ATPergic signaling disruption in human sepsis as a potential source of biomarkers for clinical use

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated inflammatory response to infection. To date, there is no specific treatment established for sepsis. In the extracellular compartment, purines such as adenosine triphosphate (ATP) and adenosine play essential roles in the immune/inflammatory responses during sepsis and septic shock. The balance of extracellular levels among ATP and adenosine are intimately involved in the signals related to immune stimulation/immunosuppression balance. Specialized enzymes, including CD39, CD73, and adenosine deaminase (ADA), are responsible to metabolize ATP to adenosine which will further sensitize the P2 and P1 purinoceptors, respectively. Disruption of the purinergic pathway had been described in the sepsis pathophysiology. Although purinergic signaling has been suggested as a potential target for sepsis treatment, the majority of data available was obtained using pre-clinical approaches. We hypothesized that, as a reflection of deregulation on purinergic signaling, septic patients exhibit differential measurements of serum, neutrophils and monocytes purinergic pathway markers when compared to two types of controls (ward and healthy). It was observed that ATP and ADP serum levels were increased in septic patients, as well as the A2a mRNA expression in neutrophils and monocytes. Both ATPase/ADPase activities were increased during sepsis. Serum ATP and ADP levels, and both ATPase and ADPase activities were associated with the diagnosis of sepsis, representing potential biomarkers candidates. In conclusion, our results advance the translation of purinergic signaling from pre-clinical models into the clinical setting opening opportunities for so much needed new strategies for sepsis and septic shock diagnostics and treatment.

Evaluation of Components of the Extracellular Purinergic Signaling System in Human Sepsis

“…In contrast to disparate results with regard to ATP levels between our two studies (current and reference [36]), both of our studies find comparable adenosine levels in septic and control patients. This, however, is inconsistent with results from other studies, in which adenosine levels were higher in septic patients than in controls (37,38).…”

“…We initially determined the levels of some of the major extracellular purines and found that ATP levels were decreased in septic patients when compared with healthy individuals, whereas no differences were noted for UTP, UDP, and adenosine. This finding of decreased ATP levels was surprising, because in a previous study conducted in a different medical center, we observed increased circulating ATP concentrations in septic patients (36). The current results also differed from our previous ones in that ATP levels in the current study were in the mid-nanomolar range, whereas in the previous one, they averaged 5 to 10 μM.…”

“…However, P2X4 and P2X7 receptor expression was unchanged in both neutrophils and PBMCs. These results are in agreement with the previous study we conducted, where P2X7 receptors on neutrophils were comparable between septic patients and controls (36). However, in a study by another group, septic monocytes had increased P2X7 receptor expression (14).…”

“…Our observation of increased NTPDase1 in PBMCs of septic patients can potentially explain the decreased ATP levels, because NTPDase1 or CD39 is the major ATP-degrading enzyme in immune cells. This observation of increased NTPDase1 is also confirmatory of our earlier data demonstrating increased serum ATPase and ADPase activities in septic compared with healthy patients (36), where the source of circulating ATPase and ADPase activities is likely NTPDase1 (39). In a recent study, NTPDase1 expression and ecto-ATPase activity were shown to be upregulated on B lymphocytes from septic patients, which was associated with increased adenosine levels in septic shock but not sepsis patients (7).…”

Platelet P2Y12 signalling pathway in the dysregulated immune response during sepsis

“…Another significant source of ADP is the secretion from platelet dense granules upon activation; it promotes platelet aggregation via a positive feedback mechanism by binding to ADP receptors on the same and other circulating platelets (Remijn et al, 2002). In a recent study, Leite et al (2022) found that on the first morning following intensive care unit admission, at the early onset of sepsis, serum ADP levels and ADPase activity were higher (about 18 and 1.6 times, respectively) when compared with control patients. They proposed that serum levels of ADP and ADPase activity may be associated with the diagnosis of sepsis and may represent potential biomarker candidates.…”