G551D cystic fibrosis mice exhibit abnormal regulation of inflammation in lungs and macrophages

The major cause of death in cystic fibrosis (CF) is chronic lung disease as sociated with persistent infection by the bacterium, Pseudomonas aeruginosa , S100A8, an S-100 calcium-binding protein with chemotactic activity, is co nstitutively expressed in the lungs and serum of CF patients. Levels of S10 0A8 mRNA were found to be three to four times higher in the lungs of mice c arrying the G551D mutation in CF transmembrane conductance regulator compar ed with littermate controls, Intravenous injection of bacterial LPS induced S100A8 mRNA in the lung to a greater extent in G551D mice than in wild-typ e littermates, Localization of S100A8 mRNA and protein in the lung indicate that it is a marker for neutrophil accumulation. Bone marrow-derived macro phages from G551D mice were shown to also exhibit hypersensitivity to LPS, measured by induction of TNF-alpha. These results provide evidence that the pathology of CF relates to abnormal regulation of the immune system.