Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis

Sepsisremains an unresolved clinical problem. Therapeutic strategies focusing on inhibition of neutrophils(polymorphonuclear neutrophils) have failed, which indicates that a more detailed understanding of the underlying pathophysiology of sepsisis required. Polymorphonuclear neutrophilactivation and chemotaxisrequire cellular adenosine triphosphaterelease via pannexin-1 channels that fuel autocrine feedback via purinergic receptors. In the current study, we examined the roles of endogenous and systemic adenosine triphosphateon polymorphonuclear neutrophilactivation and host defense in sepsis. Prospective randomized animal investigation and in vitro studies. Preclinical academic research laboratory. Wild-type C57BL/6 mice, pannexin-1 knockout mice, and healthy human subjects used to obtain polymorphonuclear neutrophilsfor in vitro studies. Wild-type and pannexin-1 knockout mice were treated with suraminor apyraseto block the endogenous or systemic effects of adenosine triphosphate. Mice were subjected to cecal ligation and puncture and polymorphonuclear neutrophilactivation (CD11b integrin expression), organ (liver) injury (plasma aspartate aminotransferase), bacterial spread, and survival were monitored. Human polymorphonuclear neutrophilswere used to study the effect of systemic adenosine triphosphateand apyraseon chemotaxis. Inhibiting endogenous adenosine triphosphatereduced polymorphonuclear neutrophilactivation and organ injury, but increased the spread of bacteria and mortality in sepsis. By contrast, removal of systemic adenosine triphosphateimproved bacterial clearance and survival in sepsisby improving polymorphonuclear neutrophil chemotaxis. Systemic adenosine triphosphateimpairs polymorphonuclear neutrophilfunctions by disrupting the endogenous purinergic signalingmechanisms that regulate cell activation and chemotaxis. Removal of systemic adenosine triphosphateimproves polymorphonuclear neutrophilfunction and host defenses, making this a promising new treatment strategy for sepsis.