Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice

Schmassmann, Adrian; Zoidl, Georg; Peskar, B. M.; Waser, Bea; Schmassmann-Suhijar, Diana; Gebbers, Jan‐Olaf; Reubi, Jean Claude

doi:10.1152/ajpgi.00416.2005

Cited by 44 publications

(44 citation statements)

References 43 publications

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“…Previous studies have shown that the impairing actions of nonselective NSAIDs on ulcer healing can be shared by selective COX-2 inhibitors, suggesting a predominant role of COX-2 in ulcer repair (Shigeta et al, 1998;Halter et al, 2001). Nevertheless, current evidence on the expression of COX isoforms in gastric ulcers is conflicting, and a role in ulcer healing also has been proposed for COX-1 (Jackson et al, 2000;To et al, 2001;Schmassmann et al, 2006). Overall, our results, taken together with the inconsistency of previous findings, support the view that COX-dependent mechanisms do not seem to play a predominant role in the impairing actions of COX inhibitors on gastric ulcer healing.…”

Section: Nsaid-activated Gene and Gastric Ulcer Healing 147supporting

confidence: 51%

“…NSAIDs are also able to impair the healing of pre-existing gastric ulcers (Halter et al, 2001;Ma et al, 2002;Schmassmann et al, 2006;Colucci et al, 2009), and here again both COX-dependent and COX-independent mechanisms seem to come into play. Current evidence suggests that NSAIDs exert their impairing effects on ulcer healing through the inhibition of COX isoforms.…”

Section: Introductionmentioning

confidence: 82%

“…Current evidence suggests that NSAIDs exert their impairing effects on ulcer healing through the inhibition of COX isoforms. In particular, the inhibiting actions of NSAIDs on ulcer healing can be mimicked by COX-2-selective inhibitors (Ma et al, 2002;Schmassmann et al, 2006), thus supporting a significant involvement of COX-2 in ulcer repair. However, COX-1 could also play relevant roles, because the combined administration of selective COX-1 and COX-2 inhibitors was found to impair ulcer healing to a higher extent than selective COX-2 inhibitors alone (Schmassmann et al, 2006).…”

Section: Introductionmentioning

confidence: 88%

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Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Colucci¹,

Antonioli²,

Bernardini³

et al. 2012

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can impair gastric ulcer healing. This study investigates the involvement of NSAIDactivated gene-1 (NAG-1) in ulcer repair impairment by cyclooxygenase (COX) inhibitors. Gastric ulcers were induced in rats by acetic acid. Four days later, animals received daily intragastric indomethacin (nonselective COX-1/COX-2 inhibitor; 1 mg/kg), 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC-560) (selective COX-1 inhibitor; 2.5 mg/kg), (5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl) phenyl-2(5H)-furanone (DFU) (selective COX-2 inhibitor; 5 mg/kg), celecoxib (selective COX-2 inhibitor; 1 mg/kg), and valdecoxib (selective COX-2 inhibitor; 1 mg/kg), for 1, 3, or 7 days. Ulcerated tissues were processed to assess: 1) COX-1, COX-2, NAG-1, proliferating cell nuclear antigen (PCNA), and activated caspase-3 expression; 2) ulcer area; and 3) prostaglandin E 2 (PGE 2 ) levels. COX-1 expression in ulcerated tissues was decreased, whereas COX-2 expression was enhanced. Ulcer healing was delayed by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. Ulcer PGE 2 levels were decreased by SC-560, DFU, celecoxib, valdecoxib, and indomethacin. NAG-1 was overexpressed in ulcerated tissues and further enhanced by indomethacin, DFU, and SC-560, but not by celecoxib or valdecoxib. PCNA expression in ulcerated areas was reduced by indomethacin, but not by the other test drugs. The expression of activated caspase-3 in ulcers was increased and enhanced further by indomethacin, DFU, and SC-560, but not by celecoxib and valdecoxib. These findings indicate that: 1) COX inhibitors exert differential impairing effects on gastric ulcer healing, through mechanisms unrelated to the inhibition of COX isoforms and prostaglandin production; and 2) NAG-1 induction, followed by activation of proapoptotic pathways, can contribute to the impairing effects of COX inhibitors on ulcer healing.

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Section: Nsaid-activated Gene and Gastric Ulcer Healing 147supporting

confidence: 51%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Colucci¹,

Antonioli²,

Bernardini³

et al. 2012

J Pharmacol Exp Ther

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“…COX-1 inhibitor (SC-560; Cayman Chemical) was dissolved at 50 mg/ml in DMSO and further dissolved in PBS in order to gavage a dose of 5 mg/kg in 100 μl. It was administered twice per day beginning 60 hours prior to APAP and continued for 48 hours after APAP injection as previously established (44).…”

Section: Methodsmentioning

confidence: 99%

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome

Imaeda¹,

Watanabe²,

Sohail³

et al. 2009

J. Clin. Invest.

419

563

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Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated specklike protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1β and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.

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“…Administration to rats of a selective COX-1 or COX-2 inhibitor did not induce GI injury; however, coadministration of selective inhibitors caused extensive damage, implying that inhibition of both COX isoforms is essential to injury formation (Tanaka et al, 2001). Studies with COX-1 or COX-2 KO mice demonstrated that COX-1 activity promotes intestinal intactness, and COX-2 activity is necessary for healing of ulcers (Schmassmann et al, 2006). That DCF-AG can inhibit both COX enzymes represents a novel finding and offers a possible cause for the enteropathy associated with DCF-AG exposure.…”

Section: Mechanisms Of Toxicity Caused By Diclofenac Acyl Glucuronidementioning

confidence: 99%

Elucidation of the Mechanisms through Which the Reactive Metabolite Diclofenac Acyl Glucuronide Can Mediate Toxicity

Scialis¹,

Manautou²

2016

Journal of Pharmacology and Experimental Therapeutics

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We have previously reported that mice lacking the efflux transporter Mrp3 had significant intestinal injury after toxic diclofenac (DCF) challenge, and proposed that diclofenac acyl glucuronide (DCF-AG), as a substrate of Mrp3, played a part in mediating injury. Since both humans and mice express the uptake transporter OATP2B1 in the intestines, OATP2B1 was characterized for DCF-AG uptake. In vitro assays using human embryonic kidney (HEK)-OATP2B1 cells demonstrated that DCF-AG was a substrate with a maximal velocity (V max ) and K m of 17.6 6 1.5 pmol/min per milligram and 14.3 6 0.1 mM, respectively. Another key finding from our in vitro assays was that DCF-AG was more cytotoxic compared with DCF, and toxicity occurred within 1-3 hours of exposure. We also report that 1 mM DCF-AG caused a 6-fold increase in reactive oxygen species (ROS) by 3 hours. Investigation of oxidative stress through inhibition of superoxide dismutase (SOD) revealed that DCF-AG had 100% inhibition of SOD at the highest tested dose of 1 mM. The SOD and ROS results strongly suggest DCF-AG induced oxidative stress in vitro. Lastly, DCF-AG was screened for pharmacologic activity against COX-1 and COX-2 and was found to have IC 50 values of 0.620 6 0.105 and 2.91 6 0.36 mM, respectively, which represents a novel finding. Since cyclooxygenase (COX) inhibition can lead to intestinal ulceration, it is plausible that DCF-AG can also contribute to enteropathy via COX inhibition. Taken in context, the work presented herein demonstrated the multifactorial pathways by which DCF-AG can act as a direct contributor to toxicity following DCF administration.

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Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice

Abstract: . Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice.

Cited by 44 publications

References 43 publications

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Plays a Role in the Impairing Effects of Cyclooxygenase Inhibitors on Gastric Ulcer Healing

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome

Elucidation of the Mechanisms through Which the Reactive Metabolite Diclofenac Acyl Glucuronide Can Mediate Toxicity

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