**1. Introduction**

Non steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed medications worldwide because of their analgesic and anti-inflammatory properties. In fact, NSAIDs are generally prescribed for pain management in musculoskeletal or osteoarticolar pathologies and for rheumatic diseases, very common diseases in the general population.

About twenty million US patients were prescribed NSAIDs every year. Although NSAIDs are generally well tolerated, chronic therapy is responsible for a significant morbidity and mortality rate; in fact, the incidence of GI events is significantly higher (about four fold) in patients receiving NSAIDs chronic therapy (Shaheen et al., 2006; Lawrence et al., 1998).

NSAIDs and aspirin present a favorable benefit profile in relief from pain, inflammation reduction and contribute to lower the risk of cancer, as demonstrated by some epidemiologic and clinical studies showing a reduced incidence of colon cancer in patients receiving low-dose aspirin (Din et al., 2010; Rothwell et al., 2010; Elwood et al., 2009).

Moreover, low-dose aspirin therapy induce a significant reduction in cardiovascular (CV) and cerebrovascular events and effectively lower the rate of deaths in patients with cardiovascular risk factors and previous CV events. On the other hand, adverse gastrointestinal events related to NSAIDs therapy occur in a little but significant amount of patients, resulting in an important morbidity and mortality; world mortality secondary to NSAIDs therapy has been estimated to be similar to that caused by HIV-related complications (Abraham et al., 2005; Laine et al., 2010). For example, in the US more than

<sup>\*</sup> Corresponding Author

Chronic NSAIDs Therapy and Upper Gastrointestinal Tract – Mechanism of Injury,

2005; Hooper, 2004; Rostom, 2002; Scheiman, 2006).

hemorrhage (Somerville, 1986).

(Malfertheiner, 2009; Laine, 2008).

*Defense mechanisms* 

injury.

Mucosal Defense, Risk Factors for Complication Development and Clinical Management 151

the onset of gastroduodenal injuries in patients receiving chronic NSAIDs therapy; however, misoprostolis poorly tolerable. Effective doses of misoprostol induce dyspepsia and are often associated to development of diarrhea and abdominal pain/bloating while low doses do not induce side effects but are ineffective as gastroprotection (Lanza, 1989; Targownik, 2008).

Other recent and effective therapies were developed in order to reduce upper GI symptoms and prevent complications: histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPI) have both demonstrated efficacy in NSAID-related GI side effects (Hawkey,

During chronic NSAIDs therapy, a significant amount of patients present with dyspeptic symptoms; however, development of GI symptoms is not predictive for development of NSAID-related injury (gastropathy or ulcers). Moreover, about 60% of patients with endoscopic findings of NSAID-related injury do not present GI symptoms until bleeding or perforation occur. Finally, only 10% of NSAID-related injury become symptomatic for

The gastroduodenal mucosa is continuously exposed to endogenous (HCl, pepsin and bile acids) and exogenous (drugs, alcohol and bacteria) noxious agents; therefore, upper GI tract is characterized by a complex biological defense system, in order to prevent and heal any

Pre-epithelial, epithelial and post-epithelial defenses were together involved in this complex mechanism preventing mucosal injury and maintaining integrity. The *pre-epithelial defense* level consists of mucus and a bicarbonate barrier, secreted by upper GI epithelial cells. Mucus is composed by water (95%), lipids (fatty acids and phospholipids) and glycoproteins (mucin), and constitutes an hydrophobic layer preventing ions and molecules (eg. pepsine) passage. Bicarbonate, directly secreted into the mucus layer, forms a high pH gradient (6-7) able to neutralize lumen acidity even when pH falls below 2. The *epithelial defense* layer is constituted by a continuous layer of GI epithelial surface cells linked to each other by tight junctions, these complexes constitute an hydrophobic barrier limiting the diffusion of hydrogen ions and water-soluble agents through the mucosa; moreover, hydrogen ions that enter into the

epithelial cells can be removed by basolateral ion pumps (i.e. Na+/H+ and a Cl-

exchanger). Minimal mucosal injury can be rapidly recovered thanks to the migration of the nearest healthy cells able to close the mucosal gap, a phenomenon known as *rapid restitution*. This event involves several growth factors such as *epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and fibroblast growth factor (FGF)*. Rapid restitution involves only cell migration not cell division so that only minor mucosal defects can be healed; large peptic lesions requires cellular proliferation and neoangiogenesis *(regeneration)*. The rich vascular system that underlies the mucosa represents the *post-epithelial defense* mechanism. Blood flow continuously provides bicarbonate to neutralize the acids released and supplies nutrients and oxygen essential for cells metabolism while taking away all the toxic catabolites produced.

GI injury occur when the caustic acid-peptic factors on gastrointestinal lumen overwhelm all

three components of epithelial defense or when those mechanisms are impaired.

/HCO3 -

**Pathophysiology of NSAIDs peptic ulceration: Defense and injury mechanisms** 

100.000 patients were admitted every year for NSAIDs related adverse events, resulting in about 15000 deaths (Weil et al., 2000; Ofman et al., 2002).

Non-selective NSAIDs (nsNSAID) inhibit both cyclooxigenase-1 (COX1) and cyclooxigenase-2 (COX2). These two enzyme have different roles in the cell and, in particular, COX1 mediates prostaglandin (PG) secretion which is one of the upper GI protective mechanisms. That is why, with the aim of reducing NSAIDs related upper GI toxicity, selective COX2 inhibitors (coxibs) were developed in the last decade. Coxibs weakly inhibit COX1 and a reduced relative risk of developing upper GI injury was demonstrated in clinical trials in patients receiving coxibs.
