Study on the role of Peroxisome Proliferator Activated Receptor Gamma (PPAR-γ) in gastric ulcer healing

Abstract

Gastric ulcer is the most prevalent gastro-intestinal disorder and also a major health problem, with a high rate of global incidence occurring across all ages, races and ethnicity. With pluricausal etiologies which are not fully understood make gastric ulcer an important target that continues to attract the attention of both clinicians and researchers. In gastric ulcer there is disruption of the mucosal integrity leading to a local defect or excavation due to active inflammation and are often chronic in nature (Valle, 2005). In the early 20th century, peptic ulcer disease was believed to be related to excessive acid secretion resulting from stressful lifestyle. The importance of the interaction of acid and pepsin in the formation of peptic ulcer disease remained unclear until the second half of the 20th century. With the introduction of histamine type 2 receptor antagonists (H2 receptor antagonists) in the 1970s, progress was made in reducing acid secretion and providing relief of symptoms. With further advancement in medical sciences, it is now well recognized that use of nonsteroidal anti-inflammatory drugs (NSAIDs) contribute to the development of peptic ulcer disease. In 1981, Warren and Marshall observed that a bacterium, Helicobacter pylori (H. pylori) was associated with peptic ulcer disease and that its elimination with antimicrobial drugs could effectively cure the disease. The identification that H. pylori play a key role in the pathogenesis of acid-peptic diseases stimulated new approaches to prevention and therapy. Pharmacological management of gastric ulceration thus is mainly directed at the reduction or neutralization of gastric acid secretion despite evidence that most patients who suffer from this disease are normal or below normal secretors of hydrochloric acid and pepsin (Hoogerwerf and Pasricha, 2006). For about three decades, suppressors of acid secretion (e.g. H2 receptor antagonists, proton pump inhibitors) have been the mainstay for promotion of ulcer healing, but their clinical evaluation have shown incidences of high rate of relapses, side effects and drug interaction (Miller and Faragher, 1986; Ariyphisi et al., 1986). Non-cancerous (benign) gastric ulcers are caused by an imbalance between aggressive and defensive factors. This imbalance leads to inflammation and the inflammatory injuries in the gastric mucosa, extending beyond the submucosa, into the muscularis mucosa. The etiologies of this condition are multifactorial and are rarely related simply to excessive acid secretion. The physicians’ goal in treating gastric ulcer is to provide relief of symptoms (pain or dyspepsia), promote ulcer healing and ultimately prevent ulcer recurrence and complication. Thus, there is an increased interest in recent years towards understanding of the mechanisms of ulcer healing. Better understanding of the mechanisms of the healing process will also provide newer avenues for development of novel therapies for improved management of ulcer healing. Discoveries in the past few years have continued to improve our understanding of mucosal defense, including pathogenesis of gastric ulcer disease and of the processes contributing to the healing of ulcers (Wallace, 2005). Several alternate hypotheses concerning the pathogenesis of gastric ulcer disease suggest the involvement of various other important targets other than acid secretion to be worthy of pharmacologic importance. These include inflammatory mediators such as, nitric oxide, the eicosanoids (prostaglandins, leukotrienes, and thromboxanes), neuropeptides, cytokines, and proteinases that coordinate inflammatory responses and also have the capability to alter the resistance of the mucosa to injury induced by noxious substances, while others render the mucosa more susceptible to injury (Wallace and Ma, 2001). This has led to the development of novel anti-ulcer therapeutic strategies which involves regulation of inflammatory conditions. Of these, recent studies hint to potential roles of Peroxisome Proliferator Activated Receptor-gamma (PPAR-γ) in gastrointestinal inflammation. Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor superfamily that share homology with the receptors for retinoic acid, steroids and thyroid hormone (Evans, 1988). Nuclear receptors are a superfamily of structurally conserved, ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Members of this subfamily include the PPARs- PPAR-α, PPAR-β (also known as PPAR-δ) and PPAR-γ (Mangelsdorf et al., 1995). Although they are encoded by distinct genes on different chromosomes, the PPAR isoforms have a high degree of sequence and structural homology. However, the isoforms are unique in their quantitative patterns of tissue distribution, have important differences in their regulatory activities and modulate specific responses after activation. PPAR-α and PPAR-γ are crucial for lipid and glucose metabolism, respectively. Although limited information is available on PPAR-β biological functions, recent studies have shown that PPAR-β also regulates glucose metabolism and fatty acid oxidation (Kota et al., 2005). Recent evidence has indicated an important role of PPARs in the control of inflammatory responses. These functions are mediated largely through the abilities of the PPAR-γ isoforms (Daynes and Jones, 2002). PPAR-γ forms a heterodimer with the retinoid X receptor (RXR) and activates target genes by binding to specific peroxisome proliferator response elements (PPREs) located in the promoter region of these genes (Gearing et al., 1993). It is involved primarily in the regulation of lipid metabolism, adipocyte differentiation and inflammation (Murphy and Holder, 2000). In addition to the well-studied effects of PPAR-γ on metabolism and cellular differentiation, abundant evidence suggests that it also acts as an important regulator of the immune system (Szeles et al, 2007). PPAR-γ has also been implicated in the pathophysiology of atherosclerosis, inflammation, obesity, diabetes, immune response and ageing (Lehrke and Lazar, 2005). However, the pathophysiological relevance of PPAR-γ in gastric ulcer remains to be established. In view of its expression and involvement in immune response and regulation of inflammation and cell proliferation, we hypothesized that PPAR-γ may have a potential role in the control of gastrointestinal inflammation induced by chronic ulcer. Inflammation of the mucosal layer of the gastrointestinal (GI) tract is a feature almost always associated with ulceration of these tissues. Amelioration of these inflammatory events might promote healing of chronic gastric ulcer. Thus the present study was designed to elucidate the molecular mechanism through which PPAR-γ modulates the inflammatory responses involved in chronic gastric ulcer healing and its crosstalk with other signaling pathways influencing its gastroprotective actions.