Cystic fibrosis hypothesis

The hypothesis that Pgp regulates volume-activated chloride channels was developed by the observation that Pgp was highly related to the cystic fibrosis transmembrane regulator protein (CFTR). CFTR belongs, like Pgp, to the ABC superfamily of transporters and is a plasma membrane chloride channel that is dysfunctional in cystic fibrosis (50). However, the role of Pgp in volume-regulatory processes has been controversial, and a current hypothesis is that Pgp does not have channel activity itself, but it may regulate swelling-induced anion channels (57). 

Two major but conflicting hypotheses have been proposed to explain the connection between abnormal CFTR activity in cystic fibrosis and the chronic neutrophil-dominated pulmonary inflammation and colonization with common bacteria. These hypotheses have been referred to as the high-salt hypothesis proposed by Michael Welsh and his colleagues at the University of Iowa, and the reduced pericellular volume hypothesis proposed by Richard Boucher and colleagues at the University of North Carolina. 

The protein factor elutes with the immunoglobulin G on diethylaminoethyl-cellulose with a molecular weight of 125,000-200,000. The protein s mode of action is not known, but it has been postulated to act as an autoantibody or a polycation that destroys membranes. Although this hypothesis is suggestive, there is no evidence of a link between the presence of the protein and the pathogenesis of cystic fibrosis [142]. 

The relationship between these defects and the clirrical marrifestations of cystic fibrosis still remains speculative. However, a reasonable hypothesis is that the ion transport defects may lead to suboptimal volttmes of airways surface liquid resulting in impaired mucociliary clearance, bacterial colonization, and... 

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