Mechanisms Behind the Increased Vulnerability of the Aging Stomach to NSAID-Related Injury: Perhaps Not As Simple As We May Think

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed to treat conditions such as arthritis and other musculoskeletal disorders in elderly patients. The usefulness of NSAIDs is, however, often limited by their associated gastrointestinal (GI) toxicity [1, 2]. Elderly patients taking long-term NSAIDs therapy are a particularly high-risk group for NSAIDs-related GI injury [3, 4]. NSAIDs-related GI injury is mainly a consequence of systemic inhibition of GI mucosal cyclooxygenase (COX) activity, which reduces levels of mucosa-protective prostaglandins (PG), for example prostaglandin E2 (PGE2), rather than a result of topical epithelial injury [5–7]. Inhibition of the two isozymes of COX, COX-1 and COX-2, is important in the pathogenesis of NSAIDs-related gastric injury [6]. COX-1 is a constitutive enzyme expressed in most cells of the body, including the stomach [6]. In contrast, COX-2 is an inducible enzyme, with increased expression in response to bacterial polysaccharides and proinflammatory cytokines [6]. Although non-selective NSAIDs (e.g., indomethacin) exert their GI ulcerogenic effects mainly through COX-1 inhibition, the GI ulcerogenic effects of NSAIDs require inhibition of both COX-1 and COX-2 [7, 8]. Mucosa-protective PGs (e.g., PGE2) contribute to gastric mucosal defense by reducing gastric acid secretion and by their nonantisecretory effects referred to as ‘‘cytoprotection’’ (e.g., stimulation of bicarbonate and glycoprotein secretion, increase in mucosal blood flow, among others) [9, 10]. It has been suggested that nitric oxide (NO) is the crucial intermediate in PGE2-mediated cytoprotection [11]. Hence, deficiency in mucosa-protective PGs or NO because of NSAIDs use is associated with compromise of gastric mucosal defense. Mechanisms independent of COX inhibition are also implicated in NSAIDs-related gastric injury. NSAIDs may also produce gastric mucosal injury by interfering with growth factors (e.g., TGF-b, TGF-a) and other mediators responsible for epithelial restitution and adaptive protection (e.g., trefoil family peptides) [12, 13]. Reactive oxygen species and apoptosis are also implicated in indomethacin-induced gastric injury [14]. Why aging stomachs are at greater risk of NSAIDsrelated injury is still poorly understood. Data from outcome studies have identified advanced age as one of the major risk factors for NSAIDs-related upper GI injury [1], possibly because of the finding that the aging gastric mucosa has reduced capacity for repair. A recent study investigating the effect of reactive oxygen species, apoptosis, and angiogenesis on the aging stomach has shown that aging gastric mucosa is gradually replaced by connective tissue, thus impairing gastric mucosal protection [15]. In rats of advanced age, angiogenesis is reduced as a result of reduced expression of VEGF and overexpression of PTEN [16]. Thus, reduction in mucosal defense mechanisms characteristic of the aging stomach may increase susceptibility to NSAIDs-related mucosal injury, although the underlying molecular pathogenesis remains poorly understood. In this issue of Digestive Diseases and Sciences, Hong et al. [17] report investigation of potential molecular mechanisms behind the increased susceptibility of the R. S. Tang (&) Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 94020, 7/F, Clinical Science Building, Shatin, New Territories, Hong Kong e-mail: rtang01@yahoo.com