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IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin

100%

Malicki S., Winiarski M., Matlok M., Kostarczyk W., Guzdek A., Konturek P. C.

Journal of Physiology and Pharmacology

2009

tom 60

nr 4

141-146

Recent investigations suggest that proinflammatory cytokines such as IL-6 and IL-8 are involved in the development of colorectal cancer (CRC), whereas statins, primarily used to decrease high levels of blood cholesterol, exhibit pleiotropic effects on carcinogenesis. In the present study we compared the expression of IL-8 and IL-6 in tissue samples of tumor and adjacent normal colon mucosa obtained from patients with advanced colorectal cancer (CRC). The analysis of mRNAs expression for these proinflammatory cytokines determined by RT-PCR showed a higher level of IL-8-mRNA in tumor tissue than in normal mucosa, while IL-6 was similarly expressed in tumor and normal tissue. The mean values of serum levels of both IL-6 and IL-8 were significantly higher in CRC patients than in healthy volunteers. Surgical removal of the tumor resulted in a prompt decrease of serum level of IL-8 already on the third day, whereas IL-6 level was transiently increased to become lower only after 7-10 days. Treatment of CRC with simvastatin (80 mg/day for 14 days) led to a significant decrease of serum IL-6, while the IL-8 level was less affected. The in vitro experiments on colorectal cancer-derived cell lines (HT-29 and Caco-2) demonstrated that application of simvastatin decreased generation of both IL-6 and IL-8. The differences in response of serum levels of IL-6 and IL-8 after tumor removal and treatment with simvastatin are novel observations suggesting distinct pathological roles of the two cytokines in CRC development. We conclude that 1) colorectal carcinogenesis is accompanied by increased synthesis and release of proinflammatory cytokines such as IL-6 and IL-8; 2) simvastatin therapy results in a decrease in serum level of proinflammatory cytokines, especially IL-6 in CRC and 3) simvastatin inhibits release of IL-8 and IL-6 from colorectal cell lines.

Cyclooxygenase-2 [COX-2] is the key event in pathophysiology of Barrett's esophagus. Lesson from experimental animal model and human subjects

84%

Majka J., Rembiasz K., Migaczewski M., Budzynski A., Ptak-Belowska A., Pabianczyk R., Urbanczyk K., Zub-Pokrowiecka A., Matlok M., Brzozowski T.

Journal of Physiology and Pharmacology

2010

tom 61

nr 4

409-418

Mixed reflux of the gastroduodenal contents induces the esophageal mucosal damage and inflammation progressing chronic esophagitis and premalignant Barrett's esophagus (BE). The role of cyclooxygenase-2 (COX-2) and chronic inflammation in the progression of BE toward adenocarcinoma of the esophagus has not been extensively studied in experimental models of BE in animals and in human subjects. We evaluated the expression of COX-2 in rat model of BE and examined the usefulness of COX-2 expression in determining the risk of malignant transformation in patients with BE treated with argon plasma coagulation (APC) that allows for effective ablation of metaplastic mucosa (group A) without or with proton pump inhibitors (PPI). In addition, the group B of patients was subjected to laparoscopic Nissen's fundoplication and group K that served as control, received PPI treatment only. Expression of COX-2 was evaluated in fresh-frozen biopsy specimens obtained from the distal esophagus in all 60 patients before and 12 months after treatment. In experimental studies, eighty rats were surgically prepared with esophagogastroduodenal anastomosis (EGDA) resulting in chronic esophagitis. At 4 months, the esophageal damage in EGDA rats was evaluated by macroscopic and histological index score, the plasma IL-1ß and TNF- levels was determined by ELISA and the mucosal expression of COX-2 mRNA and COX-2 protein were assessed by RT-PCR and Western Blot, respectively. Chronic esophagitis was developed in all EGDA animals followed by the rise in the plasma TNF- and IL-1ß levels. Histology revealed extensive esophageal ulcerations with development of columnar epithelium, formation of mucus glands in squamous epithelium, intestinal metaplasia distant to anastomosis consisting of goblet cells, infiltration of inflammatory cells including plasma cells and lymphocytes. COX-2 mRNA was absent in the esophageal mucosa of sham-control animals but strongly upregulated in metaplastic Barrett's epithelium. In BE patients, the overexpression of COX-2 was documented in patients with dysplasia. After APC (group A) or Nissen's fundoplication (group B), the expression of COX-2 mRNA was markedly reduced and these effects were positively correlated with histopathological findings. Controls failed to show significant alterations in COX-2 expression. We conclude that 1) EGDA rats serve as the suitable model of the chronic esophagitis by the gastrointestinal refluxate resembling many features of those observed in human Barrett's esophagus, as confirmed by severe morphology changes, excessive release of proinflammatory cytokines TNF- and IL-1ß and overexpression of COX-2, and 2) the significant correlation of the degree of COX-2 overexpression with histopathological findings indicates the usefulness of this inducible biomarker as a valuable indicator of the risk of malignant transformation in patients with BE.

Ograniczanie wyników

2 Journal of Physiology and Pharmacology

2 Matlok M.

1 Brzozowski T.

1 Budzynski A.

1 Guzdek A.

1 Konturek P. C.

1 Kostarczyk W.

1 Majka J.

1 Malicki S.

1 Migaczewski M.

1 Pabianczyk R.

1 Ptak-Belowska A.

1 Rembiasz K.

1 Urbanczyk K.

1 Winiarski M.

1 Zub-Pokrowiecka A.

1 2010

1 2009

Wyniki wyszukiwania

IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin

Cyclooxygenase-2 [COX-2] is the key event in pathophysiology of Barrett's esophagus. Lesson from experimental animal model and human subjects