Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2.

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

Continuous intravenous infusion of ATP in humans yields large expansions of erythrocyte ATP pools but extracellular ATP pools are elevated only at the start followed by rapid declines.

The pharmacokinetics of adenosine 5'-triphosphate (ATP) was investigated in a clinical trial that included 15 patients with advanced malignancies (solid tumors). ATP was administered by continuous intravenous infusions of 8 h once weekly for 8 weeks. Three values of blood ATP levels were determined. These were total blood (erythrocyte) and blood plasma (extracellular) ATP pools along with the initial rate of release of ATP into the blood plasma. We found that values related to erythrocyte ATP pools showed great variability (diversity) among individuals (standard deviation of about 30-40% of mean at baseline). It was discovered that erythrocyte baseline ATP pool sizes are unique to each individual and that they fall within a narrow range in each individual. At the end of an 8 h continuous intravenous infusion of ATP, intracellular erythrocyte ATP pools were increased in the range of 40-60% and extracellular ATP declined from elevated levels achieved at the beginning and middle of the infusion, to baseline levels. The ability of erythrocytes to sequester exogenously administered ATP to this degree, after its initial conversion to adenosine in the blood plasma is unexpected, considering that some of the adenosine is likely to have been degraded by in vivo catabolic activities or taken up by organs. The data suggest that administration of ATP by short-term intravenous infusions, of up to 4 h, may be a favorable way for elevating extracellular ATP pools. A large fraction of the total exogenously administered ATP is sequestered into the intracellular compartments of the erythrocytes after an 8 h intravenous infusion. Erythrocytes loaded with ATP are known to release their ATP pools by the application of previously established agents or conditions applied locally or globally to circulating erythrocytes. Rapid degradation of intravenously administered ATP to adenosine and subsequent accumulation of ATP inside erythrocytes indicate the existence of very effective mechanisms for uptake of adenosine from blood plasma. These in vivo studies offer an understanding as to how both adenosine and ATP can act as purinergic transmission signals. ATP levels in blood are always accompanied by adenosine formed by catabolism of ATP. The continuous uptake of adenosine enables both to act in transmission of sometimes opposite functions.

Involvement of Elevated Intracellular and Extracellular ATP in the Regulation of Insulin Secretion: Therapeutic Targets in Non-Insulin-Dependent Diabetes Mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disease resulting primarily from a variety of pancreatic beta-cell disorders and insulin resistance. Whereas insulin resistance, which constitutes a defect in insulin action, increases the risk of developing NIDDM and, as such, is a predictor of the onset of this disease, it is mostly the beta-cell dysfunction in regulating insulin secretion which yields the chronic hyperglycemia with all its associated clinical complications. The individual steps in the secretory pathway of insulin which is induced primarily by blood plasma glucose have now been identified. The transport of the sugar into the beta-cell is followed by its phosphorylation as the rate-determining step. The glycolytic metabolism of glucose-6-phosphate leads to the generation of ATP resulting in increases in beta-cell ATP pools (steady-state-levels) as well as ATP/ADP ratios, which, in turn, produce the closure of ATP-sensitive K(+) channels, thus depolarizing the beta-cell membrane and opening of Ca(2+) channels. The resulting influx of extracellular Ca(2+) and the increase in recruitment of Ca(2+) from intracellular stores in response to extracellular signals yield an increase in total [Ca(2+)](i) which activates the granular insulin secretory machinery. The intracellular beta-cell ATP pools have a key role in transducing the signals of the stimulus-secretion coupling pathway and toxins such as alloxan and streptozotocin which produce experimental diabetes in animals act by damaging mitochondrial oxidative phosphorylation, leading to permanent decreases in cellular ATP pools which, due to the sensitivity of beta-cell function to these pools, manifest itself as a form of diabetes. In addition to the major effects of blood plasma glucose in the regulation of insulin secretion, a variety of hormonal and neural factors producing endocrine and paracrine effects modulate and fine-tune beta-cell insulin secretion. The enteroinsular axis provides a linkage between the gastrointestinal tract and pancreatic beta-cells stimulus-secretion pathway. Although a powerful effect of ATP on insulin secretion was demonstrated more than 30 years ago, only recently has it been shown that beta-cells possess P(2)-purinoceptors. Extracellular ATP and its synthetic agonists are insulin secretagogues by virtue of their activation of membrane purinergic receptors which is coupled to increases in extracellular Ca(2+) influx and mobilization of Ca(2+) from internal stores resulting in insulin release from beta-cell granules. The physiological significance of extracellular ATP regulation of insulin secretion as well as the physiological source of these ATP pools have not yet been established. It has been recently demonstrated that the administration of adenine nucleotides in vivo can yield significant increases in tissue, blood (red blood cell), and blood plasma ATP pools. Increasing pancreatic beta-cell intracellular and blood plasma (extracellular) pools of ATP is a new therapeutic modality in non-insulin-dependent diabetes mellitus.