Telomere shortening is associated with reduced duodenal HCO3−secretory but normal gastric acid secretory capacity in aging mice

2012 ◽  
Vol 303 (12) ◽  
pp. G1312-G1321 ◽  
Author(s):  
Biguang Tuo ◽  
Zhenyu Ju ◽  
Brigitte Riederer ◽  
Regina Engelhardt ◽  
Michael P. Manns ◽  
...  
Keyword(s):  
Duodenal Ulcer ◽  
Gastric Acid ◽  
Short Circuit ◽  
Duodenal Mucosa ◽  
Ulcer Formation ◽  
Wild Type ◽  
Double Knockout ◽  
Telomere Shortening ◽  
Genetic Ablation ◽  
Secretory Capacity

The incidence of duodenal ulcer, especially Helicobacter pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescence and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO3−secretory rates in aged late-generation (G3) telomerase-deficient (mTERC−/−) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolin-stimulated HCO3−secretion and short-circuit current ( Isc) in isolated duodenal mucosa of G3mTERC−/−mice were markedly reduced compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G3mTERC−/−gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G3mTERC−/−mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. However, the ratios of cystic fibrosis transmembrane conductance regulator (CFTR) and solute-linked carrier 26 gene family (Slc26a6) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening-induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolin-stimulated duodenal HCO3−secretion and Iscin mTERC−/−p21−/−double-knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO3−secretory capacity, whereas gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation.

A novel small molecule CFTR inhibitor attenuates HCO3− secretion and duodenal ulcer formation in rats

2005 ◽  
Vol 289 (4) ◽  
pp. G753-G759 ◽  
Author(s):  
Yasutada Akiba ◽  
Michael Jung ◽  
Samedy Ouk ◽  
Jonathan D. Kaunitz
Keyword(s):  
Duodenal Ulcer ◽  
Duodenal Mucosa ◽  
Mutant Mice ◽  
Protective Mechanism ◽  
Ulcer Formation ◽  
Apparent Paradox ◽  
Duodenal Ulcers ◽  
Buffering Power ◽  
Ph Stat ◽  
Cf Transmembrane Conductance Regulator

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) plays a crucial role in mediating duodenal bicarbonate (HCO3−) secretion (DBS). Although impaired DBS is observed in CF mutant mice and in CF patients, which would predict increased ulcer susceptibility, duodenal injury is rarely observed in CF patients and is reduced in CF mutant mice. To explain this apparent paradox, we hypothesized that CFTR dysfunction increases cellular [HCO3−] and buffering power. To further test this hypothesis, we examined the effect of a novel, potent, and highly selective CFTR inhibitor, CFTRinh-172, on DBS and duodenal ulceration in rats. DBS was measured in situ using a standard loop perfusion model with a pH stat under isoflurane anesthesia. Duodenal ulcers were induced in rats by cysteamine with or without CFTRinh-172 pretreatment 1 h before cysteamine. Superfusion of CFTRinh-172 (0.1–10 μM) over the duodenal mucosa had no effect on basal DBS but at 10 μM inhibited acid-induced DBS, suggesting that its effect was limited to CFTR activation. Acid-induced DBS was abolished at 1 and 3 h and was reduced 24 h after treatment with CFTRinh-172, although basal DBS was increased at 24 h. CFTRinh-172 treatment had no effect on gastric acid or HCO3− secretion. Duodenal ulcers were observed 24 h after cysteamine treatment but were reduced in CFTRinh-172-pretreated rats. CFTRinh-172 acutely produces CFTR dysfunction in rodents for up to 24 h. CFTR inhibition reduces acid-induced DBS but also prevents duodenal ulcer formation, supporting our hypothesis that intracellular HCO3− may be an important protective mechanism for duodenal epithelial cells.

Estrogen potentiates prostaglandin E2-stimulated duodenal mucosal HCO3− secretion in mice

2012 ◽  
Vol 303 (1) ◽  
pp. E111-E121 ◽  
Author(s):  
Biguang Tuo ◽  
Guorong Wen ◽  
Xue Wang ◽  
Jingyu Xu ◽  
Rui Xie ◽  
...  
Keyword(s):  
Duodenal Ulcer ◽  
Sex Difference ◽  
Young Women ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Prostaglandin E ◽  
Lower Prevalence ◽  
Physiological Concentration ◽  
17Β Estradiol ◽  
Specific Antagonist

The cause of lower prevalence of duodenal ulcer in young women compared with men is largely unknown. We recently found that sex difference in duodenal mucosal HCO3− secretion existed in humans and mice, but the mechanisms are not clear. Prostaglandin E2 (PGE2) is an important endogenous mediator that plays an important role in the regulation of duodenal HCO3− secretion. Therefore, in the present study, we investigated the effect of estrogen on PGE2-stimulated duodenal HCO3− secretion and the underlying mechanisms. The results showed that 17β-estradiol at the physiological concentration (1 nM) had no significant effects on duodenal mucosal HCO3− secretion or short-circuit current ( Isc) in mice. However, the pretreatment of 17β-estradiol (1 nM) markedly potentiated PGE2-stimulated duodenal HCO3− secretion and Isc ( P < 0.01 and P < 0.05). Global estrogen receptor (ER) antagonist ICI-182,780 and ERα-specific antagonist MPP, but not the ERβ-specific antagonist PHTPP, abolished estrogen-potentiated PGE2-stimulated duodenal HCO3− secretion and Isc. 17β-Estradiol and PGE2 additively increased phosphatidylinositol 3-kinase (PI3K) activity and Akt phosphorylation. Wortmannin, a specific PI3K inhibitor, inhibited estrogen-potentiated PGE2-stimulated duodenal HCO3− secretion and Isc. In conclusion, estrogen at the physiological concentration potentiates PGE2-stimulated duodenal mucosal HCO3− secretion through the activation of ERα and the PI3K-dependent mechanism, which may contribute to the sex difference in duodenal mucosal HCO3− secretion and the lower prevalence of duodenal ulcer in young women.

The effect of 15 (R) 15 methyl prostaglandin E2 on gastric acid secretion in duodenal ulcer patients

1977 ◽  
Vol 13 (1) ◽  
pp. 115-124 ◽  
Author(s):  
Frederick W.K. Chen ◽  
Ho Soon Teck ◽  
Sultan M.M. Karim
Keyword(s):  
Duodenal Ulcer ◽  
Prostaglandin E2 ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid

Increased susceptibility of purinergic receptor-deficient mice to lung infection withPseudomonasaeruginosa

2005 ◽  
Vol 289 (5) ◽  
pp. L890-L895 ◽  
Author(s):  
Cara Geary ◽  
Henry Akinbi ◽  
Tom Korfhagen ◽  
Jean-Etienne Fabre ◽  
Richard Boucher ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Purinergic Receptors ◽  
Tissue Injury ◽  
Purinergic Receptor ◽  
Intratracheal Instillation ◽  
Lavage Fluid ◽  
Sublethal Dose ◽  
Wild Type ◽  
Double Knockout

Purinergic receptors are expressed throughout the respiratory system in diverse cell types. The efficiency of mucus clearance in the airways, the cascade leading to tissue injury, and inflammation are modulated by autocrine/paracrine release of nucleotides and signaling by purinergic receptors. We assessed the role of purinergic receptors in innate host defense of the lung in vivo by infecting mice deficient in P2Y1, P2Y2, or both receptors with intratracheal instillation of Pseudomonas aeruginosa. After P. aeruginosa challenge, all double knockout (P2Y1/P2Y2−/−) mice succumbed within 30 h of challenge, whereas 85% of the wild-type mice survived. Thirty-three percent of wild-type mice survived beyond 96 h. Single knockout mice, P2Y1−/−, or P2Y2−/−, exhibited intermediate survivals. Twenty-four hours following intratracheal instillation of a sublethal dose of P. aeruginosa, the level of total protein in bronchoalveolar lavage fluid was 1.8-fold higher in double knockout than in wild-type mice ( P < 0.04). Total cell count in bronchoalveolar lavage fluids at 4 h and levels of IL-6 and macrophage inflammatory protein-2 in lung homogenates at 24 h postchallenge were significantly reduced in P2Y1/P2Y2−/− mice relative to wild-type mice. These findings suggest that purinergic receptors exert a protective role against infection of the lungs by P. aeruginosa by decreasing protein leak and enhancing proinflammatory cytokine response.

5‐Hydroxytryptamine contributes significantly to a reflex pathway by which the duodenal mucosa protects itself from gastric acid injury

2006 ◽  
Vol 20 (14) ◽  
pp. 2486-2495 ◽  
Author(s):  
Anders J. Smith ◽  
Alfred E. Chappell ◽  
Andre G. Buret ◽  
Kim E. Barrett ◽  
Hui Dong
Keyword(s):  
Gastric Acid ◽  
Duodenal Mucosa ◽  
Reflex Pathway

scholarly journals Constitutive expression, not a particular primary sequence, is the important feature of the H3 replacement variant hv2 in Tetrahymena thermophila.

1997 ◽  
Vol 17 (11) ◽  
pp. 6303-6310 ◽  
Author(s):  
L Yu ◽  
M A Gorovsky
Keyword(s):  
Protein Sequence ◽  
Tetrahymena Thermophila ◽  
Histone H3 ◽  
Constitutive Expression ◽  
Histone Variants ◽  
Wild Type ◽  
Ciliated Protozoan ◽  
Knockout Mutant ◽  
Double Knockout ◽  
Constitutive Synthesis

Although quantitatively minor replication-independent (replacement) histone variants have been found in a wide variety of organisms, their functions remain unknown. Like the H3.3 replacement variants of vertebrates, hv2, an H3 variant in the ciliated protozoan Tetrahymena thermophila, is synthesized and deposited in nuclei of nongrowing cells. Although hv2 is clearly an H3.3-like replacement variant by its expression, sequence analysis indicates that it evolved independently of the H3.3 variants of multicellular eukaryotes. This suggested that it is the constitutive synthesis, not the particular protein sequence, of these variants that is important in the function of H3 replacement variants. Here, we demonstrate that the gene (HHT3) encoding hv2 or either gene (HHT1 or HHT2) encoding the abundant major H3 can be completely knocked out in Tetrahymena. Surprisingly, when cells lacking hv2 are starved, a major histone H3 mRNA transcribed by the HHT2 gene, which is synthesized little, if at all, in wild-type nongrowing cells, is easily detectable. Both HHT2 and HHT3 knockout strains show no obvious defect during vegetative growth. In addition, a mutant with the double knockout of HHT1 and HHT3 is viable while the HHT2 HHT3 double-knockout mutant is not. These results argue strongly that cells require a constitutively expressed H3 gene but that the particular sequence being expressed is not critical.

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