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Pathophysiology of Gastric Ulcer Development and Healing: Molecular Mechanisms and Novel Therapeutic Options

M. Fornai,L. Antonioli,R. Colucci,M. Tuccori,C. Blandizzi

Published 2011 in Unknown venue

ABSTRACT

The stomach plays a pivotal role in the digestion of foods that we eat. With the exception of rare cases, this organ can resist to a large variety of noxious factors, including hydrochloric acid, refluxed bile salts and alcohol, with a wide range of temperatures and osmolality. This high resistance to injuries depends on a number of physiological responses elicited by the mucosal lining against potentially harmful luminal agents, as well as to the ability of rapidly repairing the mucosal damage when it does occur (Laine et al., 2008). Nevertheless, when these protective mechanisms are overwhelmed by injurious factors, a gastric mucosal lesion may develop. Major detrimental effects on gastric mucosa are exerted by non-steroidal antiinflammatory drugs (NSAIDs). These drugs are able not only to exert gastric injuring effects, but also to delay the healing of ulcer lesions through a variety of local and systemic mechanisms (Musumba et al., 2009). Since the discovery that prostaglandin biosynthesis could be inhibited by NSAIDs through the blockade of cyclooxygenase enzymes, there has been a great interest in the contribution of prostaglandins to the mechanisms of gastric mucosal defense. Thus, it has been appreciated that these lipidic mediators are able to modulate virtually every factor involved in mucosal protection, and the importance of this contribution is made evident by the increased susceptibility of the stomach to injury following the intake of NSAIDs. Indeed, chronic treatments with these drugs can be associated with the development of ulcers in the stomach, and research over the past two decades has helped to identify some of the key events, triggered by cyclooxygenase blockade, which take part to ulcer formation and/or impairment of ulcer healing. Since many years, it has been recognized that NSAIDs can interfere with gastric mucosal physiology also through injuring mechanisms unrelated to the inhibition of prostaglandin biosynthesis, such as oxidative stress and changes in epithelial cell proliferation/apoptosis balance. Following the discovery of two isoforms of cyclooxygenase (COX-1 and COX-2), and based on the assumption that COX-2 was an inducible enzyme responsible for inflammation, but devoid of gastroprotective functions (Vane et al., 1998), selective COX-2 inhibitors (coxibs, including celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib and lumiracoxib) were

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