Amelioration of cystic fibrosis intestinal mucous disease in mice by restoration of mCLCA3.

BACKGROUND & AIMS: Mice deficient of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) exhibit severe intestinal lesions, particularly mucous overproduction/secretion and accumulation, which is similar to meconium ileus in CF patients. Moreover, severity of the intestinal disease in CF mice is strongly influenced by genetic modifiers, and CFTR deficiency affects the expression of multiple secondary genes that may impact on the phenotype. The murine orthologue of human hCLCA1 (mCLCA3) is expressed by goblet cells and implicated in their normal function, particularly with mucus production/secretion that is exaggerated in CF; however, its influence on the CF intestinal disease, although suggested, remains unclear.

METHODS: To investigate the role of mCLCA3 on the CF intestinal disease in mice, its expression in this tissue has been assessed, and a CF mouse line maintaining elevated mCLCA3 levels has been developed and comprehensively characterized.

RESULTS: Expression of mCLCA3 is significantly reduced in CF mouse intestines, although the number of goblet cells is elevated, indicating marked reduction per cell. Importantly, correction of this deficiency results in amelioration of the mucous-based disease leading to a marked improvement of intestinal pathology and survival, although goblet cell hyperplasia and hypertrophy were augmented. This intestinal amelioration did not appear to be related to rectification of the CF electrophysiologic defect.

CONCLUSIONS: mCLCA3 has a role in intestinal goblet cell function that includes modification of the mucous properties and/or secretion that are altered in CF. Thus, elevation of mCLCA3 (hCLCA1) levels could provide a means to reduce intestinal mucous-based lesions in CF and related diseases.