BACKGROUND & AIMS
Helicobacter pylori-induced gastric carcinogenesis has been linked to the microbial oncoprotein CagA. Spermine oxidase (SMO) metabolizes the polyamine spermine into spermidine and generates H2O2 that causes apoptosis and DNA damage. We determined if pathogenic effects of CagA are attributable to SMO.
METHODS
Levels of SMO, apoptosis, and DNA damage (8-oxoguanosine) were measured in gastric epithelial cell lines infected with cagA+ or cagA− H. pylori strains, or transfected with a CagA expression plasmid, in the absence or presence of SMO small interfering RNA, or an SMO inhibitor. The role of CagA in induction of SMO and DNA damage was assessed in H. pylori-infected gastritis tissues from humans, gerbils, and both wild-type and hypergastrinemic INS-GAS mice, using immunohistochemistry and flow cytometry.
RESULTS
cagA+ strains or ectopic expression of CagA, but not cagA− strains, led to increased levels of SMO, apoptosis, and DNA damage in gastric epithelial cells, and knockdown or inhibition of SMO blocked apoptosis and DNA damage. There was increased SMO expression, apoptosis, and DNA damage in gastric tissues from humans infected with cagA+, but not cagA− strains. In gerbils and mice, DNA damage was CagA-dependent and present in cells that expressed SMO. Gastric epithelial cells with DNA damage that were negative for markers of apoptosis accounted for 42–69% of cells in gerbils and INS-GAS mice with dysplasia and carcinoma.
CONCLUSIONS
By inducing SMO, H. pylori CagA generates cells with oxidative DNA damage, and a subpopulation of these cells are resistant to apoptosis and thus at high risk for malignant transformation.
This study provides the first systematic empirical evidence that RAP, originally defined by Apley, includes children whose symptoms are consistent with the symptom criteria for several FGIDs defined by the Rome criteria. The pediatric Rome criteria may be useful in clinical research to (1) describe the symptom characteristics of research participants who meet Apley's broad criteria for RAP, and (2) select patients with particular symptom profiles for investigation of potential biologic and psychosocial mechanisms associated with pediatric FGIDs.
Background
Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T regulatory cells (Treg) are critical for intestinal immune homoeostasis.
Objective
To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC.
Design
Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls.
Results
The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis.
Conclusion
The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.
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