|
1
|
Tarnawski AS, Ahluwalia A, Jones MK. Increased susceptibility of aging gastric mucosa to injury: The mechanisms and clinical implications. World J Gastroenterol 2014; 20:4467-4482. [PMID: 24782600 PMCID: PMC4000484 DOI: 10.3748/wjg.v20.i16.4467] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-“aging gastropathy”-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., NSAIDs-induced gastric injury) than younger patients; and (3) increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically.
Collapse
|
|
2
|
Ahluwalia A, Jones MK, Tarnawski AS. Key role of endothelial importin-α in VEGF expression and gastric angiogenesis: novel insight into aging gastropathy. Am J Physiol Gastrointest Liver Physiol 2014; 306:G338-45. [PMID: 24356884 DOI: 10.1152/ajpgi.00382.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent in vivo studies demonstrated that aging gastric mucosa has impaired angiogenesis and reduced expression of vascular endothelial growth factor (VEGF). Angiogenesis is triggered by hypoxia and VEGF gene activation, and the latter requires transport of transcription factor(s) into endothelial cell nuclei. We focused on gastric mucosal endothelial cells (GMEC), which are key targets and effectors of gastric angiogenesis, and determined whether and to what extent importin-α, a nuclear transport protein, regulates VEGF gene activation and gastric angiogenesis and the possible role of importin-α in aging gastropathy. GMEC were isolated from rats 3 and 24 mo of age, young (YGEC) and aging (AGEC), respectively. We examined in these cells 1) in vitro angiogenesis, 2) expression of VEGF and importin-α, 3) nuclear transport of hypoxia-inducible factor (HIF)-1α by importin-α, 4) binding of HIF-1α to the VEGF gene promoter, and 5) effects of importin-α silencing in YGEC and its upregulation in AGEC on angiogenesis and VEGF expression. AGEC exhibited significantly impaired in vitro angiogenesis by fourfold and decreased expression of VEGF, importin-α, and nuclear HIF-1α by 1.4-fold, 1.6-fold, and 2.9-fold, respectively, vs. YGEC. Upregulation of importin-α in AGEC significantly reversed all these abnormalities. In YGEC, knockdown of importins-α1 and -α3 significantly reduced in vitro angiogenesis by 93% and 73% and VEGF expression by 48% and 52%, respectively. The above findings demonstrate that importin-α is a novel and critical regulator of gastric angiogenesis. Its reduced expression in AGEC is the key mechanism for impaired angiogenesis and reduced VEGF.
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Medical and Research Services, Veterans Affairs Long Beach Healthcare System (VALBHS) and Southern California Institute for Research and Education
| | | | | |
Collapse
|
|
3
|
Ahluwalia A, Jones MK, Deng X, Sandor Z, Szabo S, Tarnawski AS. An imbalance between VEGF and endostatin underlies impaired angiogenesis in gastric mucosa of aging rats. Am J Physiol Gastrointest Liver Physiol 2013; 305:G325-32. [PMID: 23788612 DOI: 10.1152/ajpgi.00127.2013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric mucosa of aging individuals exhibits increased susceptibility to injury and delayed healing. Our previous studies in young rats showed that healing of mucosal injury depends on and is critically dependent on VEGF and angiogenesis. Since angiogenesis in aging gastric mucosa has not been examined before, in this study we examined the extent to which angiogenesis is impaired in gastric mucosa of aging vs. young rats and determined the underlying mechanisms with a focus on mucosal expression of VEGF (proangiogenic factor) and endostatin (antiangiogenic factor). Aging rats had significantly impaired gastric angiogenesis by ~12-fold, 5-fold, 4-fold, and 3-fold, respectively (vs. young rats; all P < 0.001) at 24, 48, 72, and 120 h following ethanol-induced gastric injury and reduced and delayed healing of mucosal erosions. In gastric mucosa of aging (vs. young) rats at baseline, VEGF expression was significantly reduced, whereas endostatin levels were significantly increased (P < 0.05 and P < 0.01, respectively). In contrast to young rats, gastric mucosal VEGF levels did not increase following ethanol-induced injury in aging rats. MMP-9 enzyme activity was significantly higher in gastric mucosa of aging vs. young rats both at baseline (2.7-fold) and 24 h (3.8-fold) after ethanol injury (both P < 0.001). Since endostatin is generated from collagen XVIII by MMP-9, this finding can explain the mechanism of increased endostatin expression in aging gastric mucosa. The above findings demonstrate that reduced VEGF and increased endostatin result in the impaired angiogenesis and delayed injury healing in gastric mucosa of aging rats.
Collapse
Affiliation(s)
- Amrita Ahluwalia
- Veterans Affairs Long Beach Healthcare System, and Univ. of California, Irvine, 5901 E. 7th St., 09/151, Bldg. 162, Rm. 115, Long Beach, CA 90822. or
| | | | | | | | | | | |
Collapse
|
|
4
|
Seo PJ, Kim N, Kim JH, Lee BH, Nam RH, Lee HS, Park JH, Lee MK, Chang H, Jung HC, Song IS. Comparison of Indomethacin, Diclofenac and Aspirin-Induced Gastric Damage according to Age in Rats. Gut Liver 2012; 6:210-7. [PMID: 22570750 PMCID: PMC3343159 DOI: 10.5009/gnl.2012.6.2.210] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 09/17/2011] [Accepted: 10/10/2011] [Indexed: 12/26/2022] Open
Abstract
Background/Aims Aging gastric mucosa is known to have decreased mucosal defenses and increased susceptibility to injury by nonsteroidal anti-inflammatory drugs. Depending on the type of nonsteroidal anti-inflammatory drug (NSAID), the underlying mechanisms and the extent of damage to the stomach or intestine may differ. This study was performed to evaluate the acute gastric damage caused by different doses of indomethacin, diclofenac and aspirin in rats of various ages. Methods For the acute models, indomethacin (10, 20 or 40 mg/kg), diclofenac (40 or 80 mg/kg) or aspirin (100 mg/kg) was given to 7- and 25-week-old and 1-year-old Sprague-Dawley rats by intragastric gavage. The gross ulcer index, damage area as assessed by imaging, histological index, myeloperoxidase (MPO) activity, and cytosolic phospholipase A2 (cPLA2) levels were measured after 24 hours. Results The gross ulcer index and damage area increased with age in the presence of three NSAIDs (p<0.05). The increases in MPO levels induced by diclofenac and aspirin were significantly higher in 1-year-old than 7-week-old rats (p<0.05). cPLA2 expression induced by indomethacin (10 and 40 mg/kg) was greater in the 1-year-old rats, compared with 7-week-old rats (p<0.05). Conclusions NSAID-induced acute gastric damage increased in a dose- and age-dependent manner.
Collapse
Affiliation(s)
- Pyoung Ju Seo
- Department of Internal Medicine Seoul National University Bundang Hospital, Seongnam, Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
5
|
Influence of aging on experimental gastrointestinal motility in extraction of rat molar teeth. PEDIATRIC DENTAL JOURNAL 2012. [DOI: 10.1016/s0917-2394(12)70246-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
|
|
6
|
Kawachi M, Matsunaga Y, Tanaka T, Hori Y, Ito K, Nagahama K, Ozaki T, Inoue N, Toda R, Yoshii K, Hirayama M, Kawabata Y, Takei M. Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats. Eur J Pharmacol 2011; 666:218-25. [PMID: 21651906 DOI: 10.1016/j.ejphar.2011.05.049] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Revised: 05/19/2011] [Accepted: 05/22/2011] [Indexed: 12/12/2022]
Affiliation(s)
- Masanao Kawachi
- Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., 2512-1 Numagami, Oshikiri, Kumagaya-shi, Saitama, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Tarnawski A, Pai R, Deng X, Ahluwalia A, Khomenko T, Tanigawa T, Akahoshi T, Sandor Z, Szabo S. Aging gastropathy-novel mechanisms: hypoxia, up-regulation of multifunctional phosphatase PTEN, and proapoptotic factors. Gastroenterology 2007; 133:1938-47. [PMID: 18054565 DOI: 10.1053/j.gastro.2007.08.037] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2006] [Accepted: 07/19/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Aging gastric mucosa has impaired mucosal defense and increased susceptibility to injury. Our aims were to determine the mechanisms responsible for above abnormalities. METHODS We used Fisher F-344 rats, 3 and 24 months of age. We measured gastric mucosal blood flow; visualized mucosal hypoxia; examined expression of early growth response-1 transcription factor and phosphatase and tensin homologue deleted on chromosome 10 (PTEN); assessed apoptosis; and determined expression of caspase-3, caspase-9, and survivin. We also examined susceptibility of gastric mucosa of young and aging rats to ethanol injury and whether down-regulation of PTEN affects susceptibility of aging gastric mucosa to injury. To determine human relevance, we examined expression of PTEN and survivin in human gastric specimens of young and aging individuals. RESULTS Gastric mucosa of aging (vs young) rats has a 60% reduction in mucosal blood flow; prominent hypoxia; and increased early growth response-1 transcription factor and PTEN messenger RNAs, and proteins. It also has increased expression of proapoptotic proteins caspase-3 and capase-9, reduced survivin, and a 6-fold increased apoptosis vs mucosa of young rats. Ethanol-induced gastric mucosal injury in aging (vs young) rats was significantly increased. The down-regulation of PTEN in gastric mucosa of aging rats completely reversed its increased susceptibility to ethanol injury. In aging human gastric mucosa, PTEN expression was significantly increased, whereas survivin was significantly reduced. CONCLUSIONS (1) Gastric mucosa of aging rats has significantly reduced blood flow, tissue hypoxia, activation of Egr-1, PTEN; increased caspases; and reduced survivin. (2) These changes increase susceptibility of aging gastric mucosa to injury.
Collapse
Affiliation(s)
- Andrzej Tarnawski
- Department of Medicine, VA Long Beach Healthcare System and the University of California, Irvine, California, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Okabe S, Amagase K. An overview of acetic acid ulcer models--the history and state of the art of peptic ulcer research. Biol Pharm Bull 2005; 28:1321-41. [PMID: 16079471 DOI: 10.1248/bpb.28.1321] [Citation(s) in RCA: 158] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Four types of experimental chronic ulcer models, named acetic acid ulcer models, have been developed to examine the healing process of peptic ulcers, screen anti-ulcer drugs, and better evaluate the adverse effects of various anti-inflammatory drugs on the gastrointestinal mucosa. The model easily and reliably produces round, deep ulcers in the stomach and duodenum, allowing acetic acid ulcer production in mice, rats, Mongolian gerbils, guinea pigs, cats, dogs, miniature pigs, and monkeys. These ulcer models highly resemble human ulcers in terms of both pathological features and healing process. The models have been established over the past 35 years and are now used throughout the world by basic and clinical scientists. One of the characteristic features of acetic acid ulcers in rats is the spontaneous relapse of healed ulcers >100 d after ulceration, an endoscopically confirmed phenomenon. Indomethacin significantly delays the healing of acetic acid ulcers, probably by reducing endogenous prostaglandins and inhibiting angiogenesis in ulcerated tissue. Helicobacter pylori significantly delays healing of acetic acid ulcers and causes relapse of healed ulcers at a high incidence in Mongolian gerbils. Anti-secretory drugs (e.g. omeprazole), prostaglandin analogs, mucosal defense agents (e.g. sucralfate), and various growth factors all significantly enhance healing of acetic acid ulcers. Gene therapy with epidermal growth factor and vascular endothelial growth factor applied to the base of acetic acid ulcers in rats is effective in enhancing ulcer healing. Since an inhibitor of nitric oxide syntase prevents ulcer healing, nitric oxide might be involved in the mechanism underlying ulcer healing. We conclude that acetic acid ulcer models are quite useful for various studies related to peptic ulcers.
Collapse
Affiliation(s)
- Susumu Okabe
- Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 602-0897, Japan.
| | | |
Collapse
|
|
9
|
Okabe S, Amagase K. [An overview of acetic acid ulcer models and their utility for drug screening]. Nihon Yakurigaku Zasshi 2003; 122:73-92. [PMID: 12843575 DOI: 10.1254/fpj.122.73] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since Takagi et al. reported an experimental chronic gastric ulcer model [acetic acid ulcers induced by submucosal injection of acetic acid (Type 1)], we further modified the methodology and subsequently devised three more models. The second model involves inducing ulcers by serosal application of an acetic acid solution (Type 2) and the third model achieves ulcer induction by intragastric application of an acetic acid solution (Type 3). The forth model was modification of the third model by giving the acetic acid solution and the same volume of air to make one ulcer in the stomach (Type 4). In general, animals accepted the procedures without problems and no undesirable effects were noticed. More importantly, this experimental animal model allows production of ulcers that highly resemble human ulcers in terms of both pathology and healing. Indeed, relapse is even endoscopically observed for 360 days after ulceration. The ulcers produced not only respond well to various anti-ulcer medications, such as antisecretory and mucosal protective drugs and growth factors, but also demonstrate appropriate responses to ulcerogenic agents such as NSAIDs. In addition, we have recently demonstrated that H. pylori infection resulted in delayed ulcer healing and recurrence of healed acetic acid ulcers induced in Mongolian gerbils. The present article gives a brief summary of the ulcer history before establishment of acetic acid ulcers and characteristic features of acetic acid ulcer, including both their merits and shortcomings.
Collapse
Affiliation(s)
- Susumu Okabe
- Department of Applied Pharmacology, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
| | | |
Collapse
|
|
10
|
Wen CY, Ito M, Wang H, Chen LD, Xu ZM, Matsuu M, Shichijo K, Nakayama T, Nakashima M, Sekine I. IL-11 up-regulates Tie-2 expression during the healing of gastric ulcers in rats. World J Gastroenterol 2003; 9:788-90. [PMID: 12679933 PMCID: PMC4611451 DOI: 10.3748/wjg.v9.i4.788] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2002] [Revised: 01/06/2003] [Accepted: 01/13/2003] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate Tie-2 expression during the repair of acetic acid-induced gastric ulcers in rats treated with recombinant human IL-11 (rhIL-11) and in untreated control animals. METHODS Gastric ulcers were induced in male Wistar rats by applying acetic acid to the fundus of the stomach. RhIL-11 (100 microg/kg twice daily, subcutaneously) was administered from two days before ulcer induction and continued for five days after the induction. Control rats received bovine serum albumin. Gastric specimens were collected at 3 and 5 days after the induction of ulcer for immunohistochemical observation, Western blotting, and reverse transcription polymerase chain reaction (RT-PCR). RESULTS Immunohistochemical and Western blot analysis demonstrated that Tie-2 expression was enhanced in the rhIL-11-treated rats compared with the control animals at both intervals. CONCLUSION These findings suggested that IL-11 could accelerate ulcer healing, in part, by up-regulating Tie-2 expression and promoting angiogenesis.
Collapse
Affiliation(s)
- Chun-Yang Wen
- Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Goto H, Tachi K, Hisanaga Y, Kamiya K, Ohmiya N, Niwa Y, Hayakawa T. Exacerbatory mechanism responsible for water immersion stress-induced gastric lesions in aged rats compared with young rats. Clin Exp Pharmacol Physiol 2001; 28:659-62. [PMID: 11473533 DOI: 10.1046/j.1440-1681.2001.03497.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
1. The present study was designed to investigate whether or not ageing affects the development of water immersion stress-induced gastric lesions in rats. Effects of cetraxate, an anti-ulcer drug, were also examined. 2. Gastric lesions were induced by 6 h water immersion stress in rats. Gastric mucosal blood flow was determined by the hydrogen gas clearance technique and nitric oxide synthase (NOS) activity was measured enzymatically. 3. Early development of gastric lesions was observed in aged rats and exacerbation of gastric lesions was also found. Lowering of gastric mucosal blood flow and reduced NOS activity were observed in aged rats. 4. Cetraxate mitigated the development of gastric lesions in young rats and also increased gastric mucosal blood flow and NOS activity. However, these favourable effects were diminished in aged rats. 5. Decreased NOS activity may be an important exacerbatory factor to the development of gastric lesions in aged rats. 6. Effects of cetraxate differed between young rats and aged rats. 7. These results may explain the refractoriness and drug resistance in gastric ulcers encountered by elderly individuals.
Collapse
Affiliation(s)
- H Goto
- Department of Endoscopy, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
12
|
Turner JR, Liu L, Fligiel SE, Jaszewski R, Majumdar AP. Aging alters gastric mucosal responses to epidermal growth factor and transforming growth factor-alpha. Am J Physiol Gastrointest Liver Physiol 2000; 278:G805-10. [PMID: 10801273 DOI: 10.1152/ajpgi.2000.278.5.g805] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Administration of pharmacological doses of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) in young rats stimulates gastric mucosal proliferation, but, in aged rats, the same treatment inhibits proliferation. This may be due to enhanced ligand-induced internalization of EGF receptor (EGFR). In support of this, we demonstrated that although a single injection of EGF (10 microg/kg) or TGF-alpha (5 microg/kg) in young (4-6 mo old) rats greatly increased membrane-associated EGFR tyrosine kinase activity, the same treatment slightly inhibited the enzyme activity in aged (24 mo old) rats. This treatment also produced a greater abundance of punctate cytoplasmic EGFR staining in gastric epithelium of aged rats, consistent with EGFR internalization. In vitro analyses demonstrated that exposure of isolated gastric mucosal cells from aged but not young rats to 100 pM TGF-alpha resulted in marked increases in intracellular EGFR tyrosine kinase activity and that induction of EGFR tyrosine kinase activity in mucosal membranes from aged rats occurred at doses 1,000-fold less than those required in young rats. Our data suggest that aging enhances sensitivity of the gastric mucosa to EGFR ligands. This may partly explain EGFR-mediated inhibition of gastric mucosal proliferation in aged rats.
Collapse
Affiliation(s)
- J R Turner
- Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
| | | | | | | | | |
Collapse
|
|
13
|
Ichikawa T, Ishihara K, Kusakabe T, Kawakami T, Hotta K. Age-related stimulation by tetragastrin of gastric mucin biosynthesis in rat. Eur J Pharmacol 1999; 366:87-92. [PMID: 10064156 DOI: 10.1016/s0014-2999(98)00863-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The effects of tetragastrin on gastric mucin biosynthesis in middle-aged rats were compared with those in young rats. The incorporation of [3H]glucosamine and [35S]sulfate into mucin was stimulated by tetragastrin in cultured corpus mucosa from 7-week-old rats. In contrast, tetragastrin could not enhance mucin biosynthesis in stomachs from 52-week-old rats. The isosorbide dinitrate-induced stimulation of corpus mucin biosynthesis observed in middle-aged rats was essentially the same as that seen in young rats. Nitric oxide (NO) synthase activity of the corpus was significantly reduced in the middle-aged rats compared to the young rats. NO synthase-immunoreactivity was observed at surface mucous cells in the corpus mucosa of young, but not of middle-aged, rats. These results suggest that aging decreases the effect of gastrin on gastric mucin biosynthesis through the age-related loss of NO synthase function in the surface mucous cell layer of rat stomach.
Collapse
Affiliation(s)
- T Ichikawa
- Department of Biochemistry, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
| | | | | | | | | |
Collapse
|
|
14
|
Penney AG, Andrews FJ, O'Brien PE. Influence of age on natural and delayed healing of experimentally-induced gastric ulcers in rats. Dig Dis Sci 1996; 41:1838-44. [PMID: 8794804 DOI: 10.1007/bf02088755] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
This study aimed to investigate the effect of age on natural ulcer healing and delayed ulcer healing induced by nonsteroidal antiinflammatory drugs, using a rat model. Gastric ulcers were induced in young, adult, and aged rats using serosal or mucosal (kissing ulcers) application of acetic acid. Rats were treated with indomethacin 1 mg/kg/day subcutaneously or vehicle for two weeks. Ulcers were assessed by macroscopic and histological measurements of ulcer size. Ulcer induction was affected by age. Aged rats developed significantly smaller ulcers when induced by serosal application of acetic acid and significantly larger ulcers from mucosal application of acetic acid. However, measurements of ulcer size from both models showed no age-related differences in natural ulcer healing. Similarly, indomethacin-induced delayed gastric ulcer healing was not effected by age. We conclude that there are age-related differences in the development of gastric ulcers but there are no age-related differences in natural or delayed ulcer healing in rats.
Collapse
Affiliation(s)
- A G Penney
- Department of Surgery, Monash University Medical School, Alfred Hospital, Prahran, Victoria, Australia
| | | | | |
Collapse
|