Intra- and extrapulmonary lipopolysaccharides-induced acute lung injury and pharmacotherapeutic response patterns in ventilated 7-day-old rabbits.

Abstract

We explored pharmacotherapeutic response patterns of lipopolysaccharides (LPS)-induced pneumonia and sepsis as direct and indirect acute lung injury (ALI), and efficacy of a combined surfactant (S) and inhaled nitric oxide (iNO), simulating critical care, in rabbits of post-neonatal infancy. Anaesthetized 7-day-old healthy rabbits were injected intratracheally (IT) or intravenously (IV) with LPS (15-20-25 mg/kg, L) or saline as a control (C), and subjected to initial 2-hour mechanical ventilation (MV) with standardized tidal volume to induce ALI. They were then treated with S (200 mg/kg) and iNO (10 ppm, N), or not, thereby allocating to 6 groups (ITC, ITL, ITLSN, IVC, IVL, IVLSN) for another 8 h. Survival time/rate (ST), and variables as biomarkers in lung physiology, histopathology, biochemistry, and pathophysiology were measured. The survival was LPS-route, but not dosing, dependent. Compared to the IVL, ITL had relatively higher ST, lung injury score (LIS), lower intrapulmonary phospholipid pools, mRNA expressions in surfactant proteins (SPs) and pulmonary vascular endothelial cell injury (VEI)-related variables. ITLSN had higher phospholipid pools but no improvement in ST, lung mechanics, LIS or mRNA expression of SPs, proinflammatory mediators and VEI-related variables. IVLSN had improved lung mechanics, LIS, phospholipid pools, and SP-A mRNA expression, but worse ST, metabolic acidosis, higher interleukin mRNA expression in the lungs, liver and kidney, suspected as sepsis-associated multiorgan involvement. Using the infant rabbit LPS-ALI model, we characterized the survival as LPS-route dependent, the lung impairment and response pattern in surfactant and iNO treatment ineffectiveness/failure, as pharmacotherapeutic response patterns, with causal implication pertinent to the underlying pathophysiology of experimental pediatric ARDS.