119 Toll-Like Receptor-4 Agonist Monophosphoryl Lipid A Attenuates Severity of Acute Lung Injury and Hemodynamic Changes in an Ovine Model of Cutaneous Burn and Pneumonia Sepsis

Abstract

Sepsis remains the most detrimental complication of burn patients. About 47% of mortalities following severe burn can be attributed to sepsis. P. aeruginosa is the most common cause of infections in burn patients. Monophosphoryl Lipid A (MPLA), a Toll-like receptor 4 agonist is used as an adjunct vaccine to support host response. The genomic responses to MPLA in sheep are quite similar to those of humans. The aim of this study was that MPLA treatment significantly attenuates severity of multi-organ dysfunctions using well-characterized ovine model of sepsis induced by cutaneous burn and pneumonia. Twelve chronically instrumented female sheep were subjected to 20% total body surface area, 3rd° cutaneous burn under anesthesia and analgesia. 24 hrs after burn, sheep were randomly allocated into 2 groups; 1) MPLA (2.5 µg/kg IV for 50 mins), n=6, 2) Control (saline IV), n=6. After 24 hrs of MPLA/saline treatment, pneumonia was induced by instillation of P. aeruginosa (1.6–2.5 x 1010 CFUs) into the lungs by bronchoscope. Then sheep were placed on ventilator, fluid resuscitated and cardiopulmonary variables were monitored for 24 hrs in a conscious state (total duration: 72 hrs). All sheep survived the 72-hr study period. MPLA significantly improved pulmonary gas exchange (PaO2/FiO2 ratio and oxygenation index) compared to control (63–72 hrs). MPLA significantly attenuated decreases in mean arterial pressure, stroke volume index and systemic vascular resistance index changes (60–72, 54–57, and 69–72 hrs, respectively), and stabilized cardiac index (60–69 hrs) compared to control. MPLA also reduced plasma troponin-I level (72 hr), and reversed increased blood lactate to normal levels (54–66 hrs). Modified sheep SOFA scores were significantly lower in MPLA group compared to control (54 - 72 hrs). During MPLA infusion, transient increases in heart rate, body temperature and pulmonary artery pressure were observed, but these changes were returned to baseline within 2 hrs. Post burn treatment with MPLA not only attenuated severity of acute lung injury, but also stabilized hemodynamic changes and prevented onset of sepsis following pneumonia induction. This novel immuno-modulation approach should be considered as an adjunct therapy for burn patients to prevent further infections. The results are highly translational to the clinical care of burn patients.