Manipulating the Macrophage Iron-Hepcidin Axis to Prevent Acute Lung Injury/Acute Respiratory Distress Syndrome Secondary to Severe Trauma and Hemorrhagic Shock
Technical Report,15 May 2017,14 May 2019
Massachusetts General Hospital Boston United States
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Our hypothesis at the time of initiation of this project was that severe traumatic injury serves as a priming insult, causing sequestration of iron into macrophages by upregulating hepcidin, the principal iron-regulating hormone. We therefore expected to see an exaggerated inflammatory response to our second hit stimulus after trauma, intratracheallipopolysachharide LPS. To our surprise, the acute inflammatory response after intratracheal LPS was highly diminished compared to the response to intratracheal LPS alone. To determine the reason for the observed immune suppression we performed a hypothesis-neutral screen of the pulmonary transcriptome in our experimental groups using RNA sequencing. Analysis of the transcriptome led to the identification of Peroxisome-Proliferator Activated Receptor PPAR-gamma, a ligand induced transcription factor, that has well documented immunosuppressive effects. Our results suggest that severe trauma can invoke an early, specific induction of PPAR-gamma that dramatically suppresses the inflammatory response to a subsequent stimulus. Further study is required to determine whether pharmacologic modulation of PPAR-gamma signaling will be beneficial after acute trauma.
- Stress Physiology