Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: Implications for gastrointestinal toxicity

Wallace, John L.; Bak, Adrian W.; McKnight, Webb; Asfaha, Samuel; Sharkey, Keith A.; MacNaughton, Wallace K.

doi:10.1016/s0016-5085(98)70370-1

Cited by 286 publications

(196 citation statements)

References 27 publications

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“…In accordance, observations from our present study of impaired healing strongly suggest that the biosynthesis of pro-inflammatory as well as anti-inflammatory PGs is most completely restricted to expression and activity of COX-1 in skin tissue. Remarkably, COX-1 has indeed been described to make an important contribution to inflammatory responses in a model of induced paw inflammation (32). This is in contrast to studies from animal models of induced gastric ulceration, which demonstrated a pivotal role for COX-2 in ulcer healing.…”

Section: Discussionmentioning

confidence: 82%

Wound Inflammation in Diabeticob/obMice

et al. 2005

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This study focused on the regulation of prostaglandin (PG) production in diabetes-impaired wound tissue. Cyclooxygenase (COX)-1 and -2 expression and activity were severely dysregulated in chronic wounds of diabetic ob/ob mice. Those wounds were characterized by a reduced expression of COX-1 and the presence of strongly elevated levels of COX-2 when compared with conditions observed in healthy animals. Resolution of the diabetic and impaired wound-healing phenotype by systemic administration of leptin into ob/ob mice increased COX-1 expression in wound margin keratinocytes and decreased COX-2 expression in inner wound areas to levels found in wild-type animals. Notably, improved wound healing was characterized by a marked increase in PGE 2 /PGD 2 biosynthesis that colocalized with induced COX-1 in new tissue at the margin of the wound. COX-2 expression did not significantly contribute to PGE 2 /PGD 2 production in impaired wound tissue. Accordingly, only late wound tissue from SC-560 -treated (selective COX-1 inhibitor) but not celecoxibtreated (selective COX-2 inhibitor) ob/ob mice exhibited a severe loss in PGE 2 , PGD 2 , and prostacyclin at the wound site, and this change was associated with reduced keratinocyte numbers in the neo-epithelia. These data constitute strong evidence that a dysregulation of COX-1-coupled prostaglandin contributes to diabetes-impaired wound healing. Diabetes 54: 1543-1551, 2005

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Section: Discussionmentioning

confidence: 82%

Wound Inflammation in Diabeticob/obMice

et al. 2005

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“…Rats in which ulcers had been induced (as above) were given antiplatelet serum (n ϭ 9) or normal rabbit serum (n ϭ 7) i.v. on days 3 and 7, as described previously (24). The rats were killed on day 10 for assessment of ulcer area.…”

Section: Methodsmentioning

confidence: 99%

Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

Elliott

Cirino

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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193

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Bleeding and delayed healing of ulcers are well recognized clinical problems associated with the use of aspirin and other nonsteroidal antiinflammatory drugs, which have been attributed to their antiaggregatory effects on platelets. We hypothesized that antiplatelet drugs might interfere with gastric ulcer healing by suppressing the release of growth factors, such as vascular endothelial growth factor (VEGF), from platelets. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily oral treatment with vehicle, aspirin, or ticlopidine (an ADP receptor antagonist) was started 3 days later and continued for 1 week. Ulcer induction resulted in a significant increase in serum levels of VEGF and a significant decrease in serum levels of endostatin (an antiangiogenic factor). Although both aspirin and ticlopidine markedly suppressed platelet aggregation, only ticlopidine impaired gastric ulcer healing and angiogenesis as well as reversing the ulcerassociated changes in serum levels of VEGF and endostatin. The effects of ticlopidine on ulcer healing and angiogenesis were mimicked by immunodepletion of circulating platelets, and ticlopidine did not influence ulcer healing when given to thrombocytopenic rats. Incubation of human umbilical vein endothelial cells with serum from ticlopidine-treated rats significantly reduced proliferation and increased apoptosis, effects reversed by an antibody directed against endostatin. Ticlopidine treatment resulted in increased platelet endostatin content and release. These results demonstrate a previously unrecognized contribution of platelets to the regulation of gastric ulcer healing. Such effects likely are mediated through the release from platelets of endostatin and possibly VEGF. As shown with ticlopidine, drugs that influence gastric ulcer healing may do so in part through altering the ability of platelets to release growth factors.angiogenesis ͉ ticlopidine ͉ aspirin ͉ proliferation ͉ endothelium

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“…A longitudinal section of tissue that included the ulcer base and both sides of ulcer margins was fixed in 4% neutral buffered formalin (4°C) and then embedded in paraffin and sectioned. A subset of rats (n ϭ 5) from each group was killed and the stomach was removed for assessment of prostaglandin E 2 (PGE 2 ) synthesis, as described (19). In brief, a sample of tissue from the ulcer margin was taken from each rat and placed in 1 ml of sodium phosphate buffer (pH 7.4).…”

Section: Methodsmentioning

confidence: 99%

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

Soldato

Wallace

2002

Proc. Natl. Acad. Sci. U.S.A.

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132

105

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Delayed gastric ulcer healing is a well recognized problem associated with the use of cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (flurbiprofen), a nitric oxide-releasing COX inhibitor (HCT-1026), and a selective COX-2 inhibitor (celecoxib) on gastric ulcer healing, angiogenesis, and platelet͞serum levels of vascular endothelial growth factor (VEGF) and endostatin. Gastric ulcers were induced in rats by serosal application of acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week. Celecoxib and flurbiprofen impaired angiogenesis and delayed ulcer healing, as well as increasing serum endostatin levels relative to those of VEGF. HCT-1026 did not delay ulcer healing nor impair angiogenesis, and also did not change the ratio of serum endostatin to VEGF. Incubation of human umbilical vein endothelial cells with serum from celecoxib-or flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay ulcer healing, namely, through altering the balance of anti-and proangiogenic factors in the serum. The absence of a delaying effect of HCT-1026 on ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro-and antiangiogenic growth factors.nitric oxide ͉ angiogenesis ͉ nonsteroidal antiinflammatory drug ͉ endothelium ͉ growth factors

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Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: Implications for gastrointestinal toxicity

Cited by 286 publications

References 27 publications

Wound Inflammation in Diabeticob/obMice

Wound Inflammation in Diabeticob/obMice

Platelets modulate gastric ulcer healing: Role of endostatin and vascular endothelial growth factor release

Divergent effects of new cyclooxygenase inhibitors on gastric ulcer healing: Shifting the angiogenic balance

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