A new model of cystic fibrosis pathology: Lack of transport of glutathione and its thiocyanate conjugates

Summary

Many of the symptoms of cystic fibrosis are not explained by the current disease mechanisms. Therefore, the authors conducted an extensive literature review and present a new model of cystic fibrosis pathology, which is the culmination of this research. Understanding that the cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for glutathione (GSH) transport, the authors hypothesize that mutations of the CFTR, which create abnormal GSH transport, will lead to aberrations of GSH levels in both the intracellular as well as the extracellular milieu. These alterations in normal cellular GSH levels affect the redox state of the cell, thereby affecting the intracellular stress protein, metallothionein. The authors describe how this disruption of the redox state caused by excess cellular GSH, will naturally prevent the delivery of zinc as a cofactor for various enzymatic processes, and how these disruptions in normal redox may cause alterations in both humoral and cell-mediated immunity. Moreover, the symptom of thick sticky mucus in these patients might be explained through the understanding that oversulfation of mucus is a direct result of elevated cellular GSH and cysteine. The issues of hyperinflammation, altered pH and the imbalance of fatty acids that are typical in cystic fibrosis are addressed—all of which may also be linked to disruptions in GSH homeostasis. Additionally, this new model of cystic fibrosis pathology, clarifies the relationship between the CFTR and the multi-drug resistance proteins, and the lack of cell-mediated immunity by predicting that the substrate of these proteins is a glutathione adduct of thiocyanate. Finally, a new therapeutic strategy by using isothiocyanates to rectify the GSH imbalance and restore the immune system is suggested for the treatment of cystic fibrosis patients.

Introduction

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by repeated and destructive lower respiratory infections, resulting in the gradual destruction of the lung tissue in patients, and ending in an early death. The disease affects approximately 30,000 children and adults in the United States. The etiology of the disease has been traced to the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein which has long been thought to govern chloride ion conductance in epithelial cells. And, while loss of chloride conductance is the “gold standard” in terms of diagnostic parameters, loss of this function does not fully explain the diverse pathologies seen in this disease.

Since the discovery of the CFTR and its respective gene in 1989, there has been an enormous drive to further understand the disease and in fact, try to correct the imperfection via gene therapy. Because CFTR has been the center of attention in CF research, it has become much clearer what its function is as a membrane protein, and there is a better understanding of its similarities to other ATP-binding cassette (ABC) membrane proteins [1]. It is now known that the CFTR, just as the other ABC proteins, is permeable to glutathione (GSH) and that the lining of the CF lung which has a defective CFTR is abnormally deficient in this anti-oxidant protein [2]. There is now a better understanding of the disease, but the cause of the various pathologies associated with CF still remains elusive.

In order to shed further light on the various disease mechanisms in CF, it is important to consider the role of the CFTR, its relationship to GSH, and the intracellular and extracellular resulting effects due to transport deficiency. Further, there has been a great deal of CF related papers published which discuss the activity of enzymes and various DNA factors, that are either inactive or overactive, all of which depend on zinc as a cofactor. Owing to zinc’s ability to act as a cofactor in various enzymatic reactions, and because the proper activity of zinc is dependent upon the redox state of the cell, our interest has been the effects of altered zinc homeostasis due to the abnormalities of GSH homeostasis.

Moreover, the immune system in CF is compromised, particularly in the respiratory tract, which remains a major cause of mortality. The immune system in CF seems to be skewed toward the humoral immune response, while cell-mediated immunity is lacking [3], [4]. The obvious result is hyperinflammation, which is destructive to the lung, and creates an inability to combat invading bacteria, such as Pseudomonas aeruginosa, which colonizes the lungs of these patients at a very young age. Certain immune factors such as the lactoperoxidase system and neutrophil activity are faulty in CF. And, anti-inflammation therapy remains central in most treatment protocols.

In the last couple of decades, the average life span of a person with CF has increased remarkably due to new treatment options and a better understanding of nutrition. However, treatments for CF, as with most diseases, are geared toward easing symptoms. Since CF is a systemic disease, involving multiple organ pathophysiology, stopping its progression has been difficult. Thus, because the authors believe that the aberrations in GSH homeostasis are crucial in terms of the pathophysiology of the disease, they performed an extensive literature review, and in this paper they propose a new model of disease pathology, and present a new treatment, which might prove to be ameliorative to both the symptoms of CF as well as its lethal effects on the lungs.