Attenuation of hemorrhage-associated lung injury by adjuvant treatment with C23, an oligopeptide derived from cold-inducible RNA-binding protein.

Abstract

Hemorrhagic shock (HS) is an important cause of mortality. HS is associated with an elevated incidence of acute lung injury and acute respiratory distress syndrome, significantly contributing to HS morbidity and mortality. Cold-inducible RNA-binding protein (CIRP) is released into the circulation during HS and can cause lung injury. C23 is a CIRP-derived oligopeptide that binds with high affinity to the CIRP receptor and inhibits CIRP-induced phagocyte secretion of TNF-α. This study was designed to determine whether C23 is able to attenuate HS-associated lung injury. C57BL/6 mice were subjected to controlled hemorrhage leading to a mean arterial pressure of 25 ± 3 mm Hg for 90 minutes. Mice were then volume-resuscitated for 30 minutes with normal saline solution alone (vehicle) or plus adjuvant treatment with C23 (8 mg/kg BW). At 4.5 hours after resuscitation, the blood and lungs were harvested. Serum levels of organ injury markers lactate dehydrogenase, aspartate aminotransferase were significantly elevated in hemorrhaged mice receiving vehicle and were reduced by 51.3% and 52.2% in mice adjuvantly treated with C23, respectively. Similarly, lung mRNA levels of IL-1β, TNF-α, and IL-6, and lung myeloperoxidase activity were elevated after HS and reduced by 66.1%, 54.4%, 69.7%, and 24.3%, respectively, in mice treated with C23. Adjuvant treatment with C23 also decreased the lung histology score by 33.9%, lung extravasation of albumin carrying Evans blue dye by 36.8%, and the protein level of intercellular adhesion molecule-1, and indicator of vascular endothelial cell activation, by 40.3%. Together, these results indicate that adjuvant treatment with the CIRP-derived oligopeptide C23 is able to improve lung inflammation and vascular endothelial activation secondary to HS, lending support to the development of CIRP-targeting adjuvant treatments to minimize lung injury after HS.