Genetic deletion of SLPI results in increased protease activity and mucus clearance in a murine model of chronic lung disease

Abstract

An important regulator of innate and adaptive airway immunity, the primary function of Secretory Leukocyte Protease Inhibitor (SLPI) is considered to be the inhibition of damaging neutrophil elastase activity. In addition to anti-proteolytic activity, SLPI expresses both anti-microbial and anti-inflammatory properties, through action on NF-kB. Although elevated in chronic lung diseases such as Chronic Obstructive Pulmonary Disease, lower concentrations of SLPI are associated with frequent exacerbations of muco-obstructive disorders. In this study we evaluated a role for SLPI in the development of airway pathogenesis and mucus obstruction in chronic lung disease. A murine model of chronic lung disease, the β-epithelial sodium channel-overexpressing transgenic (ENaC) mouse was crossed with SLPI null (SLPI^−/−) strains to generate four genotypes: Wild Type (WT), SLPI^−/−, ENaC and ENaC/SLPI^−/−. At juvenile (2-3 weeks) and adult (8-14 weeks) ages mice were assessed for mucus plugging, inflammatory cell counts and protease activity. Genetic deletion of SLPI resulted in increased lung inflammatory cell counts in adult WT and ENaC mice, while no effect was identified in juvenile ENaC/SLPI^−/− mice. In addition, decreased airway mucus volume and plugging was observed in adult ENaC/SLPI^−/− mice, but not juvenile mice. However, genetic deletion of SLPI was shown to increase protease activity in juvenile ENaC/SLPI^−/− mice alone. These data suggest genetic deletion of SLPI decreases mucus plugging in adult ENaC mice, while increasing immune cell infiltration. However, ablation of SLPI in juvenile strains of ENaC mice results in increased lung protease activity.