ABSTRACT
Title
Peroxisome proliferators activated receptors gamma and the inflammatory state of gastric mucosa
Authors
A. Sapone1, S. Melega1, D. Canistro1, L. Gatta2-3, D. Vaira3, D. Ranieri1, A. Ieronimo1, M. Paolini1.
1Dept. of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum - University of Bologna, Via Irnerio 48 - 40126 Bologna, Italy.2 Versilia Hospital, Lido di Camaiore, Italy;3 Dpt. of Internal Medicine and Gastroenterology, Alma Mater Studiorum- University of Bologna,Via Massarenti, 9 - 40138 Bologna, Italy
1Dept. of Pharmacology, Molecular Toxicology Unit, Alma Mater Studiorum - University of Bologna, Via Irnerio 48 - 40126 Bologna, Italy.2 Versilia Hospital, Lido di Camaiore, Italy;3 Dpt. of Internal Medicine and Gastroenterology, Alma Mater Studiorum- University of Bologna,Via Massarenti, 9 - 40138 Bologna, Italy
Abstract
Helicobacter pylori (HP) colonization leads to epithelial cell hyperproliferation within inflamed mucosa, causing chronic gastritis, gastric and duodenal ulcer, and has been recognized as a class I gastric carcinogen. HP might contribute to differences in gastric cancer risk among infected populations. The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) regulates inflammatory and growth response of intestinal epithelial cells and might influence HP-induced apoptosis. PPARγ activation was shown to have an inhibitory effect on gastric inflammation and apoptosis induced by HP, and on the proliferation of gastric cancer cells, suggesting that PPARγ may play a significant role in suppressing gastric mucosal inflammation and tumor genesis (1-2).
The aim of this work was to evaluate the role of PPARγ on gastric inflammation on patients who underwent endoscopy complaining upper gastrointestinal symptoms. 312 patients (male/female:140/172; mean age 53 years SD ±14.5 years) undergoing endoscopy during which bioptic samples were obtained, have been studied. HP was evaluated and histological examination was assessed using the updated Sydney System score. Blood sample was also taken to assess single genotype for each individual enclosed in the study using molecular biology techniques (PCR, restriction enzyme digestion, electrophoresis and sequencing). It was assessed that 62.5% (95%CI: 57 to 67.7) of patients were HP positive. 59 showed endoscopic lesions (18.9%; 95%CI: 15 to 23.6), 32 had oesophagitis (10.3%; 95%CI: 7.4 to 14.1), 11 gastric ulcer (3.5%; 95%CI: 2 to 6.2), and 22 duodenal ulcer (7.1%; 95%CI: 4.7 to 10.4). 120 patients (38.5%; 95%CI:33.2 to 44) presented intestinal metaplasia (IM) and atrophy. 130 patients (41.7%; 95%CI: 36.3 to 47.2) had PPARγ genetic variants different from the wild type (Table 1) (3-4). Among the PPARγ alleles, the γ*2 allele was significantly associated with the presence of HP infection (OR 3.19; 95% CI: 1.86 to 5.47; p<0.001) and not associated with IM/atrophy (OR 1.57; 95% CI: 0.98 to 2.51; p=0.058), by simple regression analysis. The multivariate analysis including gender and age confirmed the association between the allele γ*2 and the presence of HP infection (OR 3.18; 95%CI 1.85 to 5.46; p<0.001), whilst failed to show any significant association between the allele γ*2 and IM/atrophy. noteworthy, the γ*2 allele was significantly associated with the severity of polymorphonucleated cells infiltration of the antral gastric mucosa (chi-squared test for trend: p<0.0001). Our observations suggest that this family of receptors is involved in the HP inflammatory process. People carrying mutated alleles are strongly predisposed to develop HP infection of high hystopatological degree.
1. Takahashi, N. et al. Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells . FEBS Lett. 455, 135-139 (1999).
2. Gupta, R.A. et al.Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells. J. Biol. Chem. 276, 31059-31066 (2001).
3. Huang X, et al. Effects of peroxisome proliferator activated receptor-gamma 2 gene Pro12Ala polymorphism on fasting blood lipids: A meta-analysis.Atherosclerosis. 215, 136-44 (2011).
4. Bidzińska-Speichert B, Demissie M, Tworowska U, Slezak R, Dobosz T, Bednarek-Tupikowska G, Milewicz A.Leptin level and the PPARgamma2 Pro12Ala and Pro115Gln polymorphisms in women with functional hyperandrogenism. Preliminary report].Przegl Lek. 62, 833-7 (2005).
The aim of this work was to evaluate the role of PPARγ on gastric inflammation on patients who underwent endoscopy complaining upper gastrointestinal symptoms. 312 patients (male/female:140/172; mean age 53 years SD ±14.5 years) undergoing endoscopy during which bioptic samples were obtained, have been studied. HP was evaluated and histological examination was assessed using the updated Sydney System score. Blood sample was also taken to assess single genotype for each individual enclosed in the study using molecular biology techniques (PCR, restriction enzyme digestion, electrophoresis and sequencing). It was assessed that 62.5% (95%CI: 57 to 67.7) of patients were HP positive. 59 showed endoscopic lesions (18.9%; 95%CI: 15 to 23.6), 32 had oesophagitis (10.3%; 95%CI: 7.4 to 14.1), 11 gastric ulcer (3.5%; 95%CI: 2 to 6.2), and 22 duodenal ulcer (7.1%; 95%CI: 4.7 to 10.4). 120 patients (38.5%; 95%CI:33.2 to 44) presented intestinal metaplasia (IM) and atrophy. 130 patients (41.7%; 95%CI: 36.3 to 47.2) had PPARγ genetic variants different from the wild type (Table 1) (3-4). Among the PPARγ alleles, the γ*2 allele was significantly associated with the presence of HP infection (OR 3.19; 95% CI: 1.86 to 5.47; p<0.001) and not associated with IM/atrophy (OR 1.57; 95% CI: 0.98 to 2.51; p=0.058), by simple regression analysis. The multivariate analysis including gender and age confirmed the association between the allele γ*2 and the presence of HP infection (OR 3.18; 95%CI 1.85 to 5.46; p<0.001), whilst failed to show any significant association between the allele γ*2 and IM/atrophy. noteworthy, the γ*2 allele was significantly associated with the severity of polymorphonucleated cells infiltration of the antral gastric mucosa (chi-squared test for trend: p<0.0001). Our observations suggest that this family of receptors is involved in the HP inflammatory process. People carrying mutated alleles are strongly predisposed to develop HP infection of high hystopatological degree.
|
PPARγ *2 (exon B) |
PPARγ *3 (exon 2) |
PPARγ *2*3 (exon B+exon 2) |
| P12A | P115Q | P12A + P115Q |
|
122 (39.1%) (95%CI: 33.9 to 44.6) |
5 (1.6%) (95%CI: 0.7 to 3.7) |
3 (0.1%) (95%CI:0.3 to 2.8) |
1. Takahashi, N. et al. Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells . FEBS Lett. 455, 135-139 (1999).
2. Gupta, R.A. et al.Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells. J. Biol. Chem. 276, 31059-31066 (2001).
3. Huang X, et al. Effects of peroxisome proliferator activated receptor-gamma 2 gene Pro12Ala polymorphism on fasting blood lipids: A meta-analysis.Atherosclerosis. 215, 136-44 (2011).
4. Bidzińska-Speichert B, Demissie M, Tworowska U, Slezak R, Dobosz T, Bednarek-Tupikowska G, Milewicz A.Leptin level and the PPARgamma2 Pro12Ala and Pro115Gln polymorphisms in women with functional hyperandrogenism. Preliminary report].Przegl Lek. 62, 833-7 (2005).