Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Purinergic Signal. 2023 Dec;19(4):651-662. doi: 10.1007/s11302-022-09915-w. Epub 2023 Jan 4.
Neutrophils (PMNs) require extracellular ATP and adenosine (ADO) to fight bacterial infections, which often have life-threatening consequences in pediatric patients. We wondered whether the ATP and ADO levels in the plasma of children change with age and if these changes influence the antimicrobial efficacy of the PMNs of these children. We measured plasma concentrations of ATP and ADO and the activities of the enzymes responsible for the breakdown of these mediators in plasma samples from healthy children and adolescents (n = 45) ranging in age from 0.2 to 15 years. In addition, using blood samples of these individuals, we compared how effective their PMNs were in the phagocytosis of bacteria. In an experimental sepsis model with young (10 days) and adolescent mice (10 weeks), we studied how age influenced the resilience of these animals to bacterial infections and whether addition of ATP could improve the antimicrobial capacity of their PMNs. We found that plasma ATP levels correlated with age and were significantly lower in infants (< 1 year) than in adolescents (12-15 years). In addition, we observed significantly higher plasma ATPase and adenosine deaminase activities in children (< 12 years) when compared to the adolescent population. The activities of these ATP and ADO breakdown processes correlated inversely with age and with the ability of PMNs to phagocytize bacteria. Similar to their human counterparts, young mice also had significantly lower plasma ATP levels when compared to adolescent animals. In addition, we found that mortality of young mice after bacterial infection was significantly higher than that of adolescent mice. Moreover, bacterial phagocytosis by PMNs of young mice was weaker when compared to that of older mice. Finally, we found that ATP supplementation could recover bacterial phagocytosis of young mice to levels similar to those of adolescent mice. Our findings suggest that rapid ATP hydrolysis in the plasma of young children lowers the antimicrobial functions of their PMNs and that this may contribute to the vulnerability of pediatric patients to bacterial infections.
中性粒细胞 (PMN) 需要细胞外 ATP 和腺苷 (ADO) 来对抗细菌感染，而这在儿科患者中常常具有危及生命的后果。我们想知道儿童血浆中的 ATP 和 ADO 水平是否会随年龄而变化，以及这些变化是否会影响这些儿童 PMN 的抗菌功效。我们测量了来自健康儿童和青少年（n = 45）的血浆样本中的 ATP 和 ADO 浓度以及负责这些介质分解的酶的活性，这些个体的年龄从 0.2 岁到 15 岁不等。此外，我们使用这些个体的血液样本，比较了他们的 PMN 在吞噬细菌方面的有效性。在年轻（10 天）和青少年（10 周）小鼠的实验性败血症模型中，我们研究了年龄如何影响这些动物对细菌感染的抵抗力，以及添加 ATP 是否可以提高其 PMN 的抗菌能力。我们发现，血浆 ATP 水平与年龄相关，且婴儿（<1 岁）的血浆 ATP 水平明显低于青少年（12-15 岁）。此外，与青少年人群相比，我们还观察到儿童（<12 岁）的血浆 ATP 酶和腺苷脱氨酶活性明显更高。这些 ATP 和 ADO 分解过程的活性与年龄呈负相关，与 PMN 吞噬细菌的能力呈负相关。与人类一样，与青少年动物相比，年轻小鼠的血浆 ATP 水平也明显降低。此外，我们发现，感染后年轻小鼠的死亡率明显高于青少年小鼠。此外，与老年小鼠相比，年轻小鼠的 PMN 吞噬细菌的能力较弱。最后，我们发现，ATP 补充可以恢复年轻小鼠的细菌吞噬作用，使其达到与青少年小鼠相似的水平。我们的研究结果表明，儿童血浆中 ATP 的快速水解降低了其 PMN 的抗菌功能，这可能导致儿科患者易受细菌感染的影响。
