Lipoxins, The Novel Mediators of Gastroprotection and Gastric Adaptation to Ulcerogenic action of Aspirin

Abstract

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

“…As expected, we did not observe any changes in cell morphology after the BM treatment at the concentrations of 100 μM and 250 μM. Additionally, GI mucosa is known to adapt after chronic exposure to low doses of noxious agents such as, e.g., acetylsalicylic acid [ 83 , 84 ]. We assumed that the non-linear response seen for the expression of a few molecular targets in cells between groups treated with BM applied in 100 and 250 μM could be due to enhanced adaptation under these specific experimental conditions.…”

The role of L-carnitine in acetyl salicylic acid-induced acute gastric mucosal injury in rats

“…Synthetic analogues of lipoxins as well as the newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAID ingestion [37]. In the present study, pretreatment with PPI significantly reduced the NO levels in rat stomach compared to animals given ASA alone.…”

“…Acetyl salicylic acid (ASA) significantly increased NO levels compared to those in control rats. Pretreatment with a proton pump inhibitor (ASA + PPI) significantly improved NO levels increased by ASA, but pretreatment with L-carnitine (ASA + LC) did not pression of prostaglandin (PG)-mediated effects on mucosal protection, but the exact pathogenic mechanism remains to be elucidated [37]. The ROS plays a crucial role in the pathogenesis of oxidative damage.…”