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Satoh H, Akiba Y, Urushidani T, Kaunitz JD. Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice. Dig Dis Sci 2024; 69:1156-1168. [PMID: 38448762 DOI: 10.1007/s10620-024-08352-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/09/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND/AIMS We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. METHODS Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. RESULTS IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. CONCLUSIONS These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.
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Affiliation(s)
- Hiroshi Satoh
- Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
| | - Yasutada Akiba
- Greater Los Angeles Veterans Affairs Healthcare System, B114, R217, West LA VAMC, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90025, USA
| | - Tetsuro Urushidani
- Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan
| | - Jonathan D Kaunitz
- Greater Los Angeles Veterans Affairs Healthcare System, B114, R217, West LA VAMC, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90025, USA
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Protective effects of camellia oil (Camellia brevistyla) against indomethacin-induced gastrointestinal mucosal damage in vitro and in vivo. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.103539] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Takeuchi K. Nonsteroidal Antiinflammatory Drug-Induced Gastrointestinal Toxicity. COMPREHENSIVE TOXICOLOGY 2018:208-218. [DOI: 10.1016/b978-0-12-801238-3.64291-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Schuck-Phan A, Phan T, Dawson PA, Dial EJ, Bell C, Liu Y, Rhoads JM, Lichtenberger LM. Formula Feeding Predisposes Gut to NSAID-Induced Small Intestinal Injury. ACTA ACUST UNITED AC 2016; 6. [PMID: 31565540 DOI: 10.4172/2161-1459.1000222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Objectives Breast feeding protects infants from many diseases, including necrotizing enterocolitis, peptic ulceration and infectious diarrhea. Conversely, maternal separation stress and Non-Steroidal Anti-Inflammatory Drugs (NSAID's) can induce intestinal injury and bleeding. This study aimed to evaluate in suckling rats if maternal separation/formula feeding leads to increased intestinal sensitivity to indomethacin (indo)-induced intestinal injury and to look at potential mechanisms involved. Methods Nine-day-old rats were dam-fed or separated/trained to formula-feed for 6 days prior to indo administration (5 mg/kg/day) or saline (control) for 3 days. Intestinal bleeding and injury were assessed by measuring luminal and Fecal Hemoglobin (Hob) and jejunal histology. Maturation of the intestine was assessed by measuring luminal bile acids, jejunal sucrase, serum corticosterone, and mRNA expression of ileal Apical Sodium-Dependent Bile Acid Transporter (ASBT). Results At 17 days, formula-fed indo-treated pups had a 2-fold increase in luminal Hb compared to formula-fed control pups and had evidence of morphological injury to the small intestinal mucosa as observed at the light microscopic level, whereas indo had no effect on dam-fed littermates. In addition, formula-fed rats had significant increases in luminal bile acid, sucrase specific activity, serum corticosterone, and expression of ASBT mRNA compared to dam-fed rats. Conclusion Maternal separation stress may cause early intestinal maturational changes induced by corticosteroid release, including increased epithelial exposure to bile acids. These maturational changes may have a sensitizing rather than protective effect against indo-induced injury in the new-born.
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Affiliation(s)
- A Schuck-Phan
- Department of Pediatrics, Division of Pediatric Gastroenterology, University of Texas Health Science Center, Houston, TX, USA
| | - T Phan
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, USA
| | - P A Dawson
- Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - E J Dial
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, USA
| | - C Bell
- Department of Pediatrics, Division of Pediatric Gastroenterology, University of Texas Health Science Center, Houston, TX, USA
| | - Y Liu
- Department of Pediatrics, Division of Pediatric Gastroenterology, University of Texas Health Science Center, Houston, TX, USA
| | - J M Rhoads
- Department of Pediatrics, Division of Pediatric Gastroenterology, University of Texas Health Science Center, Houston, TX, USA
| | - L M Lichtenberger
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, USA
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Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-κB and Nrf2. J Nutr Biochem 2016; 27:289-98. [DOI: 10.1016/j.jnutbio.2015.09.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/16/2015] [Accepted: 09/18/2015] [Indexed: 12/30/2022]
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Narimatsu K, Higashiyama M, Kurihara C, Takajo T, Maruta K, Yasutake Y, Sato H, Okada Y, Watanabe C, Komoto S, Tomita K, Nagao S, Miura S, Hokari R. Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling. J Gastroenterol Hepatol 2015; 30:1610-7. [PMID: 25867219 DOI: 10.1111/jgh.12980] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/02/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage. METHODS LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured. RESULTS Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner. CONCLUSION TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages.
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Affiliation(s)
- Kazuyuki Narimatsu
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Masaaki Higashiyama
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Chie Kurihara
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Takeshi Takajo
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Koji Maruta
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yuichi Yasutake
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Hirokazu Sato
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yoshikiyo Okada
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Chikako Watanabe
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shunsuke Komoto
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kengo Tomita
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shigeaki Nagao
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Soichiro Miura
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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Sahagún AM, Vaquera J, García JJ, Calle ÁP, Diez MJ, Fernández N, Loro JF, Portilla HO, Sierra M. Study of the protective effect on intestinal mucosa of the hydrosoluble fiber Plantago ovata husk. Altern Ther Health Med 2015; 15:298. [PMID: 26318340 PMCID: PMC4553002 DOI: 10.1186/s12906-015-0827-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 08/25/2015] [Indexed: 12/16/2022]
Abstract
Background Several studies have indicated that dietary fiber may have a protective effect on gastrointestinal mucosa. The aim of this study was to evaluate the protective action of the soluble fiber Plantago ovata husk against intestinal damage. Methods To evaluate the anti-ulcerogenic effect on duodenal mucosa of the soluble fiber Plantago ovata husk, low-dose acetylsalicylic acid (10 mg/kg) was given orally to animals once daily for 14 or 28 days with and without Plantago ovata husk (100 mg/kg). 24 h after final dosing duodenal samples were removed for anatomopathological evaluation. Villi were examined by both light and scanning electron microscopy. Results Acetylsalicylic acid induced severe lesions in duodenal mucosa of rabbits, including erosions, epithelium disorganization, and cell vacuolization, increasing as well the amount of mononuclear and caliciform cells. Damage was much more severe in animals treated for 28 days. In groups receiving Plantago ovata husk, a significant attenuation of acetylsalicylic acid-induced lesions was already observed in group treated for 14 days, becoming more evident in those treated for 28 days, all of them with duodenal cytoarchitecture normal and similar to control animals. Conclusions These findings suggest that Plantago ovata husk may protect intestinal mucosa probably by limiting acetylsalicylic acid penetration into epithelial cells, although further studies are needed to confirm the same effect in other experimental models of induced mucosal damage and to elucidate the mechanisms of fiber protection.
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Waltz P, Escobar D, Botero AM, Zuckerbraun BS. Nitrate/Nitrite as Critical Mediators to Limit Oxidative Injury and Inflammation. Antioxid Redox Signal 2015; 23:328-39. [PMID: 26140517 PMCID: PMC4692126 DOI: 10.1089/ars.2015.6256] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 06/30/2015] [Accepted: 07/01/2015] [Indexed: 12/31/2022]
Abstract
SIGNIFICANCE Nitric oxide (NO) is a critical signaling molecule marked by complex chemistry and varied biological responses depending on the context of the redox environment. In the setting of inflammation, NO can not only contribute to tissue injury and be causative of oxidative damage but can also signal as an adaptive molecule to limit inflammatory signaling in multiple cell types and tissues. RECENT ADVANCES An advance in our understanding of NO biology was the recognition of the nitrate-nitrite-NO axis, whereby nitrate (predominantly from dietary sources) could be converted to nitrite and nitrite could be reduced to NO. CRITICAL ISSUES Intriguingly, the recognition of multiple enzymes that serve as nitrite reductases in the setting of hypoxia or ischemia established the concept of nitrite as a circulating endocrine reservoir of NO, with the selective release of NO at sites that were primed for this reaction. This review highlights the anti-inflammatory roles of nitrite in numerous clinical conditions, including ischemia/reperfusion, transplant, cardiac arrest, and vascular injury, and in gastrointestinal inflammation. FUTURE DIRECTIONS These preclinical and clinical investigations set up further clinical trials and studies that elucidate the endogenous role this pathway plays in protection against inflammatory signaling.
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Affiliation(s)
- Paul Waltz
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Daniel Escobar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ana Maria Botero
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Brian S. Zuckerbraun
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
- The Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
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Sinha K, Sadhukhan P, Saha S, Pal PB, Sil PC. Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-κB pathway. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1850:769-783. [PMID: 25603542 DOI: 10.1016/j.bbagen.2015.01.008] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 12/24/2014] [Accepted: 01/12/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND Deregulation in prostaglandin (PG) biosynthesis, severe oxidative stress, inflammation and apoptosis contribute to the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Unfortunately, most of the prescribed anti-ulcer drugs generate various side effects. In this scenario, we could consider morin as a safe herbal potential agent against IND-gastropathy and rationalize its action systematically. METHODS Rats were pretreated with morin for 30 min followed by IND (48 mgkg(-1)) administration for 4 h. The anti-ulcerogenic nature of morin was assessed by morphological and histological analysis. Its effects on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COXs, PGE(2)), and signaling parameters (NF-κB and apoptotic signaling) were assessed by biochemical, RP-HPLC, immunoblots, IHC, RT-PCR, and ELISA at the time points of their maximal changes due to IND administration. RESULTS IND induced NF-κB and apoptotic signaling in rat's gastric mucosa. These increased proinflammatory responses, but reduced the antioxidant enzymes and other protective factors. Morin reversed all the adverse effects to prevent IND-induced gastric ulceration in a PGE2 independent manner. Also, it did not affect the absorption and/or primary pharmacological activity of IND. CONCLUSIONS The gastroprotective action of morin is primarily attributed to its potent antioxidant nature that also helps in controlling several IND-induced inflammatory responses. GENERAL SIGNIFICANCE For the first time, the study reveals a mechanistic basis of morin mediated protective action against IND-induced gastropathy. As morin is a naturally abundant safe antioxidant, future detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as a gastroprotective agent.
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Affiliation(s)
- Krishnendu Sinha
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Pritam Sadhukhan
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Sukanya Saha
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Pabitra Bikash Pal
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
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Park JM, Han YM, Kangwan N, Lee SY, Jung MK, Kim EH, Hahm KB. S-allyl cysteine alleviates nonsteroidal anti-inflammatory drug-induced gastric mucosal damages by increasing cyclooxygenase-2 inhibition, heme oxygenase-1 induction, and histone deacetylation inhibition. J Gastroenterol Hepatol 2014; 29 Suppl 4:80-92. [PMID: 25521739 DOI: 10.1111/jgh.12730] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Nonsteroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, are associated with gastric mucosal damages including ulcer directly or indirectly. This study was aimed to document the preventive effects of an organosulfur constituent of garlic, S-allyl cysteine (SAC), against NSAIDs-induced gastric damages, as well the elucidation of its pharmacological actions, such as anti-inflammatory, anti-oxidative, and cytoprotective actions. METHODS Different doses of SAC were administrated intragastrically before the indomethacin administration. After killing, in addition to gross and pathological evaluations of ulcer, the expressions of inflammatory mediators, including cyclooxygenase-2, prostaglandin E2 , IL-1β, tumor necrosis factor-α, IL-6, and anti-oxidant capacity, were analyzed by Western blot analysis or ELISA, respectively. Transferase deoxytidyl uridine end labeling assay, periodic acid and Schiff staining, F4/80 staining, and CD31 staining were compared among doses of SAC. Detailed documentation of in vitro biological actions of SAC, including NF-κB, histone deacetylator inhibition, phase 2 enzyme, and MAPKs, was performed. RESULTS SAC was very effective in preventing indomethacin-induced gastric damages in a low dose through significant decreases in macrophage infiltration as well as restorative action. Indomethacin-induced expressions of inflammatory mediators were all significantly attenuated with SAC in accordance with histone deacetylator inhibition. In addition, SAC significantly increased the total anti-oxidant concentration and mucus secretion, and allows for a significant induction of HO-1. However, these preventive effects of SAC were dependent on dosage of SAC; higher dose above 10 μM paradoxically aggravated NSAID-induced inflammation. CONCLUSION Synthetic SAC can be promising therapeutics agent to provide potent anti-inflammatory, anti-oxidative, and mucosa protective effects against NSAID-induced damages.
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Affiliation(s)
- Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seoul, Korea
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Bindu S, Mazumder S, Dey S, Pal C, Goyal M, Alam A, Iqbal MS, Sarkar S, Azhar Siddiqui A, Banerjee C, Bandyopadhyay U. Nonsteroidal anti-inflammatory drug induces proinflammatory damage in gastric mucosa through NF-κB activation and neutrophil infiltration: anti-inflammatory role of heme oxygenase-1 against nonsteroidal anti-inflammatory drug. Free Radic Biol Med 2013; 65:456-467. [PMID: 23892052 DOI: 10.1016/j.freeradbiomed.2013.07.027] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Revised: 06/26/2013] [Accepted: 07/19/2013] [Indexed: 12/24/2022]
Abstract
Nonsteroidal anti-inflammatory drug (NSAID)-induced mitochondrial oxidative stress (MOS) is an important prostaglandin (PG)-independent pathway of the induction of gastric mucosal injury. However, the molecular mechanism behind MOS-mediated gastric pathology is still obscure. In various pathological conditions of tissue injury oxidative stress is often linked with inflammation. Here we report that MOS induced by indomethacin (an NSAID) induces gastric mucosal inflammation leading to proinflammatory damage. Indomethacin, time dependently stimulated the expression of proinflammatory molecules such as intercellular adhesion molecule 1(ICAM-1), vascular cell adhesion molecule 1(VCAM-1), interleukin1β (IL-1β), and monocyte chemotactic protein-1 (MCP-1) in gastric mucosa in parallel with the increase of neutrophil infiltration and injury of gastric mucosa in rat. Western immunoblotting and confocal microscopic studies revealed that indomethacin induced nuclear translocation of nuclear factor kappa-B (NF-κB) in gastric mucosal cells, which resulted in proinflammatory signaling. The prevention of MOS by antioxidant tryptamine-gallic acid hybrid (SEGA) inhibited indomethacin-induced expression of ICAM-1, VCAM-1, IL-1β, and MCP-1. SEGA also prevented indomethacin-induced NF-κB activation and neutrophil infiltration as documented by chromatin immunoprecipitation studies and neutrophil migration assay, respectively. Heme oxygenase-1 (HO-1), a cytoprotective enzyme associated with tissue repair mechanisms is stimulated in response to oxidative stress. We have investigated the role of HO-1 against MOS and MOS-mediated inflammation in recovering from gastropathy. Indomethacin stimulated the expression of HO-1 and indomethacin-stimulated HO-1 expression was reduced by SEGA, an antioxidant, which could prevent MOS. Thus, the data suggested that the induction of HO-1 was a protective response against MOS developed by indomethacin. Moreover, the induction of HO-1 by cobalt protoporphyrin inhibited inflammation and chemical silencing of HO-1 by zinc protoporphyrin aggravated the inflammation by indomethacin. Thus, NSAID by promoting MOS-induced proinflammatory response damaged gastric mucosa and HO-1 protected NSAID-induced gastric mucosal damage by preventing NF-κB activation and proinflammatory activity.
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Affiliation(s)
- Samik Bindu
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Somnath Mazumder
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Sumanta Dey
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Chinmay Pal
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Manish Goyal
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Athar Alam
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Mohd Shameel Iqbal
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Souvik Sarkar
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Asim Azhar Siddiqui
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Chinmoy Banerjee
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India
| | - Uday Bandyopadhyay
- Department of Infectious Diseases and Immunology, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India.
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Takeuchi K. Pathogenesis of NSAID-induced gastric damage: importance of cyclooxygenase inhibition and gastric hypermotility. World J Gastroenterol 2012; 18:2147-60. [PMID: 22611307 PMCID: PMC3351764 DOI: 10.3748/wjg.v18.i18.2147] [Citation(s) in RCA: 135] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 04/20/2012] [Accepted: 04/22/2012] [Indexed: 02/06/2023] Open
Abstract
This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE₂ and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E₂ (PGE₂) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.
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Jädert C, Petersson J, Massena S, Ahl D, Grapensparr L, Holm L, Lundberg JO, Phillipson M. Decreased leukocyte recruitment by inorganic nitrate and nitrite in microvascular inflammation and NSAID-induced intestinal injury. Free Radic Biol Med 2012; 52:683-692. [PMID: 22178413 DOI: 10.1016/j.freeradbiomed.2011.11.018] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 11/09/2011] [Accepted: 11/12/2011] [Indexed: 01/13/2023]
Abstract
Nitric oxide (NO) generated by vascular NO synthases can exert anti-inflammatory effects, partly through its ability to decrease leukocyte recruitment. Inorganic nitrate and nitrite, from endogenous or dietary sources, have emerged as alternative substrates for NO formation in mammals. Bioactivation of nitrate is believed to require initial reduction to nitrite by oral commensal bacteria. Here we investigated the effects of inorganic nitrate and nitrite on leukocyte recruitment in microvascular inflammation and in NSAID-induced small-intestinal injury. We show that leukocyte emigration in response to the proinflammatory chemokine MIP-2 is reduced by 70% after 7 days of dietary nitrate supplementation as well as by acute intravenous nitrite administration. Nitrite also reduced leukocyte adhesion to a similar extent and this effect was inhibited by the soluble guanylyl cyclase inhibitor ODQ, whereas the effect on emigrated leukocytes was not altered by this treatment. Further studies in TNF-α-stimulated endothelial cells revealed that nitrite dose-dependently reduced the expression of ICAM-1. In rats and mice subjected to a challenge with diclofenac, dietary nitrate prevented the increase in myeloperoxidase and P-selectin levels in small-intestinal tissue. Antiseptic mouthwash, which eliminates oral nitrate reduction, markedly blunted the protective effect of dietary nitrate on P-selectin levels. Despite attenuation of the acute immune response, the overall ability to clear an infection with Staphylococcus aureus was not suppressed by dietary nitrate as revealed by noninvasive IVIS imaging. We conclude that dietary nitrate markedly reduces leukocyte recruitment to inflammation in a process involving attenuation of P-selectin and ICAM-1 upregulation. Bioactivation of dietary nitrate requires intermediate formation of nitrite by oral nitrate-reducing bacteria and then probably further reduction to NO and other bioactive nitrogen oxides in the tissues.
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Affiliation(s)
- Cecilia Jädert
- Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden
| | - Joel Petersson
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden
| | - Sara Massena
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden
| | - David Ahl
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden
| | - Liza Grapensparr
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden
| | - Lena Holm
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden
| | - Jon O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institute, S-171 77 Stockholm, Sweden.
| | - Mia Phillipson
- Department of Medical Cell Biology, Uppsala University, S-751 23 Uppsala, Sweden.
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Jiang GL, Im WB, Donde Y, Wheeler LA. EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing. World J Gastroenterol 2009; 15:5149-56. [PMID: 19891013 PMCID: PMC2773893 DOI: 10.3748/wjg.15.5149] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers.
METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacin-induced apoptosis was assessed by flow cytometry.
RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro, the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis.
CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.
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15
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Gomes AS, Lemos HP, Medeiros JVR, Cunha FQ, Souza MHLP. Lipopolysaccharide from Escherichia coli prevents indomethacin-induced gastric damage in rats: role of non-protein sulfhydryl groups and leukocyte adherence. Inflamm Res 2009; 58:717-23. [DOI: 10.1007/s00011-009-0040-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 03/04/2009] [Accepted: 04/07/2009] [Indexed: 11/24/2022] Open
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16
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Mota JMSC, Soares PMG, Menezes AAJ, Lemos HP, Cunha FQ, Brito GAC, Ribeiro RA, de Souza MHLP. Amifostine (Wr-2721) prevents indomethacin-induced gastric damage in rats: role of non-protein sulfhydryl groups and leukocyte adherence. Dig Dis Sci 2007; 52:119-25. [PMID: 17160473 DOI: 10.1007/s10620-006-9496-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Accepted: 06/19/2006] [Indexed: 12/09/2022]
Abstract
This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and increased gastric NP-SH, in a dose-dependent manner, with a maximal effect at a dose of 90 mg/kg. Subcutaneous, but not i.p., amifostine administration decreased (P < 0.05) the indomethacin-induced increase in leukocyte adherence. Indomethacin-induced PGE2 depletion was not reversed by amifostine. Amifostine has a protective effect against indomethacin-induced gastropathy by increasing gastric NP-SH and decreasing leukocyte adherence.
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Affiliation(s)
- José Maurício S C Mota
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
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17
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Walsh-Reitz MM, Huang EF, Musch MW, Chang EB, Martin TE, Kartha S, Toback FG. AMP-18 protects barrier function of colonic epithelial cells: role of tight junction proteins. Am J Physiol Gastrointest Liver Physiol 2005; 289:G163-71. [PMID: 15961882 PMCID: PMC1444946 DOI: 10.1152/ajpgi.00013.2005] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antrum mucosal protein (AMP)-18 and a synthetic peptide of amino acids 77-97 have mitogenic and motogenic properties for epithelial cells. The possibility that AMP-18 is also protective was evaluated in the colonic mucosa of mice and monolayer cultures of human colonic epithelial Caco-2/bbe (C2) cells. Administration of AMP peptide to mice with dextran sulfate sodium (DSS)-induced colonic injury delayed the onset of bloody diarrhea and reduced weight loss. Treatment of C2 cells with AMP peptide protected monolayers against decreases in transepithelial electrical resistance induced by the oxidant monochloramine, indomethacin, or DSS. A molecular mechanism for these barrier-protective effects was sought by asking whether AMP peptide acted on specific tight junction (TJ) proteins. Immunoblots of detergent-insoluble fractions of C2 cells treated with AMP peptide exhibited increased accumulation of specific TJ proteins. Occludin immunoreactivity was also increased in detergent-insoluble fractions obtained from colonic mucosal cells of mice injected with AMP peptide. Observations using laser scanning confocal (CF) microscopy supported the capacity of AMP peptide to enhance accumulation of occludin and zonula occludens-1 in TJ domains of C2 cell monolayers and together with immunoblot analysis showed that the peptide protected against loss of these TJ proteins following oxidant injury. AMP peptide also protected against a fall in TER during disruption of actin filaments by cytochalasin D and stabilized perijunctional actin during oxidant injury when assessed by CF. These findings suggest that AMP-18 could protect the intestinal mucosal barrier by acting on specific TJ proteins and stabilizing perijunctional actin.
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Affiliation(s)
| | | | | | | | - Terence E. Martin
- Molecular Genetics and Cell Biology The University of Chicago, Illinois 60637
| | | | - F. Gary Toback
- Departments of Medicine, and
- F. Gary Toback, M.D., Ph.D. The University of Chicago Department of Medicine, MC5100 5841 South Maryland Avenue Chicago, IL 60637 Telephone: 773-702-1476 FAX: 773-702-5818
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18
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Souza MHLP, Lemos HP, Oliveira RB, Cunha FQ. Gastric damage and granulocyte infiltration induced by indomethacin in tumour necrosis factor receptor 1 (TNF-R1) or inducible nitric oxide synthase (iNOS) deficient mice. Gut 2004; 53:791-6. [PMID: 15138204 PMCID: PMC1774069 DOI: 10.1136/gut.2002.012930] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Tumour necrosis factor alpha (TNF-alpha) is involved in non-steroidal anti-inflammatory drug induced gastropathy. Nitric oxide (NO) is a mediator of gastrointestinal mucosal defence but, paradoxically, it also contributes to mucosal damage. AIMS We optimised the C57BL/6 mouse model of indomethacin induced gastropathy to evaluate the role of TNF-alpha and inducible nitric oxide synthase (iNOS) generated NO in gastric damage and granulocyte infiltration using tumour necrosis factor receptor 1 (TNF-R1-/-) or iNOS (iNOS-/-) deficient mice. METHODS Different doses of indomethacin (2.5, 5, 10, 20 mg/kg) were administered and animals were assessed 6, 12, or 24 hours later. Gastric damage was measured by the sum of all erosions in the gastric mucosa, and gastric granulocyte infiltration was determined by myeloperoxidase (MPO) activity. Other groups of wild-type mice received thalidomide, dexamethasone, fucoidin, L-NAME, or 1400W, and then indomethacin was administered. Additionally, indomethacin was administered to TNF-R1-/- or iNOS-/-. Gastric damage and MPO activity were evaluated 12 hours later. RESULTS Indomethacin induced dose and time dependent gastric damage and increase in MPO activity in wild-type mice, with the greatest effect at a dose of 10 mg/kg and after 12 hours. Treatment with thalidomide, dexamethasone, or fucoidin reduced gastric damage and MPO activity induced by indomethacin. After indomethacin administration, TNF-R1-/- had less gastric damage and MPO activity than controls. Genetic (knockout mice) or pharmacological (1400W and L-NAME) inhibition of iNOS activity reduced indomethacin induced gastric damage, despite no reduction in MPO activity. CONCLUSION TNF-alpha, acting via TNF-R1, is involved in indomethacin induced gastric damage and granulocyte infiltration. Furthermore, iNOS generated NO is involved in gastric damage induced by indomethacin.
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Affiliation(s)
- M H L P Souza
- Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza-CE, Brazil.
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19
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Lamarque D. Physiopathologie des lésions gastro-duodénales induites par les anti-inflammatoires non stéroïdiens. ACTA ACUST UNITED AC 2004; 28 Spec No 3:C18-26. [PMID: 15366671 DOI: 10.1016/s0399-8320(04)95275-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The pathogenesis of the gastroduodenal lesions induced by non-steroidal anti-inflammatory drugs and aspirin is primarily caused by a reduction in mucosal blood flow, which is the consequence of inhibition of cyclooxygenase-producing vasodilator prostaglandins. The subsequent phase is adherence of leukocytes to the endothelium, which may depend on cyclooxygenase-2. Endothelial lesions accentuate the fall of mucosal blood flow and promote the inflammatory process in the gastric mucosa. The inflammatory process is amplified by expression of TNFalpha in polymorphonuclears induced by non-steroidal anti-inflammatory drugs. A few days after starting treatment, epithelial proliferation and increased mucosal blood flow, partly dependent on cyclooxygenase-2 and nitric oxide expression, compensates for the damaging process. Selective inhibitors of inducible cyclooxygenase-2 have reduced gastrointestinal toxicity, which could partially be explained by the protection effect of cyclooxygenase-2 on the gastrointestinal mucosa during inflammation or epithelial repair. Selective inhibitors may worsen inflammatory bowel disease. Non-steroidal inflammatory drugs and aspirin, but perhaps not selective inhibitors, increase the mucosal lesions associated with Helicobacter pylori-induced gastritis. Co-administration of selective inhibitors and aspirin leads to gastrointestinal toxicity equivalent to that of non-specific anti-inflammatory drugs.
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20
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Toback FG, Walsh-Reitz MM, Musch MW, Chang EB, Del Valle J, Ren H, Huang E, Martin TE. Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic and motogenic. Am J Physiol Gastrointest Liver Physiol 2003; 285:G344-53. [PMID: 12851219 DOI: 10.1152/ajpgi.00455.2002] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Antrum mucosal protein (AMP)-18 is a novel 18-kDa protein synthesized by cells of the gastric antrum mucosa. The protein is present in secretion granules of murine gastric antrum epithelial cells and is a component of canine antrum mucus, suggesting that it is secreted into the viscoelastic gel layer on the mucosal surface. Release of the protein appears to be regulated because forskolin decreased the amount of immunoreactive AMP-18 in primary cultures of canine antrum mucosal epithelial cells, and indomethacin gavaged into the stomach of mice reduced AMP-18 content in antrum mucosal tissue before inducing histological injury. A functional domain of the protein was identified by preparing peptides derived from the center of human AMP-18. A 21-mer peptide stimulated growth of gastric and intestinal epithelial cells, but not fibroblasts, and increased restitution of scrape-wounded gastric epithelial monolayers. These functions of AMP-18 suggest that its release onto the apical cell surface is regulated and that the protein and/or peptide fragments may protect the antral mucosa and promote healing by facilitating restitution and proliferation after injury.
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Affiliation(s)
- F Gary Toback
- The Univ. of Chicago, Dept. of Medicine, Chicago, IL 60637, USA.
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21
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Ishikawa H, Yoshida M, Wakabayashi G, Nakamura M, Shimazu M, Kitajima M. Sialyl Lewis X analog attenuates gastric microcirculatory disturbance and gastric mucosal erosion induced by thermal injury in rats. J Gastroenterol Hepatol 2003; 18:47-52. [PMID: 12519223 DOI: 10.1046/j.1440-1746.2003.02908.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM We hypothesize that selectins, which are adhesion molecules, are involved in the pathogenesis of stress-induced gastropathy. We therefore investigated whether the novel Sialyl Lewis X (SLex) analog, which is a clinically available antagonist of selectins, attenuate gastric mucosal lesions induced by thermal injury. METHODS Male Wistar rats were anesthetized and a 30% full-skin thickness dorsal burn was inflicted on each rat. The SLex analog was administrated into the jugular vein 30 min before and 2.5 h after the thermal injury. Saline was administered to the vehicle group. The distribution of E-selectin immunoreactivity on the luminal side of the gastric mucosal microvascular network was observed by immunohistochemical methods. Active oxygen species were measured by the chemiluminescence method. Rolling leukocytes and endothelial damage, investigated by using Monastral Blue B (MBB), of the gastric mucosal microvascular network were observed through an intravital microscope. RESULTS A high intensity of E-selectin fluorescence was observed on the luminal surface of the venular endothelial cells 5 h after thermal injury in the vehicle group. However, E-selectin-associated fluorescence was almost negligible in the non-injury group and in the SLex analog group. The SLex analog also attenuated the rolling of leukocytes in the venules, venular deposits of MBB, luminol-dependent chemiluminescence activities, and gastric mucosal lesion formation. CONCLUSION It is suggested that the selectin family is involved in gastric microcirculatory disturbance and the pathogenesis of gastric mucosal lesions after thermal injury. A novel preventive therapy using the SLex analog is considered to effectively protect both gastric microcirculation and the gastric mucosa in rats with thermal injury.
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Affiliation(s)
- Hideki Ishikawa
- Department of Surgery, School of Medicine, Keio University and Center for Basic Research, The Kitasato Institute, Tokyo, Japan.
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22
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Zhou T, Chen JL, Song W, Wang F, Zhang MJ, Ni PH, Geng JG. Effect of N-desulfated heparin on hepatic/renal ischemia reperfusion injury in rats. World J Gastroenterol 2002; 8:897-900. [PMID: 12378638 PMCID: PMC4656583 DOI: 10.3748/wjg.v8.i5.897] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of N-desulfated heparin on hepatic/renal ischemia and reperfusion injury in rats.
METHODS: Using rat models of 60 min hepatic or renal ischemia followed by 1 h, 3 h, 6 h and 24 h reperfusion, animals were randomly divided into following groups, the sham operated controls, ischemic group receiving only normal saline, and treated group receiving N-desulfated heparin at a dose of 12 mg/kg at 5 min before reperfusion. P-selectin expression was detected in hepatic/renal tissues with immunohistochemistry method.
RESULTS: P-selectin expression, serum ALT, AST, BUN and Cr levels were significantly increased during 60 minute ischemia and 1 h, 3 h, 6 h and 24 h reperfusion, while the increment was significantly inhibited, and hepatic/renal pathology observed by light microscopy was remarkably improved by treatment with the N-desulfated heparin. Furthermore, the heparin was found no effects on PT and KPTT.
CONCLUSION: P-selectin might mediate neutrophil infiltration and contribute to hepatic/renal ischemia and reperfusion. The N-desulfated heparin might prevent hepatic/renal damage induced by ischemia and reperfusion injury without significant anticoagulant activity.
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Affiliation(s)
- Tong Zhou
- Department of Nephrology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025,China.
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23
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Krieglstein CF, Salter JW, Cerwinka WH, Russell JM, Schuermann G, Bruewer M, Laroux FS, Grisham MB, Granger DN. Role of intercellular adhesion molecule 1 in indomethacin-induced ileitis. Biochem Biophys Res Commun 2001; 282:635-42. [PMID: 11401508 DOI: 10.1006/bbrc.2001.4609] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Adhesion molecules have been implicated in the pathogenesis of inflammatory bowel diseases. We investigated their expression and contribution to leukocyte recruitment in experimental intestinal inflammation. Ileitis was induced in Sprague-Dawley rats by two injections of indomethacin (7.5 mg/kg), given 24 h apart. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression was quantified using the dual radiolabeled monoclonal antibody technique and Mac-1 (CD11b/CD18) expression on leukocytes by flow cytometry. Leukocyte infiltration was monitored by tissue myeloperoxidase (MPO) activity. The first indomethacin injection induced a time- and site-dependent increase of ICAM-1 expression in ileal mucosa and muscularis. The second injection resulted in a reduction of ICAM-1 expression below constitutive levels whereas Mac-1 was upregulated. MPO changes paralleled lesion development over 48 h. ICAM-1 and MPO values were correlated for the first 24 h. Immunoneutralization of either ICAM-1 or Mac-1 attenuated mucosal injury. We conclude that (i) indomethacin-induced ileitis is associated with a temporally disassociated upregulation of ICAM-1 and (ii) despite a reduction in ICAM-1 after 24 h, ICAM-1, in concert with Mac-1, contributes to mucosal injury and leukocyte infiltration elicited by indomethacin.
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Affiliation(s)
- C F Krieglstein
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA
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24
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Alvarez A, Piqueras L, Bello R, Canet A, Moreno L, Kubes P, Sanz MJ. Angiotensin II is involved in nitric oxide synthase and cyclo-oxygenase inhibition-induced leukocyte-endothelial cell interactions in vivo. Br J Pharmacol 2001; 132:677-84. [PMID: 11159720 PMCID: PMC1572608 DOI: 10.1038/sj.bjp.0703867] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. Chronic inhibition of nitric oxide synthase (NOS) provokes a hypertensive state which has been shown to be angiotensin II (Ang-II) dependent. In addition to raising blood pressure, NOS inhibition also causes leukocyte adhesion. The present study was designed to define the role of Ang-II in hypertension and in the leukocyte-endothelial cell interactions induced by acute NOS or cyclo-oxygenase (COX) inhibition using intravital microscopy within the rat mesenteric microcirculation. 2. While pretreatment with an Ang-II AT(1) receptor antagonist (losartan) reversed the prompt increase in mean arterial blood pressure (MABP) caused by indomethacin, it had no effect on the increase evoked by systemic L-NAME administration. 3. Pretreatment with losartan inhibited the leukocyte rolling flux, adhesion and emigration which occurs after 60 min NOS inhibition by 83, 80 and 70% respectively, and returned leukocyte rolling velocity to basal levels. 4. Losartan significantly reduced the leukocyte-endothelial cell interaction elicited by COX inhibition. In contrast, leukocyte recruitment induced by acute mast cell activation was not inhibited by losartan. 5. AT(1) receptor blockade also prevented the drop in haemodynamic parameters such as mean red blood cell velocity (V(mean)) and shear rate caused by NOS and COX inhibition. 6. In this study, we have demonstrated a clear role for Ang-II in the leukocyte-endothelial cell interactions and haemodynamic changes which arise in the absence of NO or prostacyclin (PGI(2)). This is of interest since leukocyte recruitment, which culminates in the vascular lesions that occur in hypertension, atherosclerosis and myocardial ischemia-reperfusion injury, might be prevented using AT(1) Ang-II receptor antagonists.
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Affiliation(s)
- Angeles Alvarez
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
| | - Laura Piqueras
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
| | - Regina Bello
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
| | - Amparo Canet
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
| | - Lucrecia Moreno
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
| | - Paul Kubes
- Immunology Research Group, University of Calgary, Calgary, Alberta, Canada
| | - Maria-Jesus Sanz
- Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain
- Author for correspondence:
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25
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Emanueli C, Zacheo A, Minasi A, Chao J, Chao L, Salis MB, Stacca T, Straino S, Capogrossi MC, Madeddu P. Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol 2000; 20:2379-85. [PMID: 11073841 DOI: 10.1161/01.atv.20.11.2379] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We investigated whether local delivery of the tissue kallikrein gene induces angiogenesis in normoperfused mouse hindlimb muscles. Intramuscular injection of adenovirus containing the human tissue kallikrein gene under the control of a cytomegalovirus enhancer/promoter sequence resulted in local production and release of recombinant human tissue kallikrein, whereas transgene expression was absent in muscles of the contralateral hindlimb. Angiogenesis in infected muscles was documented by histological evidence of increased capillary density. In contrast, no angiogenic effect was seen either in the ipsilateral gastrocnemius or contralateral hindlimb muscles. Neovascularization was associated with a transient increase in muscular blood flow as determined by laser Doppler flowmetry. We also investigated the mechanisms of kallikrein-induced angiogenesis. We found that the angiogenic response to kallikrein was abolished by chronic blockade of the kinin B(1) or B(2) receptor or by inhibition of nitric oxide synthase. In addition, inhibition of cyclooxygenase-2 by nimesulide significantly reduced kallikrein-induced effects. These results indicate that (1) human tissue kallikrein acts as an angiogenic factor in normoperfused skeletal muscle and (2) nitric oxide and prostacyclin are essential mediators of kallikrein-induced angiogenesis. Our findings provide new insights into the role of the tissue kallikrein-kinin system in vascular biology.
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Affiliation(s)
- C Emanueli
- Laboratorio di Patologia Vascolare, Istituto Dermopatico dell' Immacolata, Rome
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