An extracellular cold-inducible RNA-binding protein-derived small peptide targeting triggering receptor expressed on myeloid cells-1 attenuates hemorrhagic shock.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern, which is released into the circulation after hemorrhagic shock (HS). Recently, we discovered that triggering receptor expressed on myeloid cells-1 (TREM-1) serves as a new receptor of eCIRP to exaggerate inflammation. Here, we hypothesize that by inhibiting the interaction between eCIRP and TREM-1 with the use of a novel short peptide derived from human eCIRP known as M3, we can inhibit the inflammatory response and acute lung injury in HS.

Methods: Hemorrhagic shock was induced using C57BL/6 mice by cannulating both femoral arteries. One femoral artery was used for removal of blood while the other was used for continuous monitoring of mean arterial blood pressure. The mean arterial pressure of 25 mm Hg to 30 mm Hg was maintained for 90 minutes, followed by a resuscitation phase of 30 minutes with 1 mL of normal saline. The treatment group was given 10 mg/kg of M3 during the resuscitation phase. Four hours after resuscitation, serum and lungs were collected and analyzed for various injury and inflammatory markers by using colorimetry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay.

Results: There was an increase in the serum levels of tissue injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as cytokines (TNF-α and IL-6) when comparing the vehicle group versus the sham group. This increase was significantly inhibited in the M3-treated group. The mRNA expression of proinflammatory cytokines TNF-α, IL-6, and IL-1β and the chemokines MIP-2 and KC in lungs was significantly increased in the vehicle-treated HS mice, while their expression was significantly decreased in M3-treated HS mice. Finally, M3 treatment significantly decreased the lung injury score compared with vehicle-treated HS mice.

Conclusion: The novel eCIRP-derived TREM-1 antagonist (M3) can be a potential therapeutic adjunct in the management of hemorrhagic shock.