Infection leading to very severe or multiple organ dysfunction is called severe sepsis, a leading cause of death in children. Worsening organ dysfunction develops due to an impaired host response that can progress even after clearance of the pathogen. Most therapeutic approaches to improve outcome in septic patients have resulted in disappointment. Progress in this field requires a better understanding of the reasons why the immune response in critically ill children is impaired. Our previous work has revealed that endogenous ATP release and autocrine purinergic signaling mechanisms regulate neutrophil (PMN) functions and that exogenous ATP and adenosine disrupt normal PMN functions. Based on this work, we hypothesize that infections and tissue damage elevate plasma ATP levels, which impairs the ability of PMNs to eliminate bacteria and promotes PMN-mediated tissue damage that causes MODS in pediatric critical care patients.
Aim 1 : Contribution of systemic ATP to MODS in pediatric patients: First, we will assess ATP and adenosine levels in the plasma of pediatric patients with sepsis with varying degrees of MODS. Next, we will study how these levels influence PMN functions that protect patients and functions that worsening MODS.
Aim 2 : Does the purinergic system of pediatric PMNs contribute to MODS? Next, we will study how the PMNs of children differ from adults with regard to the purinergic signaling mechanisms that regulate protective and harmful PMN functions.
Aim 3 : Possible therapeutic targets for sepsis-related MODS: Finally, we will study how purinergic signaling can be targeted to improve the protective functions of PMNs and to minimize collateral damage to host organs. We expect to find that innate differences in plasma ATP levels and purinergic signaling impair PMNs of children, making them susceptible to infections. Common pathogens in children produce cytolysins that further increase systemic ATP levels and PMN dysregulation, preventing antimicrobial host defenses and promoting collateral tissue damage and MODS. Blocking ATP release or removal of systemic ATP are promising therapeutic strategies to restore PMN function and reduce the risks of severe MODS during infection.
This application focuses on plasma ATP and adenosine levels as causes of impaired neutrophil function in pediatric patients with infections, sepsis, and MODS. We plan to study whether and how therapeutic targeting of ATP and adenosine improves outcome in these patients.