activity was measured by murine thymocyte proliferation assay and by an indirect bioassay using NOB1 cells, which evidenced higher IL-1 amounts than the former. This discrepancy appeared to be partly due to the simultaneous production of one or more inhibitor(s) of the thymocyte proliferation by BAEC. The IL-6 assay was performed with the murine hybridoma cell line B9. In other respects, the cyclooxygenase inhibitor indomethacin enhanced the IL-1 like production, but was ineffective on IL-6 like production. The present study provides additional evidence that endothelial cells from large arteries may also participate in inflammatory and immunological processes.

Animals↗
PubMed1990

Retinoids enhance the number of EGF receptors in corneal endothelial cells.

Corneal endothelium appears to be an important target tissue for retinoids and epidermal growth factor (EGF). We report here that retinoic acid, or its synthetic analogue CBS-211 A (10(-8)-10(-7) M) dose-dependently enhances the mitogenic effect of EGF on cultured bovine corneal endothelial cells (BCEC). Furthermore, retinoid treatment, especially with CBS-211 A, increases the EGF-binding capacity of BCEC without any modification of EGF receptor affinity. The addition of cycloheximide (0.5 microgram ml-1) to cultures simultaneously with retinoids suppressed the retinoid effect on EGF-binding, whereas this protein synthesis inhibitor was ineffective when added 24 hr later. These results suggest that retinoids could induce the expression of EGF receptors on BCEC as an early event. This study, which demonstrates a cooperation between retinoids and EGF in corneal endothelium, could explain the beneficial effect of retinoic acid previously reported on this tissue repair in vivo. Our data could offer clues for new pharmaceutical strategies in ophthalmology therapy.

Animals↗
PubMed1990

PAF-induced conjunctivitis in the rabbit is mediated by peptido-leukotrienes.

Platelet activating factor (PAF) released by many cell types is involved in several steps of inflammatory reactions in various organs including the eye. It has been reported that some effects of PAF could be mediated by arachidonic acid metabolites generated after PAF-receptor interaction. In the study we investigated the protective effect of CBS-113A, a dual inhibitor of 5-lipoxygenase/cyclooxygenase in PAF-induced conjunctivitis in the rabbit. Moreover, the characterization of the icosanoid potentially mediating the PAF activity has been performed by using specific pharmacological agents. Subconjunctival injection of PAF (10-1000 ng) provoked Evans' blue extravasation measured in tissues within 30 min. Simultaneous injection of a PAF antagonist (BN 50730) inhibited the dye leakage, showing specific PAF receptor-mediated vascular reaction. CBS-113A applied in eye drops also inhibited Evans' blue extravasation. By contrast, indometacin administered either topically or by subconjunctival injection was not effective in reducing the effect of PAF. These results suggesting the involvement of a 5-lipoxygenase metabolite were confirmed by the effectiveness of local injection of SKF 104353, a specific leukotriene D4 antagonist. The present study shows that PAF-induced plasma leakage in conjunctivitis is mediated by peptido-leukotrienes.

Animals↗
PubMed1990

Use of a specular microscope with pachymeter in ocular tolerance studies of eye drops in the rabbit. Evaluation of ocular tolerance of benzalkonium chloride in aqueous solution 0.01% and 0.1%.

Eye drops, unlike cosmetics or chemicals, only cause minor irritations which often prove difficult to objectively observe and assess. A specular microscope with pachymeter is used to measure corneal thickness, and to examine and photograph corneal endothelium in ocular tolerance studies in the rabbit. Rabbits were instilled 5 times a day for 16 days with BKC aqueous solution, 0.01% or 0.1% and subjected after anaesthesia to 4 corneal inspections (before treatment, 7th and 14th days of treatment, 5th day after treatment). Only the 0.1% concentration provoked an increase in corneal thickness. Thickening progressed during the treatment period (5.3% on day 7, 26% on day 14) and strongly regressed 5 days after treatment stopped (3%). A slit lamp examination revealed very light or light corneal opacities, but the correlation between corneal thickening ratio and opacity was poor (r = 0.62).

Animals↗
PubMed1990

Retinoid-induced potentiation of epidermal growth factor mitogenic effect on corneal endothelial cells.

Epidermal growth factor (EGF) is mitogenic for bovine corneal endothelial cells in culture. Pretreatment with either retinoic acid or the synthetic analog CBS-211 A ((E)-4-[2-(2-isopropyl-5-thienyl)propenyl]benzoic acid) at 10(-8)-10(-6) M enhanced the EGF effect. This potentiating effect of retinoids contrasts with their intrinsic activity, which results in cell growth inhibition in the absence of growth factor. The present data emphasize the previously reported beneficial effect of retinoic acid on corneal endothelium wound healing. This effect could be related to the potentiation of endogenous growth factors and further underlines the importance of retinoids in the medical treatment of corneal endothelial lesions.

Animals↗
PubMed1989

Comparative biological activities of the four synthetic (5,6)-dihete isomers.

(5,6)-dihydroxy-7,9-trans-11,14-cis-eicosatetraenoic acids [5,6)-DiHETEs) were synthesized and separated into four pure diastereoisomers. They were tested for comparative binding affinities to leukotriene receptors (LTC4, LTD4, LTB4) in guinea pig lung membranes. Only (5S,6R)-DiHETE was recognized by the LTD4 receptor, the other receptors interacted with neither of the four isomers. (5S,6R)-DiHETE also contracted ileum in vitro and this effect was inhibited by the LTD4 receptor antagonists ICI 198,615 and SKF104,353. These data suggest that the bioproduct (5S,6R)-DiHETE generated by enzymatic conversion of LTA4 could have some LTD4-like activity when produced in large concentrations.

Animals↗
PubMed1989

The role of platelets in blood-aqueous barrier breakdown induced by anterior chamber paracentesis in the rabbit.

Anterior chamber paracentesis of the rabbit eye causes disruption of the blood-aqueous barrier, which is characterized by a rapid increase in the albumin and total protein content of the aqueous humor. Prostaglandins appear to be implicated as major mediators in this reaction, since a cyclooxygenase inhibitor, indomethacin, very efficiently prevents protein leakage. When paracentesis was performed in platelet-depleted rabbits (either by transfusion or by treatment with an antiplatelet plasma), the protein content in the aqueous humor did not rise to values observed in normal animals. These data suggest that platelets play some role in the response to paracentesis, a fact in accordance with histological results. In contrast to cyclooxygenase inhibitors, dexamethasone inhibits neither the blood-aqueous barrier breakdown nor prostanoid release from platelets. These data also indirectly indicate the possible role of platelets in triggering the paracentesis reaction in the rabbit.

Animals↗
PubMed1989

2-(2-hydroxy-4-methylphenyl)aminothiazole hydrochloride as a dual inhibitor of cyclooxygenase/lipoxygenase and a free radical scavenger. 1st communication: in vitro studies.

2-(2-Hydroxy-4-methylphenyl)aminothiazole hydrochloride (CBS-113 A) inhibits cyclooxygenase in platelets and 5-lipoxygenase in leukocytes at micromolar concentrations. On the other hand the drug is a potent scavenger of oxygen-derived free radicals. Moreover and possibly consequently, CBS-113 A inhibits the oxygen burst of stimulated leukocytes and the release of an interleukin 1-like compound from vascular endothelial cells in culture. These properties could lead to another activity of therapeutic interest in comparison with anti-inflammatory drugs already available.

Animals↗
PubMed1989

2-(2-hydroxy-4-methylphenyl)aminothiazole hydrochloride as a dual inhibitor of cyclooxygenase/lipoxygenase and a free radical scavenger. 2nd communication: anti-inflammatory activity.

The paper describes the topical anti-inflammatory activity of 2-(2-hydroxy-4-methylphenyl)aminothiazole hydrochloride (CBS-113 A), a dual inhibitor of cyclooxygenase/lipoxygenase and a potent free radical scavenger. When applied in eye drops (0.01 to 0.1% according to the model used), the drug inhibited inflammation in experimental conjunctivitis and uveitis induced by various procedures (e.g. paracentesis, endotoxin, S-antigen, albumin, Fe2+). The compound also inhibited leukocyte infiltration and histamine release when administered locally in pleural cavity with carrageenan. CBS-113 A could decrease plasma leakage induced by arachidonic acid or platelet activating factor in skin and airway, respectively. However, it was devoid of any activity when administered by systemic route. The compound appears as a potentially useful anti-inflammatory drug, in particular in ophthalmology and as an alternative to glucocorticoids, since it does not present the side effects of these steroids (e.g. worsening of herpetic keratitis).

Animals↗