Genetic deletion of SLPI promotes inflammatory cell recruitment in a model of chronic lung disease

Abstract

Secretory leukocyte proteinase inhibitor (SLPI) is a major airways antiprotease. Its primary function is considered to be the inhibition of damaging neutrophil elastase activity, however, it also exerts antimicrobial and immunomodulatory activity. The presence of a protease/antiprotease imbalance and associated dysregulation of the levels and/or activity of host defence proteins like SLPI are features of chronic lung diseases such as cystic fibrosis and chronic obstructive pulmonary disease. The aim of this study was to elucidate the effects of sustained SLPI inactivation on the development and progression of chronic muco-inflammatory lung disease. β-epithelial Na+ channel-overexpressing transgenic (ENaC) mice, a model of chronic lung disease, were crossed with SLPI null (SLPI^-/-) mice to generate four genotypes; WT, SLPI^-/-, ENaC and ENaC/SLPI^-/-. Juvenile (2-3 wk old) and adult (8-14 wk old) mice were assessed for inflammatory markers, lung damage and mucus plugging. Levels of SLPI were elevated in the ENaC mice. Genetic deletion of SLPI resulted in increased protease activity and immune cell infiltration in both WT and ENaC mice. However, there was no significant effect on lung damage, airway mucus plugging or lung function in these mice. These data suggest that, while SLPI may ameliorate the recruitment of inflammatory cells in chronic lung disease, it does not limit the development of lung damage or airway mucus plugging in this model during the timeframe analysed. Further work to examine the mechanisms by which SLPI specifically regulates inflammatory cell recruitment in this model of muco-inflammatory lung disease is ongoing.