PubMed · 14922347
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H SEEL. 1952. [Dosage problems in practical therapy].. https://pubmed.ncbi.nlm.nih.gov/14922347/
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Cystic fibrosis (CF) is a fatal, autosomal, recessive genetic disease that is characterized by profound lung inflammation. The inflammatory process is believed to be caused by massive overproduction of the proinflammatory protein IL-8, and the high levels of IL-8 in the CF lung are therefore believed to be the central mechanism behind CF lung pathophysiology. We show here that digitoxin, at sub nM concentrations, can suppress hypersecretion of IL-8 from cultured CF lung epithelial cells. Certain other cardiac glycosides are also active but with much less potency. The specific mechanism of digitoxin action is to block phosphorylation of the inhibitor of NF-kappa B (I kappa B alpha). I kappa B alpha phosphorylation is a required step in the activation of the NF-kappa B signaling pathway and the subsequent expression of IL-8. Digitoxin also has effects on global gene expression in CF cells. Of the informative genes expressed by the CF epithelial cell line IB-3, 58 are significantly (P < 0.05) affected by gene therapy with wild-type (CFTR CF transmembrane conductance regulator). Of these 58 genes, 36 (62%) are similarly affected by digitoxin and related active analogues. We interpret this result to suggest that digitoxin can also partially mimic the genomic consequences of gene therapy with CF transmembrane conductance regulator. We therefore suggest that digitoxin, with its lengthy history of human use, deserves consideration as a candidate drug for suppressing IL-8-dependent lung inflammation in CF.
In the last two decades extensive study has been carried out on the isolation, identification and biosynthesis of the "endogenous digitalis-like compounds" whose physiological and pathophysiological functions are only starting to be understood. Besides ouabain (strophanthin) and digoxin, four further endogenous cardiac glycosides were isolated and identified so far. These compounds are found in almost all mammalian tissues, including blood plasma and urine, but with the highest concentrations in the adrenal gland, pituitary and hypothalamus. De novo biosynthesis of these glycosides occurs in zona fasciculata cells of adrenal glands, precursors such as progesterone, pregnenolone, and rhamnose increase the synthesis of the ouabain-like immunoreactive material. The secretion of these compounds from the adrenocortical cells are controlled by adrenerg mechanisms, as well as via the renin-angiotensin system. The hydrophobic cardiac glycosides are transported in blood as complexes bound to specific binding globulins. The identified endogenous cardiac glycosides fulfill all the postulated criterions of the hormones, so they represent a new class of steroid hormones. The cardiac glycosides influence the active sodium pump, indirectly the intracellular free calcium concentration and therefore exert a positive inotropic effect on cardiac muscle. Furthermore, in physiological concentrations they can regulate the cell growth and protein synthesis inducing activation of intracellular signal pathways. Under pathological conditions, however, when the concentration of these steroids are high, they play a crucial role in the development of different serious illnesses such as essential hypertension as well as congestive heart failure. Further intensive investigations are needed to clarify some contradictory details accumulated during the last few years in this field.
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