Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury?

Lichtenberger, Lenard M.

doi:10.1016/s0006-2952(00)00576-1

Cited by 123 publications

(115 citation statements)

References 67 publications

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“…Our data are consistent with published work [3] that suggests inhibition of mucosal cyclooxygenase (COX) and loss of protective prostaglandins (PG) are insufficient to explain NSAID effects on epithelial restitution. The COX-2 antagonist NS-398 and the non-specific COX anatagonist indomethacin impeded intestinal epithelial cell migration, whereas the COX-1 antagonist SC-560 did not.…”

Section: Discussionsupporting

confidence: 92%

“…Adverse GI effects of NSAIDs including GI ulceration [1][2][3][4] result in 100,000 emergency admissions, high medical costs and 17,500 deaths per year in the US alone [5,6]. Despite extensive investigation, the mechanisms responsible for NSAID-associated GI damage are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

“…Despite extensive investigation, the mechanisms responsible for NSAID-associated GI damage are incompletely understood. A growing body of data suggests that inhibition of mucosal cyclooxygenase (COX) and loss of protective prostaglandins (PG) are insufficient to explain NSAID enteropathies [3]. Moreover, the recently recognized untoward cardiac effects of COX-2 inhibitors suggest that the development of less ulcerogenic NSAIDs through manipulation of COX-selectivity is not a viable therapeutic strategy [7,8].…”

Section: Introductionmentioning

confidence: 99%

“…To date, NSAIDs have been hypothesized to diminish normal mucosal defense mechanisms and to promote ulcer formation not only by inhibiting cyclooxygenase (COX), but also by diminishing nitric oxide synthesis, uncoupling oxidative phosphorylation, decreasing intracellular pH, reducing surface hydrophobicity, and inducing apoptosis [3,[9][10][11][12][13]. It has also been shown that NSAIDs contribute to ulcer formation and delay ulcer healing by inhibiting intestinal epithelial cell migration and mucosal restitution [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (E m ) and altered surface expression of K + channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 μM), phenylbutazone (100 μM) and NS-398 (100 μM) but not by SC-560 (1 μM). NSAIDinhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E m , whereas treatment with SC-560 had no effect on E m . The E m of IEC-Cdx2 cells was: −38.5±1.8 mV under control conditions; −35.9±1.6 mV after treatment with SC-560; −18.8±1.2 mV after treatment with indomethacin; and −23.7±1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K v 1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K v 1.4, but also the cell surface expression of both K v 1.4 and K v 1.6 channel subunits in IEC-Cdx2. Both K v 1.4 and K v 1.6 channel proteins were immunoprecipitated by K v 1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K v channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E m and decreased surface expression of heteromeric K v 1 channels.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution

Freeman

Narváez

McCoy

et al. 2007

Biochemical Pharmacology

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“…The mechanism by which aspirin and related NSAIDs injure the GI mucosa was once thought to be strictly due to disruption of the biosynthesis of cytoprotective prostaglandins via inhibition of constitutive cyclooxygenase-1 (COX-1) [19], leading to the development of highly selective COX-2 inhibitors (coxibs) as safer anti-inflammatory drugs. However, over time this concept has been challenged, with the demonstration that NSAIDs can induce GI injury by COX-independent mechanisms [20], and the demonstration that a number of highly selective coxibs have unanticipated and potentially life-threatening cardiovascular, renal, and hepatic side effects [21], eventuating in their withdrawal from the US market.…”

mentioning

confidence: 99%