Manipulating the Macrophage Iron-Hepcidin Axis to Prevent Acute Lung Injury/Acute Respiratory Distress Syndrome Secondary to Severe Trauma and Hemorrhagic Shock
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2019
- Accession Number
- AD1095230
Entities
People
- Aranya Bagchi
Organizations
- Massachusetts General Hospital