Engineered Albumin Nanoparticles Targeting Inflammatory Neutrophils in Human Lungs Mitigate Endotoxemia-Induced Lung Injury

Dysregulated neutrophil infiltration and activity in lung tissues are pathogenic features of sepsis-induced acute respiratory distress syndrome (ARDS), an important cause of morbidity and mortality in critically ill patients. Therapeutic reduction of excessive neutrophil transmigration from the vasculature into the distal airspaces to mitigate lung tissue damage and improve survival is an important objective. Human peripheral blood polymorphonuclear neutrophils (PMNs) can be separated into two subsets as recently described: one that readily endocytoses albumin nanoparticles (ANPs) referred to as ANP high PMN and another that fails to endocytose ANPs referred to as ANP low PMN. Here, we tested the hypothesis that targeting ANP high human PMNs with ANPs loaded with the drug piceatannol (PANPs), a selective spleen tyrosine kinase (Syk) inhibitor that inhibits β2-integrin signaling, would mitigate lipopolysaccharide (LPS)-induced accumulation of PMNs in human lungs and reduce lung edema. In the present study, human lungs were perfused ex vivo with fresh whole blood containing human PMNs and 6 mg of LPS to induce injury accompanied by PMN infiltration into the lungs. Following the LPS exposure, intravenous injection of PANPs reduced transmigration and accumulation of PMNs in the lungs as determined by bronchoalveolar lavage counts and histologic scoring. A parallel reduction in lung weight gain, a surrogate for pulmonary edema fluid accumulation, suggested protection from edema in this human lung injury model. The results demonstrate the potential of therapeutic drug loading of albumin nanoparticles (PANPs) for targeting an injurious, inflammation-inducing population of PMNs in ARDS patients.