Fibrinogen based resuscitation mitigates lung injury in mice with bacterial pneumonia after hemorrhagic shock

Abstract

While pneumonia is a common complication following severe trauma, the optimal treatment for this complication remains unclear. Our previous studies have shown that fibrinogen and fresh frozen plasma (FFP) administration have beneficial effects in mitigating lung dysfunction in mice after trauma and hemorrhagic shock (HS), due to the restoration of endothelial syndecan-1. The objective of the current study was to test these two therapeutics in a combined model of HS and pneumonia. We hypothesized they would be equally protective. C57BL/6 mice underwent HS [mean arterial pressure (MAP) of 40–45 mmHg for 1 h] and fluid resuscitation with lactated Ringer's (LR), fibrinogen concentrate (FIB, 5 mg/mouse in LR), and FFP all at 1x bled volume. Mice were then infected by P. aeruginosa [strain PA103, 3 × 10⁴ colony-forming units (CFUs)] via intratracheal instillation. After 24 h, mice were euthanized, and lung tissue, bronchoalveolar lavage (BAL) fluid, and plasma were harvested for assays. HS + P. aeruginosa infection induced increases in permeability, syndecan-1 cleavage, and MMP9 activation in the lungs, and an increase in plasma shed syndecan-1. These alterations were significantly attenuated by fibrinogen but not by FFP, implying that fibrinogen prevented the endothelial injury. Additionally, lung tissue MPO and neutrophil infiltration were significantly decreased after HS + P. aeruginosa. These alterations were reversed by fibrinogen but not by FFP, indicating fibrinogen is able to correct the neutrophil deficiency state caused by HS + P. aeruginosa infection. Taken together, these results suggest that fibrinogen has therapeutic benefit in a model of HS and pneumonia.