Cyclooxygenase-2–derived lipoxin A4 increases gastric resistance to aspirin-induced damage

Fiorucci, Stefano; Lima, Octávio Menezes de; Mencarelli, Andrea; Palazzetti, Barbara; Distrutti, Eleonora; McKnight, Webb; Dicay, Michael; Ma, Li; Romano, Mario; Morelli, Antonio; Wallace, John L.

doi:10.1053/gast.2002.36558

Cited by 131 publications

(146 citation statements)

References 25 publications

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“…Furthermore, rapid induction of COX-2 in the gastric mucosa after administration of nonsteroidal anti-inflammatory drugs has been shown to play an important role in limiting mucosal damage. 15,23 In the case of aspirin, this appears to be related to the generation, via COX-2, of gastroprotective lipoxins. 15 Thus, inadequate up-regulation of COX-2 in male Muc-2-deficient mice after oral challenge with indomethacin could contribute to impair healing of the ensuing damage.…”

Section: Discussionmentioning

confidence: 99%

“…15,23 In the case of aspirin, this appears to be related to the generation, via COX-2, of gastroprotective lipoxins. 15 Thus, inadequate up-regulation of COX-2 in male Muc-2-deficient mice after oral challenge with indomethacin could contribute to impair healing of the ensuing damage. We noted that the defective up-regulation of COX-2 in male Muc-2-deficient mice was not limited to the stomach.…”

Section: Discussionmentioning

confidence: 99%

“…14 Additional experiments were conducted, as described above, in which the mice were euthanized 5 hours after administration of indomethacin or vehicle, and the stomach was then processed for measurement of gastric synthesis of prostaglandin E2, as described previously. 15 Gastric tissue samples were collected and processed for COX-1 and COX-2 mRNA expression by quantitative PCR. 14 Other tissues were fixed in neutral-buffered formalin and were processed by routine techniques for immunohistochemical examination of Muc-2 and Muc-5ac expression (see Immunohistochemistry).…”

Section: Healing Of Indomethacin-induced Gastric Injurymentioning

confidence: 99%

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Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Wallace

Vong

Dharmani

et al. 2011

The American Journal of Pathology

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Mucus is known to contribute significantly to the prevention and repair of mucosal damage throughout the gastrointestinal tract. Although not normally expressed in the stomach, mucin-2 (MUC-2, encoded by the MUC2 gene) is expressed in certain disease states. The aim of this study was to determine in a mouse model whether the absence of Muc-2 would result in impaired susceptibility to and healing of gastric mucosal injury. Acute gastric damage was induced in mice deficient in Muc-2 and in wild-type controls, through oral administration of indomethacin. Chronic gastric ulcers were induced by serosal application of acetic acid. The extent of injury and the extent of healing of the damage over time were examined in both models. Indomethacin administration caused similar levels of gastric damage in Muc-2-deficient and wild-type mice, but the erosions healed more slowly in the former. Acetic acid-induced gastric ulcers were initially similar in size in Muc-2-deficient and wildtype mice of both sexes, but ulcer healing was significantly impaired in male Muc-2-deficient mice. Induction of cyclooxygenase-2 in the stomach, in response to indomethacin-or acetic acid-induced ulceration, was significantly reduced in male Muc-2-deficient mice. This phenomenon, and the sex specificity, was also apparent in bone marrow-derived macrophages stimulated with endotoxin. These results demonstrate a marked impairment of gastric mucosal repair in male Muc-2-deficient mice that may be related to an insufficient induction of cyclooxygenase-2, an enzyme known to contribute to mucosal repair.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Healing Of Indomethacin-induced Gastric Injurymentioning

confidence: 99%

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Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Wallace

Vong

Dharmani

et al. 2011

The American Journal of Pathology

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“…Samples intended for PGE 2 measurement were kept on ice (4°C) before processing, whereas those used for immunohistochemical analysis were fixed in 10% neutral-buffered formalin. The measurements of PGD 2 and PGE 2 were performed as described previously (14,28).…”

Section: Methodsmentioning

confidence: 99%

A pro-resolution mediator, prostaglandin D ₂ , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Vong

Ferraz

Panaccione

et al. 2010

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

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Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D 2 in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD 2 synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD 2 was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFα and IFNγ) and colonic PGE 2 synthesis. In contrast, colonic PGD 2 synthesis was only elevated (∼3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD 2 . Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD 2 in the induction and maintenance of remission from colitis.inflammation | inflammatory bowel disease | eicosanoid | colon cancer

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“…Although there is evidence for an in vivo link between COX-2 and mPGES1, it does not preclude the formation of other COX-2-derived products, such as the 15-epi-lipoxins or resolvins that display antiinflammatory and proresolving properties (31). In addition to disruption of these proresolving biosynthetic circuits for ATL (33) and resolvins (31), inhibition of COX-2 is associated with several adverse effects, including impaired renal and cardiac function as well as increased thrombogenesis (34,35). Similar reductions in inflammation with mPGES1 and COX-2 knockouts now provide new and potentially more selective targets for new antiinflammatory drug design that could spare the COX-2-derived proresolving lipid mediators.…”

mentioning

confidence: 99%

Success of prostaglandin E ₂ in structure–function is a challenge for structure-based therapeutics

Serhan

Levy²

2003

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

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Cyclooxygenase-2–derived lipoxin A4 increases gastric resistance to aspirin-induced damage

Cited by 131 publications

References 25 publications

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

A pro-resolution mediator, prostaglandin D ₂ , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Success of prostaglandin E ₂ in structure–function is a challenge for structure-based therapeutics

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Cyclooxygenase-2–derived lipoxin A4 increases gastric resistance to aspirin-induced damage

Cited by 131 publications

References 25 publications

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

A pro-resolution mediator, prostaglandin D 2 , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Success of prostaglandin E 2 in structure–function is a challenge for structure-based therapeutics

Contact Info

Product

Resources

About

A pro-resolution mediator, prostaglandin D ₂ , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Success of prostaglandin E ₂ in structure–function is a challenge for structure-based therapeutics