[50] These human studies may support the actual involvement

Raf inhibitor of exogenous NO in the pathogenesis of reflex esophagitis. In this context, another recent study demonstrated a diverse esophageal microbiome in relation to inflammation and metaplasia in the distal esophagus.[51] Further studies are warranted to investigate how the diversity of microbiomes in the oral cavity as well as the esophagus affect the exogenous luminal NO production at the GE junction or at the distal esophagus by modulating the conversion of nitrate to nitrite. One important observation concerning esophageal adenocarcinoma is its strong male predominance (male : female ratios of 3:1 to 12:1).[52, 53] The male-predominant see more gender difference consistently exists across the GERD spectrum,[54-56] although the ratios become higher with progression toward the later stages.[56] Meanwhile, reflux symptoms or non-erosive reflux disease in general affects more women than men.[57] These epidemiological data allow us to hypothesize that the esophageal epithelium is more vulnerable in men, or more resistant in women, to the refluxed gastroduodenal contents, than in their respective counterparts. Identification of the causative luminal factors for inducing the gender-related difference would be clinically relevant to predict the actual etiologic factors involved in the pathogenesis of reflux esophagitis in humans. Employing chronic rat reflux esophagitis

models[46] of both sexes, we found that there was a striking find more male-predominant, gender-related difference in esophageal tissue damage in the presence of exogenous NO and that estrogen

attenuated the esophageal tissue damage via the estrogen receptor.[58] Further, we found a potential role of esophageal mast cells in the mediation of the suppression of the immune system under estrogen administration.[58] Interestingly, the gender-related difference in the esophagitis model was more prominently observed when exogenous NO was administered compared with exogenous acid (pH 1.8),[58] suggesting that gender-related differences may be specifically potentiated in the presence of exogenous NO as the aggravating agent. These results indicated that gender-related differences in the susceptibility of the esophageal epithelium to damage by exogenous NO might be at least partially responsible for prominent gender-related disease differences in GERD in humans. The LES is a bundle of muscles at the lower end of the esophagus, and it plays a primary role in preventing reflux of gastric contents into the esophagus. It is well known that NO endogenously derived from cNOS localized to non-adrenergic, non-cholinergic nerves mediates the relaxation of the smooth muscle cells, including those of the LES.[59] An in vitro study using muscle strips from the LES of an opossum demonstrated that a low concentration of NO (nM) was sufficient to induce relaxation of the muscle.