Duodenal epithelial cells provide a stimulus package for the recovery from an acid load

Abstract

It is widely appreciated that some of the harshest physiological conditions to which epithelial cells are exposed are found in the lumen of the upper gastrointestinal tract. The lumen-facing apical plasma membrane of these cells is regularly bathed in the ‘gemisch’ of chyme, which is comprised of HCl secreted by gastric parietal cells, hydrolytic enzymes secreted by gastric chief cells and pancreatic acinar cells, and foodstuffs. For digestion and absorption to continue, the luminal HCl must be largely neutralized to a pH that will enable the hydrolytic enzymes from the pancreas and solute transporters of intestinal epithelial cells to function at their optimum. This neutralization occurs via bicarbonate secreted into the mixture by epithelial cells of the duodenum and pancreas. Duodenal epithelial cells are also potentially directly exposed to this acidic chyme arriving from the stomach. Thus, bicarbonate secretion by these cells is critical for their own protection. While it has been recognized that part of the mechanism that protects the duodenum is comprised of an alkaline layer of fluid that is adjacent to the apical brush border membrane of duodenal epithelial cells and is in disequilibrium with the bulk luminal pH (Flemstrom & Kivilaakso, 1983), the mechanisms by which this alkaline zone is generated and regulated were largely unknown. In this issue of The Journal of Physiology, Mizumori and colleagues (Mizumori et al. 2009), using an in vivo duodenal perfusion loop, identify the key players at the apical membrane in rat duodenal epithelial cells that are involved in a feedback loop that regulates bicarbonate secretion in the duodenal response to an acid load. The work is based upon the hypothesis that an ecto-purinergic signalling system regulates this bicarbonate secretion, and the intriguing nature of this hypothesis appears to have been developed both from observations from the literature and from the authors’ unusual familiarity with duodenal physiology. Part of the novelty of their work is found in the collection of apical brush border membrane proteins that they hypothesize cooperate in this feedback loop. In addition to the more recently characterized proteins with defined physiological functions, such as apical membrane purinergic P2Y receptors and the cystic fibrosis transmembrane regulator (CFTR), some of the other proteins are ones that have been known for decades, such as intestinal alkaline phosphatase (IAP) and ecto-ATPase (Hietanen, 1973; Humphreys & Chou, 1979), which have well-characterized luminally oriented biochemical activities, but until now, no apparent physiological function. Using this duodenal perfusion loop, the authors were elegantly able to test directly this hypothesis to arrive at their model for regulated bicarbonate secretion by duodenal epithelial cells. They also benefitted significantly from the ability to use pharmacological probes for their proteins of interest. Their data have led them to propose that when bulk pH is closer to neutral, IAP activity is high. IAP degrades ATP released from duodenal epithelial cells, which in turn decreases signalling by P2Y receptors. Decreased signalling by P2Y receptors then results in decreased bicarbonate secretion. Decreased bicarbonate secretion thus results in a lower microclimate pH, thereby inhibiting IAP and completing the negative feedback loop. In the case of acid exposure, IAP activity is reduced and luminal ATP is increased. Signalling through P2Y receptors is increased and therefore bicarbonate secretion consequently increased. The acid load is neutralized, and the microclimate pH is increased, which then stimulates IAP activity. Again, the feedback loop is completed. So what about CFTR in this process? The authors speculate that CFTR may regulate bicarbonate secretion through regulating ATP release from epithelial cells because they observed that inhibition of CFTR inhibited ATP output by the duodenum. This observation is consistent with their earlier observation that the dysfunction of CFTR reduces bicarbonate secretion; however, interestingly, the duodenum is protected from ulcers in this case (Akiba et al. 2005). In this and previous work (Akiba et al. 2007), the authors have clearly begun to characterize at the molecular level the long-standing question of the regulation of bicarbonate secretion by the duodenum. Of course, as the authors acknowledge, there is more work to be done. One major question is the source of the ATP released from the duodenal epithelial cells: is it released via a membrane transporter or via exocytosis, and what is the precise relationship between CFTR and bicarbonate secretion in duodenal cells as well as in other epithelial cells? Despite these questions, at least this stimulus package is one that has led to recovery from toxic conditions.