Title

 

Authors

C. Blandizzi
 
Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa

 

Abstract

Proton pump inhibitors (PPIs) are effective in preventing and healing gastropathy associated with non-steroidal anti-inflammatory drugs (NSAIDs) [1]. Available data suggest that NSAID-induced gastric injury depends on luminal acidity, leucocyte activation, tissue oxidation, and impairment of cell turnover [2], and that PPIs can counteract all these detrimental actions [1]. The inhibition of gastric acid secretion, through the blockade of H⁺/K⁺-ATPase, represents a pivotal mechanism whereby PPIs protect the upper gastrointestinal (GI) tract from NSAIDs. Intragastric acidity facilitates the onset of NSAID-induced gastropathy, enhances its progression, and interferes with its repair by various mechanisms: a) prostaglandins can inhibit acid secretion, and the blockade of their biosynthesis by NSAIDs can increase the gastric acid output; b) most NSAIDs are endowed with lipophilic/acidic chemical structures, and, once introduced into the gastric acidic environment, they behave as detergent agents, leading to disruption of mucus barrier, and accumulate into epithelial cells, where they dissociate, causing intracellular acidosis, and uncouple mithochondrial phosphorylation, with overproduction of reactive oxygen radicals and cell death [2]; c) acid secretion contributes to the chronicity and bleeding of upper GI lesions by impairing their restitution process, interfering with haemostasis, limiting the ability of platelets to aggregate and inactivating several growth factors, thus facilitating the progression of superficial injury to deeper mucosal necrosis [1,2]. There is also evidence supporting the concept that PPIs may act via acid-independent mechanisms, targeting both directly and indirectly the inflammatory and oxidative processes in NSAID-induced upper GI injury [1]. In particular, the protective actions of PPIs call into play the following mechanisms: a) direct antioxidant activity, as shown by in vitro chemical assays where PPIs were found to blunt oxidative reactions; b) indirect antioxidant effects, resulting from an interference with the oxidative metabolism of activated neutrophils; indeed, the enhanced output of free oxygen radicals, arising from neutrophil activation, requires the acidification of phagolysomes, and such a process is accomplished by a proton pump which, like the gastric H⁺/K⁺ATPase, is susceptible to blockade by PPIs; c) induction of haeme oxygenase-1, an enzyme endowed with antioxidant, anti-inflammatory and anti-apoptotic properties; d) maintenance of adequate mucosal levels of sulfhydryl radicals, including reduced glutathione, and prevention of their consumption following NSAID administration [1]. Recent studies have shown also that PPIs can counteract the detrimental actions of NSAIDs on gastric ulcer repair via a number of actions which do not depend, at least in part, on the inhibition of acid secretion. These mechanisms include: a) enhancement of NF-kB activation; b) decrease in apoptotic cell death; c) enhancement of cell proliferation and expression of various growth factors. Overall, current evidence suggests that both the inhibition of acid secretion and a variety of acid-independent protective mechanisms contribute to the beneficial effects of PPIs against NSAID-induced gastropathy [3]. However, the clinical relevance of the acid-independent mechanisms needs to be further evaluated in human studies.
 
[1] C. Blandizzi et al. (2008) Clinical efficacy of esomeprazole in the prevention and healing of gastrointestinal toxicity associated with NSAIDs in elderly patients. Drugs Aging 25, 197-208.
[2] C. Scarpignato, R. Hunt (2010) Non-steroidal anti-inflammatory drug-related injury to the gastrointestinal tract: Clinical picture, pathogenesis and prevention. Gastroenterol Clin North Am 39, 433-464.
[3] R. Colucci et al. (2009) Characterization of mechanisms underlying the effects of esomeprazole on the impairment of gastric ulcer healing with addition of NSAID treatment. Dig Liver Dis 41, 395-405.