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

Abstract

Indirect acute respiratory distress syndrome (iARDS) is caused by a nonpulmonary inflammatory process resulting from insults such as nonpulmonary 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 composed of large webs of decondensed chromatin released from activated neutrophils into the extracellular space; they are regulated by the enzyme peptidylarginine deiminase 4 (PAD4) through mediation of chromatin decondensation via citrullination of target histones. Components of NETs have been implicated in ARDS. However, it is unknown whether there is any pathological significance of NET formation in ARDS caused indirectly by nonpulmonary insult. We subjected PAD4-/- mice and wild-type mice to a "two-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 h after Hem, mice were then subjected to CLP. Overall, PAD4 deletion led to an improved survival as compared with wild-type mice. PAD4-/- mice displayed a marked decrease in neutrophil influx into the lung, as well decreased presence of proinflammatory mediators. PAD4-/- mice were also able to maintain baseline kidney function after Hem/CLP. These data taken together suggest PAD4-mediated NET formation contributes to the mortality associated with shock/sepsis and may play a role in the pathobiology of end organ injury in response to combined hemorrhage plus sepsis.

• Authors: Bethany M Biron, Chun-Shiang Chung, Yaping Chen, Zachary Wilson, Eleanor A Fallon, Jonathan S Reichner, Alfred Ayala
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 200 Issue 5 Pg. 1817-1828 (03 01 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29374076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Chromatin
• Histones
• Hydrolases
• Protein-Arginine Deiminase Type 4
• peptidylarginine deiminase 4, mouse

Topics

• Animals
• Chromatin (metabolism)
• Disease Models, Animal
• Extracellular Traps (metabolism)
• Histones (metabolism)
• Hydrolases (metabolism)
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Multiple Organ Failure (metabolism, pathology)
• Neutrophil Activation (physiology)
• Neutrophils (metabolism)
• Protein-Arginine Deiminase Type 4
• Respiratory Distress Syndrome (metabolism, pathology)
• Sepsis (metabolism, pathology)
• Shock, Hemorrhagic (metabolism, pathology)