Mehmet Melli

Release of cysteinyl leukotrienes with aspirin stimulation and the effect of prostaglandin E2 on this release from peripheral blood leucocytes in aspirin-induced asthmatic patients

Background The decrease in prostaglandin E2 (PGE2) release due to aspirin (ASA)‐induced cyclooxygenase inhibition and the increment in cysteinyl leukotriene (Cys‐LT) release secondary to the removal of the inhibitory effect of PGE2 on Cys‐LT release have been suggested in the pathogenesis of aspirin‐induced asthma (AIA).

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity

Background Lipoxin (LX) A4, an endogenous anti‐inflammatory eicosanoid, has been found to be low in patients with severe asthma. However, few studies also suggested more diminished LX A4 levels in aspirin‐exacerbated respiratory disease (AERD) when compared with aspirin‐tolerant asthma (ATA). It is, therefore, currently not clear whether the asthma severity or the presence of AERD has a primary role in the disturbed LX metabolism.

Eicosanoids and inflammatory cells in frostbitten tissue: prostacyclin, thromboxane, polymorphonuclear leukocytes, and mast cells.

&NA; The pathophysiology of cold injury is still controversial. An inflammatory process has been implicated as the underlying mechanism and certain anti‐inflammatory substances such as ibuprofen and acetylsalicylic acid have been used in the clinical treatment of frostbite injury. It has been postulated that the progressive ischemic necrosis is secondary to excessive thromboxane A2 production, which upsets the normal balance between prostacyclin (prostaglandin I2) and thromboxane A2. It was aimed to clarify the pathophysiology of cold injury in this study. Twenty‐one New Zealand White rabbits, each weighing 1.2 to 2.9 kg, were divided into control (n = 10) and frostbitten (n = 11) groups the randomly. The rabbit ears in the frostbitten group were subjected to cold injury, and the levels of thromboxane A2 (as thromboxane B2) and of prostaglandin I2 (as 6‐keto‐prostaglandin F1&agr;) and the number of inflammatory cells (polymorphonuclear leukocytes and mast cells) were measured in normal and frostbitten skin of rabbit ears. The levels of 6‐keto prostaglandin F1&agr; and thromboxane B2, the stable metabolites of prostaglandin I2 and thromboxane A2, respectively, were increased in a statistically significant way (p < 0.002) by frostbite injury; however, thromboxane B2 increased more than 6‐keto prostaglandin F1&agr;. Polymorphonuclear leukocytes and mast cells, absent in normal skin, were present in the frostbitten skin. There was a statistically significant (p < 0.01) correlation between the time a rabbit ear was maintained at below ‐ 10°C and skin survival and between the weights of rabbits and skin survival (p < 0.024). All these findings suggest that inflammation is involved in frostbite injury; a decrease in prostaglandin I2/thromboxane A2 ratio could be one of the factors leading to necrosis; the bigger the animal, the better its ability to counter frostbite. (Plast. Reconstr. Surg. 101: 1881, 1998.)

Effect of combination of misoprostol and indomethacin on eicosanoid production in carrageenan-induced air pouch inflammation in rats

The effect of single or combined administration of indomethacin and misoprostol on the exudate leukocyte count and thromboxane B2, a stable metabolite of thromboxane A2, and on the leukotriene B4 level, as cyclooxygenase and lipoxygenase metabolites of arachidonic acid, was investigated in acute carrageenan-induced air pouch inflammation in rats. Administration of indomethacin (0.25 to 4 mg/kg) 1 h before carrageenan given by the orogastric route reduced the exudate leukocyte count and thromboxane B2 level whereas it increased the exudate leukotriene B4 level dose dependently. Administration of misoprostol, a synthetic prostaglandin E1 analogue, (12.5 to 100 microg/kg) twice daily for two days before carrageenan given by the orogastric route increased the exudate leukocyte count. Combined misoprostol and indomethacin did not change the effect of indomethacin alone on exudate leukocyte count. Misoprostol, when used alone, decreased exudate thromboxane B2 level significantly. However, misoprostol did not change the exudate leukotriene B4 level, while its combination with indomethacin prevented the indomethacin-induced increase in exudate leukotriene B4 level. In conclusion, although misoprostol can be combined with non-steroidal anti-inflammatory drugs in many chronic inflammatory situations, our results indicate that misoprostol may also be combined with indomethacin in acute inflammation without producing any change on the antiinflammatory efficacy of indomethacin in rats.

Prostaglandin E2 activity in the synovial-like membrane

The events leading to aseptic loosening of total hip prostheses occur within the synovial-like membrane that forms around the prosthetic components. Prostaglandin E2 (PGE2) activity in this membrane is believed to be one of the factors that cause aseptic loosening. In this study, the authors investigated the correlation between grades of loosening and levels of PGE2-like activity in the membranes surrounding the implants in 14 patients in which total hip arthroplasty revisions were performed. The membranes of patients with high degrees of loosening demonstrated high levels of PGE2-like activity (P < .01). Among the many factors contributing to loosening of total hip arthroplasties, PGE2 appears to have an important role with its bone-resorbing properties.

Effect of misoprostol and indomethacin on cyclooxygenase induction and eicosanoid production in carrageenan-induced air pouch inflammation in rats

Effects of misoprostol, a synthetic prostaglandin E1 (PGE1) analogue, on cyclooxygenase-2 (COX-2) protein level and exudate prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) level were investigated in acute carrageenan-induced air pouch inflammation in rats. Treatment with misoprostol (12.5, 25, and 50 microg/kg) has been started in separated groups, 30 min and 2 days before carrageenan injection and it was given twice a day (total of five doses) by orogastric route. Indomethacin, in doses of 0.5 and 5 mg/kg, and specific COX-2 inhibitor SC-58236, in doses of 5, 10, and 20 mg/kg were given 1 h before carrageenan injection by the orogastric route. Misoprostol increased the levels of PGE2 and COX-2 protein at all doses applied. Despite indomethacin and SC-58236 increased the level of COX-2 protein when they used alone, these drugs partially inhibited misoprostol-induced increase in the level of COX-2 protein. Partial inhibition of misoprostol-induced increase in the level of COX-2 protein by indomethacin or SC-58236 may indicate the modulatory roles of endogenous prostaglandins (PGs, especially, PGE2) on the COX-2 expression.

Impact of colonic mucosal lipoxin A4 synthesis capacity on healing in rats with dextran sodium sulfate-induced colitis

Ulcerative colitis is a chronic inflammatory disease of the colon. This study evaluates the role of colonic mucosal lipoxin A4 (LXA4) synthesis in an experimental rat model of dextran sodium sulfate (DSS)-induced colitis. Wistar rats were randomly assigned to four groups: healthy controls, DSS-induced colitis with no or vehicle therapy, misoprostol or 5-aminosalicylic acid (5-ASA) therapy groups. Disease severity and colonic mucosal LXA4 synthesis was assessed specifically during the acute phase (day 5), chronic phase (day 15) and healing phases (day 19). Both misoprostol and 5-ASA reduced histopathologic score during the acute phase and reduced disease activity score at the healing phase. In addition, misoprostol reduced histopathologic score and colon weight/length ratio during the healing phase. Only misoprostol therapy increased colonic mucosal LXA4 synthesis. Furthermore, LXA4 levels correlated negatively with disease progression (R=-0.953). Collectively, our findings suggest that misoprostol-induced LXA4 synthesis may be favorable for the healing of ulcerative colitis.

A simple and inexpensive device for collecting urine samples from rats

Many studies require collection of metabolic wastes from laboratory animals, and oftentimes it is important that feces and urine be collected separately. The authors describe an easily assembled and inexpensive device that can be used to collect urine samples from rats without any invasive operations. The device affords reasonable separation of feces and urine.

Acetylsalicylic acid and misoprostol combination in adjuvant arthritis of rats

The combined effect of acetylsalicylic acid (ASA) and misoprostol (MISO) on adjuvant arthritis was investigated on rats. Alteration by various doses of MISO and fixed dose of ASA was studied. Drugs were given by the nasogastric route each day beginning from the day of adjuvant injection (day 0) and continued until the 16th day. Paw swelling was measured on days 4, 17, and 29, and secondary lesions were assessed on days 17 and 29. Pathological examination of tibiodorsal junction was also evaluated on the 29th day. The results clearly showed that the combination of MISO with ASA did not inhibit the antiinflammatory effect of ASA. Unexpectedly, MISO increased the antiinflammatory effect of ASA at some dosage regimens.

Effects of Chronic Treatment with Indomethacin at Clinically Relevant Doses on Intestinal Tissue 6-Keto Prostaglandin F1α and Leukotriene B4 Level in Relation to Gastroenteropathy

This study investigated the effects of indomethacin at clinically relevant doses and its chronic usage on intestinal pathology, survival time and intestinal tissue 6-keto prostaglandin F1α and leukotriene B4 level in rats during various periods with different doses. Indomethacin was administered ranging from 0.625 to 5 mg/kg. When used in doses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestinal lesions or death during a treatment period of 30 days. On the other hand, all rats died in 7 days when 5 mg/kg of indomethacin was given. Mortality rate reached 53.3% in seven days in the group where 3.75 mg/kg indomethacin was given. The minimal dose of indomethacin, which induced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic changes were observed in the stomach. Intestinal tissue 6-keto prostaglandin F1α and leukotriene B4 levels were quantified by enzyme immunoassay after homogenisation and extraction of tissue. In dose-dependent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F1α levels during seven days application period (197.39 ± 24.26 vs 383.66 ± 46.68 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however it significantly inhibited intestinal tissue 6-keto prostaglandin F1α levels on 4th day in time-dependent studies (190.3 ± 26.62 vs 383.66 ± 46.68 ng/g tissue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinically relevant doses in rats. Inhibition of prostaglandin synthesis, which was estimated by quantification of intestinal tissue 6-keto prostaglandin F1α level, seemed not to be a prerequisite for its enteropathic effect.