Role of Phospholipids in Protection of the GI Mucosa

Abstract

The focus of peptic ulcer disease research has evolved over the past 50 years. In the past, the greatest interest understandably has been in studying the regulation of gastric acid secretion, following the century-old Schwarz’s dictum of ‘‘no acid, no ulcer’’ [1]. As a consequence, understanding the regulation of gastric acid section and the potential causes of gastric acid hypersecretion became a central research focus until 1970, with major scientific advances including the elucidation of the role of gastrin, acetylcholine, and histamine as physiological stimulants of acid secretion and the identification of luminal acid and somatostatin as physiological inhibitors [2]. Afterwards, the emphasis was on the development of pharmacological inhibitors of gastric acid secretion, with the clinically important discovery of highly effective H2 receptor antagonists (H2RAs) followed by the even more efficacious proton pump inhibitors (PPIs) [3–7]. During this same period came the major discovery by Robert and associates of the role of prostaglandins in inhibiting gastric acid secretion, and more importantly in protecting the gastric mucosa from a damaging agents and ulcerogenic conditions (e.g., stress), a remarkable finding at the time, termed ‘‘cytoprotection’’ [8]. The multi-factorial mechanism that underlies prostaglandin’s cytoprotective action appears to involve increasing and/or maintaining tight junctional integrity, increasing intestinal mucus and bicarbonate section, and increasing mucosal hydrophobicity, mitochondrial integrity, and blood flow [9, 10]. The development of prostaglandins as clinical cytoprotective agents, however, has been disappointing due to the side-effect profile of these biologically active lipids to stimulate uterine and intestinal smooth muscle contraction and intestinal secretion, which may result in miscarriages, bloating, and diarrhea [11]. Lastly, the discovery of Helicobacter pylori by Marshall and Warren [12] revolutionized the field of peptic ulcer disease by implicating a micro-organism in its pathogenesis, leading to novel antibiotic combination therapeutic approaches which not only remarkably reduced the incidence of peptic ulcer disease but of gastric cancer as well [13, 14]. The mechanism by which H. pylori causes peptic ulcer disease surprisingly has yet to be fully resolved, but appears to be dependent on the gastric localization of the infection (antrum vs. body), gastric acid hypersecretion (mostly linked to antral infection), and defects in gastroduodenal barrier function [15, 16]. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are regularly consumed by a large percentage of our populace, represent the other major cause of GI ulceration, with gastroduodenal erosions and/or ulcers affecting between 15 and 40 % of those regularly taking NSAIDs [17], and lower gut pathology being present in [50 % of chronic NSAID users [18]. The mechanism by which aspirin and related NSAIDs injure the GI mucosa was once thought to be strictly due to disruption of the biosynthesis of cytoprotective prostaglandins via inhibition of constitutive cyclooxygenase1 (COX-1) [19], leading to the development of highly selective COX-2 inhibitors (coxibs) as safer anti-inflammatory drugs. However, over time this concept has been challenged, with the demonstration that NSAIDs can induce GI injury by COX-independent mechanisms [20], and the demonstration that a number of highly selective coxibs have unanticipated and potentially L. M. Lichtenberger (&) Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, TX 77030, USA e-mail: lenard.m.lichtenberger@uth.tmc.edu