Effects of the lack of transport of thiocyanate in cystic fibrosis lung disease (Melanie Childers, Alan Himmel, Jim Caldwell)
Abstract.
Hypothiocyanate (OSCN-) is a major component in the lactoperoxidase system. This system in the lungs of cystic fibrosis (CF) patients is defective, which leads to bacterial colonization in the respiratory tract of these patients. Thiocyanate (SCN-) interacts with several strong oxidants, including hydrogen peroxide and hypochlorous acid, both to downregulate humoral immune response, and to create the strong antimicrobial OSCN-, in the lung. Since cystic fibrosis is characterized by recurrent respiratory infections, and these mutations of the cystic fibrosis transmembrane conductance regulator block the transport of SCN- to the respiratory tract in CF patients, it is likely that the lack of transport of SCN through the CFTR plays a central role in the pathology of this disease.
Cystic Fibrosis (also known as CF, mucovoidosis, or mucoviscidosis) is a hereditary disease affecting the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.
Abnormally thick mucus results in frequent lung infections. Diminished secretion of pancreatic enzymes is the main cause of poor growth, greasy stools, and deficiency in fat-soluble vitamins. Males can be infertile due to the condition congenital bilateral absence of the vas deferens.
Often, symptoms of CF appear in infancy and childhood. Meconium ileus is a typical finding in newborn babies with CF.Individuals with CF can be diagnosed prior to birth by genetic testing. Newborn screening tests are increasingly common and effective(although false positives may occur, and children need to be brought in for a sweat test to distinguish disease vs carrier status). The diagnosis of CF may be confirmed if high levels of salt are found during a sweat test, although some false positives may occur.
There is no known cure for CF. This new book presents important research in the field.
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LATEST NEWS: Sharktank Releases Revolutionary Paper
A new model of cystic fibrosis pathology: Lack of transport of glutathione and its thiocyanate conjugates has been released by Medical Hypotheses of Elsevier Press. Authored by Melanie Childers, George Eckel, Alan Himmel, and Jim Caldwell.
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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.