M. H. Ramadan1, R. Namas1, Y. Vodovotz1, T. R. Billiar1 1University Of Pittsburg,Surgery,Pittsburgh, PA, USA
Introduction:
Excessive and sustained inflammation is associated with persistent critical illness and complications such as organ dysfunction and nosocomial infection in blunt trauma patients. The roles of many proximal mediators of trauma induced inflammation, such as IL-6 and MCP-1 are well studied. However, the involvement of key downstream mediators including IL-17/F remains unknown. IL-17A/F, which can be produced by Th17 cells or certain populations of innate lymphoid cells, can promote sustained inflammation and organ injury in both acute and chronic conditions. Here, we hypothesized that IL-17A/F levels would correlate with a complicated course in human trauma patients and organ injury in mice subjected to hemorrhagic shock and trauma (HS/T).
Methods:
Animal experiments: Anesthetized C57BL/6 mice were subjected to bilateral lower extremity injury and pressure-targeted sever hemorrhagic shock (HS) with mean BP 25-30mmHg, monitored for 2 hours via bilateral femoral cannulation. Animals were then resuscitated with X3 volume of shed blood with lactated Ringer’s solution. One group of mice received IL-17-blocking antibody 12 hours prior to HS and re-dosed at the time of resuscitation. Equal volume of PBS was administered to the mice in the control group. Plasma IL-6, MCP-1 levels and ALT were measured at 6 hours (n=6/group).
Human Samples: Plasma IL-17A/F levels were measured in the serum of 88 consented, severely injured (average ISS=26, 44 patients with a complicated course and 44 with an uncomplicated course) blunt trauma patients upon admission and over time. The two cohorts were matched for ISS, age and sex.
Results:
The human data showed elevated IL-17A/F Levels in the complicated patient group; those levels were elevated within the first 24 hours of injury. These levels remained elevated and significantly higher than the uncomplicated patient group even prior to the development of infectious complications.
In the mice we were able to demonstrate significantly elevated plasma IL-17A/F levels that peaked at 6 hours after trauma correlating with peak organ damage. There were no baseline differences between the antibody treated mice and the controls. Both the treatment and control groups had similar plasma IL-6 and MCP-1 levels indicating and equivalent proximal inflammatory responses. The Blocking of IL-17 lead to a significant reduction in liver damage, measured by 62% lower ALT p= 0.007 in the antibody treatment group; supporting our hypothesis.
Conclusion:
Our clinical data show that IL-17A/F levels correlate with persistent critical illness in human trauma patients while our mechanistic studies in a mouse polytrauma model confirms that IL-17A participates in organ damage as a mediator downstream of IL-6. These data also suggest that IL-17 producing lymphocyte populations become activated early in clinical and experimental trauma.