Annexin-1 modulates repair of gastric mucosal injury

Abstract

Martin GR, Perretti M, Flower RJ, Wallace JL. Annexin-1 modulates repair of gastric mucosal injury. Am J Physiol Gastrointest Liver Physiol 294: G764-G769, 2008. First published January 17, 2008 doi:10.1152/ajpgi.00531.2007.-Annexin-1 is a glucocorticoidinducible protein that plays an important effector role in the resolution of inflammation and has recently been shown to contribute to the resistance of the stomach to injury. Using an integrated genetic and pharmacological approach, we have tested the hypothesis that annexin-1 contributes to the healing of mucosal injury, given that such injury is accompanied by an inflammatory response, which is often associated with an overexpression of annexin-1 expression. Gastric ulcers were induced in mice through serosal application of acetic acid. Annexin-1 expression during the healing of the ulcers was examined. The effects on gastric ulcer healing of treatment with an annexin-1 mimetic (Ac2-26), an antagonist of the annexin-1 receptor (Boc2), or a glucocorticoid (dexamethasone) were examined. Finally, susceptibility to and healing of indomethacin-induced gastric lesions were compared in wild-type and annexin-1-deficient mice. Expression of annexin-1 was significantly increased in the gastric ulcer margin throughout the healing process. Treatment with an annexin-1 mimetic (Ac2-26) significantly enhanced gastric ulcer healing. In contrast, both dexamethasone and an formyl peptide receptor-like-1 (FPRL-1) antagonist impaired the early phase of ulcer healing. Annexin-1-deficient mice exhibited the same susceptibility as wild-type mice to indomethacin-induced gastric damage, but the healing of that damage was impaired in the former. These data support the hypothesis that annexin-1 contributes significantly to the process of healing of gastric mucosal damage. gastric ulcer; glucocorticoid; resolution of inflammation GASTRIC ULCER HEALING IS a highly regulated process that involves inflammation, cell proliferation, formation of granulation tissue, and angiogenesis. For decades, agents that suppress acid secretion (H 2 receptor antagonists and proton-pump inhibitors) have been widely used for promoting ulcer healing. However, there remains strong interest in better understanding the mechanisms through which ulcers heal and the possibility that both the speed and quality of healing may be pharmacologically enhanced (32).Glucocorticoids are widely used, powerful anti-inflammatory agents, but they can significantly delay the healing of wounds (8, 21). Several human and animal studies have demonstrated that glucocorticoids depress angiogenesis and inhibit epithelial cell proliferation, which results in delayed gastric ulcer healing and an increase in the risk of ulcer perforation (5,7,16,18). Annexin-1 is a 37-kDa member of the annexin family of proteins that bind to and activate "formyl-peptide" receptors (FPR) (3,10,19). The expression of this protein can be modulated by glucocorticoids and has been shown to account for a substantial part of the anti-inflammatory effects of gl...

A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation

“…30 Pro-resolving processes have been detailed, mostly, in experimental models of tissue inflammation, including peritonitis, pleurisy, and dorsal air pouches, with important confirmation in experimental and human colitis. 31,32 More recent studies have corroborated these pharmacological findings with investigations in transgenic mice, including AnxA1 . We measured consistent increases in LXA 4 levels during ischemia, with marked amounts seen after reperfusion.…”

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

“…In response, the epithelium has evolved a remarkable capacity to efficiently reseal the barrier defects. Such important reparative responses are modulated by mucosal mediators, such as anti-inflammatory protein ANXA1 (60)(61)(62)(63). The beneficial effects of ANXA1 are exerted by a unique N-terminal peptide that is released by proteolysis from the full-length protein (2,13,14,64).…”

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

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