The bicarbonate before chloride hypothesis Most of the symptoms associated with the CF are thought to stem from cells’ inability to transport Cl- ions, however, the CFTR protein has been found to conduct other substances such as HCO3- (Wine, 2001) and more recently reduced glutathione (GSH) to be described later. The former compound forms an important constituent of pancreatic secretions that empty into the duodenal ampulla. HCO3- acts as a buffer to the highly acidic chyme produced in the stomach, thus protecting the enzymes in the pancreatic juices and the cells of the intestine from denaturation or damage.In CF patients, acini cells in the pancreas are deficient for the CFTR gene and as a result are not able to secrete HCO3- into the juices they produce. CF pancreatic secretions will be deficient in the necessary ions as other positively charged ions will not move out of the cells to counter the anion efflux. This has the effect that such secretions will be thicker as water molecules will be less likely to diffuse out of cells in association with the ions, and subsequently the secretory ducts (that empty into the pancreatic duct) become blocked.
Blockage of these ducts initiates the process of apoptosis, followed by infiltration of fibrous scar tissue and eventual lack of function in the pancreas.Further, those ducts that remain unblocked for a time continue to secrete a solution rich in enymes but unable to counter the acidic nature of chyme and so the enzymes present become denatured and less able to digest food material. The inability to digest food particles leads to malabsorbtion in the small intestine, and coupled with other adverse effects of the disease causes CF patients to be under nourished despite dietary supplements (Cystic fibrosis – SHALE?).GSH Transport The CFTR has been found to transport a number of molecules across cell membranes, e.g. reduced glutathione (GSH), a large organic anion with powerful antioxidant properties.
The fact that the CFTR conducts tripeptides as well as small molecules has paved the way for new hypotheses about its role in the cells of the body. It is possible that the CFTR allows the passage of a variety of different molecules that may have wide ranging effects on the pathology of cystic fibrosis.Many of the clinical manifestations of the disease remain unaccounted for by the model proposing a defective Cl- channel as the cause of the disease. Recent hypotheses such as Hudson’s (2001) offer alternative viewpoints for considering the CFTR gene, it may be more accurate to see it as a multi-functional channel, performing a range of important regulatory functions.
Normally GSH is synthesised in cells e.g. epithelial cells, leukocytes; and secreted into the extracellular milieu where it can be oxidised by reactive oxygen species (ROS), such as hydrogen peroxide or superoxide, that would otherwise damage the surrounding tissue. Such ROS are common in the airways, which can sometimes have elevated levels of GSH over 100 times the normal level. GSH deficiency is by no means restricted to CF, as it has been recorded in a number of other respiratory illnesses e.g.
chronic obstructive pulmonary disease (COPD).The human antioxidant system comprises a number of molecules (some of which are enzymes) that offset the effects of ROS, however, GSH is a precursor for one of these enzymes. GSH also forms an interdependent system with two other antioxidants i.e. when GSH levels fall the other components’ levels also fall.
The result of lowered GSH in the extracellular milieu therefore leads to a breakdown of the whole system, which would previously have protected the epithelium. However, the complications arising through depletion of GSH levels must not be interpreted as causative of CF, but rather as an exacerbation of symptoms all ready present.