Role of neutrophils in indomethacin-induced gastric mucosal lesions in rats

Ali̇can, İnci̇; Coşkun, Tamer; Çorak, Ahmet; Yeğen, Berrak Ç.; Oktay, Şule; Kurtel, Hızır

doi:10.1007/bf01782814

Cited by 21 publications

(9 citation statements)

References 24 publications

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“…Although we did not observe any significant changes in the levels of TBARS and sulfhydryls between the groups, indomethacin perfusion significantly increased carbonyl formation, indicating an oxidative modification of plasma proteins which is known to alter their function and turnover (Oliver et al 1987). Our results are in agreement with a previously published report demonstrating that tissue levels of carbonyls, but not glutathione or TBARS, increase after indomethacin administration (Alican et al 1995). The elevated plasma carbonyl content in the indomethacin-treated group also suggests that oxidation of these proteins may be an early component of the sequence of events leading to tissue damage.…”

Section: Resultssupporting

confidence: 93%

Role of Nitric Oxide in Indomethacin‐Induced Gastric Mucosal Dysfunction in the Rat

Gürbüz

Ali̇can

Yeğen

et al. 1999

Experimental Physiology

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summaryThe present study was undertaken to explore the role of nitric oxide (NO) in the pathogenesis of experimental non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy. We assessed the role of NO inhibition and donation in indomethacin-induced gastric mucosal dysfunction. The stomach was perfused with vehicle (control) for 20 min, followed by indomethacin (10 mg ml¢ in 1·25% sodium bicarbonate, pH 8·4) for 120 min. N G -nitro-¬_arginine methyl ester (¬_NAME, 5 and 10 mg kg¢, i.v. bolus), ¬_arginine, ª_arginine (100 mg kg¢ i.v. bolus, 10 mg kg¢ h¢, 2 h infusion) and the NO donor glyceryl trinitrate (GTN) were given at the same time (20, 40 and 80 ìg kg¢ min¢, 15 min infusion) as perfusion with indomethacin was started. Epithelial permeability was quantified by measuring blood-to-lumen clearance of 51 Cr-labelled EDTA. Indomethacin caused a 20-fold increase in 51 Cr-EDTA leakage compared with that of the control group. Treatment with ¬_NAME or ¬_arginine did not affect the indomethacin-induced alterations in mucosal permeability. Administration of GTN (20 ìg kg¢ min¢) significantly reduced the indomethacin-induced mucosal dysfunction. By contrast, higher doses of GTN (80 ìg kg¢ min¢) exacerbated epithelial dysfunction induced by indomethacin. Elevated levels of carbonyls and myeloperoxidase (MPO) observed after indomethacin administration were significantly reduced, to the control values, when GTN (20 ìg kg¢ min¢) was administered along with indomethacin.

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Section: Resultssupporting

confidence: 93%

Role of Nitric Oxide in Indomethacin‐Induced Gastric Mucosal Dysfunction in the Rat

Gürbüz

Ali̇can

Yeğen

et al. 1999

Experimental Physiology

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“…Moreover, after their activation, neutrophils release ORS and proteases which are in large measure responsible for lesion formation. In this way, an increase in neutrophilic activation and in oxidative stress has been associated with intake of NSAIDs, such as indomethacin [209], piroxicam [210] and diclofenac [211]. TNFα seems to play an important role in the process of leucocyte adhesion to the endothelium in response to NSAIDs.…”

Section: Dual Action Of Nitric Oxide From Cnos and Inos On Gutmentioning

confidence: 99%

New Issues about Nitric Oxide and its Effects on the Gastrointestinal Tract

Martín

Jiménez²,

Motilva³

2001

CPD

111

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Over the last years the important role of nitric oxide (NO) as endogenous modulator of numerous physiological functions has been shown. NO is involved in the regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and modulation of the activity of the mastocytes. It also plays a key role as neurotransmitter in the central and peripheric nervous system (non adrenergic non colinergic, NANC, neurons), in the nervous control of the cerebral blood flow and in the neuroendocrine regulation or synaptic plasticity. However, NO shows a dual behavior: at physiological concentrations, released through the constitutive synthase (cNOS), it regulates house-keeping functions, whereas its overproduction by the inducible isoenzyme (iNOS) exhibits cytotoxic activity because interacting with reactive species producing peroxinitrites (ONOO) and other compounds, which are highly damaging for the tissues. In the gastrointestinal tract (GIT) NO participates in the modulation of the smooth musculature tone, such as the regulation of intestinal peristaltism, gastric emptying and antral motor activity. It also regulates acid and gastric mucus secretion, alkaline production, and is involved in the maintenance of mucosal blood flow. In physiological conditions, NO acts as an endogenous mediator modulating both, the repairing and integrity of the tissues, and exhibits gastroprotective properties against different types of aggressive agents. However, high concentrations of NO are related to numerous pathological processes of GIT including peptic ulcer, chronic gastritis, gastrointestinal cancer, bacterial gastroenteritis, celiac or chronic inflammatory bowel diseases. Recently, this hypothesis that cNOS is always beneficial and iNOS is always deleterious, has been questioned, since that a series of data suggest that the increase of cNOS activity could be responsible for the derived pathological changes and, by contrast, NO liberated by the inducible isoenzyme might play a repairing effect in certain pathological disorders. The pharmaceutical industry is really interested in proving the clinical benefits of the mediator. Numerous NO-donor drugs, nitrate derivatives, have been frequently used in the cardiovascular diseases due to their vasodilating properties, which allow an enhancement of coronary blood flow. More recently, the protective effect of NO against non steroidal antiinflammatory drugs (NSAID)-gastroenteropathy has been shown, because its vasodilating and antioxidant properties render it a potentially useful agent. Different NSAID, including acetyl salicylic acid, diclofenac or naproxen, have been formulated by attaching a NO releasing-moiety. These NO-NSAID, antiinflammatories combined with precursors of the mediator, or with inhibitors of the inducible synthase, are currently being evaluated. However, although the pharmacotherapeutical possibilities of NO are considerable, it is necessary to elucidate the exact mechanisms derived from stimulation/inhibition of the isoenzymes in order to determine th...

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“…injection of methotrexate (2 mg/ml PBS, pH 7.5, Sigma) for 5 consecutive days (37,38). The next day, animals were injected s.c. with 1 ϫ 10 6 T9.F/IL6/hi cells.…”

Section: Induction Of Neutropeniamentioning

confidence: 99%

IL-6 Secretion by a Rat T9 Glioma Clone Induces a Neutrophil-Dependent Antitumor Response with Resultant Cellular, Antiglioma Immunity

Gräf¹,

Prins

Merchant

2001

The Journal of Immunology

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Previously, we reported that IL-6 transduction attenuates tumor formation of a rat T9 glioma clone (termed T9.F). This study focuses on the mechanisms of the antitumor response elicited by IL-6 and the generation of glioma immunity. Ten days post s.c. inoculation of T9.F- or IL-6-secreting T9.F cells (T9.F/IL6/hi), tumor nodules were removed and their leukocytic infiltrate was analyzed by FACS with Ab markers for T cells, B cells, granulocytes, and monocytes. T9.F/IL6/hi tumors showed a marked increase in granulocytes as compared with parental T9.F tumors, and histological examination revealed that the granulocytes were neutrophils. Animals made neutropenic failed to reject T9.F/IL6/hi tumors. FACS analysis of 17-day T9.F/IL6/hi regressing tumors and T9.F progressing tumors did not reveal any significant differences in the leukocytic infiltrates. Tumor-specific effector cells were detected in the spleens harvested from animals bearing 17-day, regressing, T9.F/IL6/hi tumors. In vitro, these effector cells lysed T9.F cells, proliferated in response to T9.F stimulator cells, and produced Th1 cytokines (IL-2 and IFN-γ) but not the Th2 cytokine, IL-4, when cocultured with T9.F stimulator cells. Rats that had rejected s.c. T9.F/IL6/hi tumors displayed a delayed-type hypersensitivity response when injected with viable T9.F cells in the contralateral flank. Passive transfer of spleen cells from these animals transferred glioma immunity to naive recipients and depletion of CD3+ T cells, before transfer, completely abolished immunity, whereas depletion of CD8+ T cells had moderate inhibitory effects on the transfer of immunity.

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Role of neutrophils in indomethacin-induced gastric mucosal lesions in rats

Cited by 21 publications

References 24 publications

Role of Nitric Oxide in Indomethacin‐Induced Gastric Mucosal Dysfunction in the Rat

Role of Nitric Oxide in Indomethacin‐Induced Gastric Mucosal Dysfunction in the Rat

New Issues about Nitric Oxide and its Effects on the Gastrointestinal Tract

IL-6 Secretion by a Rat T9 Glioma Clone Induces a Neutrophil-Dependent Antitumor Response with Resultant Cellular, Antiglioma Immunity

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