Rationale:The susceptibility of neonates to pulmonary and systemic infection has been associated with the immaturity of both lung structure and the immune system. Surfactant Protein D is a member of the collectin family of innate immune molecules that plays an important role in innate host defense of the lung. Objectives: We tested whether treatment with recombinant human Surfactant Protein D influenced the response of the lung and systemic circulation to intratracheally administered E.coli Iipopolysaccharides. Methods:After intratracheal lipopolysaccharide instillation, preterm newborn lambs were treated with surfactant and ventilated for 5 hours. Measurement:Survival rate, physiological lung function, lung and systemic inflammation and endotoxin level in plasma were evaluated. Main Results:In control lambs, intratracheal Iipopolysaccharides caused septic shock and death associated with increased endotoxin in plasma. In contrast, all lambs treated with recombinant human Surfactant Protein D were physiologically stable and survived. Leakage of Iipopolysaccharides from the lungs to the systemic circulation was prevented by intratracheal recombinant human Surfactant Protein D. Recombinant human Surfactant Protein D prevented systemic inflammation and decreased the expression of IL-1, IL-8 and IL-6 in the spleen and liver. Likewise, recombinant human Surfactant Protein D decreased IL-1 and IL-6 in the lung and IL-8 in the plasma. Recombinant human Surfactant Protein D did not alter pulmonary mechanics following endotoxin exposure. Recombinant human Surfactant Protein D was readily detected in the lung 5 hours after intratracheal instillation. Conclusions: Intratracheal recombinant human Surfactant Protein D prevented shock caused by endotoxin released from the lung during ventilation in the premature newborn.