PAD4 Deficiency Leads to Decreased Organ Dysfunction and ImprovedSurvival in a Dual Insult Model of Hemorrhagic Shock and Sepsis

摘要

Indirect Acute Respiratory Distress Syndrome (iARDS) is caused by a non-pulmonary inflammatory process resulting from insults such as non-pulmonary sepsis. Neutrophils are thought to play a significant role in mediating ARDS, with the development of iARDS being characterized by dysregulation and recruitment of activated neutrophils into the lung. Recently, a novel mechanism of microbial killing by neutrophils was identified through the formation of neutrophil extracellular traps (NETs). NETs are comprised of large webs of decondensed chromatin released from activated neutrophils into the extracellular space; they are regulated by the enzyme PAD4 through mediation of chromatin decondensation via citrullination of target histones. Components of NETs have been implicated in ARDS. However, it is unknown if there is any pathological significance of NET formation in ARDS caused indirectly by non-pulmonary insult.We subjected PAD4^-/- mice and wildtype (WT) mice to a “2 hit” model of hypovolemic shock (fixed-pressure hemorrhage; Hem) followed by septic cecal ligation and puncture (CLP) insult (Hem/CLP). Mice were hemorrhaged and resuscitated; 24 hours post-Hem mice were then subjected to CLP. Overall, PAD4 deletion led to an improved survival ascompared to WT mice. PAD4^-/- mice displayed a markeddecrease in neutrophil influx into the lung, as well decreased presence ofpro-inflammatory mediators. PAD4^-/- mice were alsoable to maintain baseline kidney function after Hem/CLP.These data taken together suggest PAD4-mediated NET formation contributesto the mortality associated with Shock/Sepsis and may play a role in thepathobiology of end organ injury in response to combined hemorrhage plussepsis.