Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

Abstract

Growth deficits are common in cystic fibrosis (CF), but their cause is complex, with contributions from exocrine pancreatic insufficiency, pulmonary complications, gastrointestinal obstructions, and endocrine abnormalities. The CF mouse model displays similar growth impairment despite exocrine pancreatic function and in the absence of chronic pulmonary infection. The high incidence of intestinal obstruction in the CF mouse has been suggested to significantly contribute to the observed growth deficits. Previous studies by our group have shown that restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium prevents intestinal obstruction but does not improve growth. In this study, we further investigate growth deficits in CF and gut-corrected CF mice by assessing insulin-like growth factor 1 (IGF-1). IGF-1 levels were significantly decreased in CF and gut-corrected CF adult mice compared to wildtype littermates and were highly correlated with weight. Interestingly, perinatal IGF-1 levels were not significantly different between CF and wildtype littermates, even though growth deficits in CF mice could be detected late in gestation. Since CFTR has been suggested to play a role in water and nutrient exchange in the placenta through its interaction with aquaporins, we analyzed placental aquaporin expression in late-gestation CF and control littermates. While significant differences were observed in Aquaporin 9 expression in CF placentas in late gestation, there was no evidence of placental fluid exchange differences between CF and control littermates. The results from this study indicate that decreased IGF-1 levels are highly correlated with growth in CF mice, independent of CF intestinal obstruction. However, the perinatal growth deficits that are observed in CF mice are not due to decreased IGF-1 levels or differences in placenta-mediated fluid exchange. Further investigation is necessary to understand the etiology of early growth deficits in CF, as growth has been shown to be a significant factor in disease outcomes.

Activated L-Arginine/Nitric Oxide Pathway in Pediatric Cystic Fibrosis and Its Association with Pancreatic Insufficiency, Liver Involvement and Nourishment: An Overview and New Results

“…It has been observed that IGF-1, as well as insulin, stimulates NO production in endothelial cells [96]. In CF mice, IGF-1 reduction was seen in late adolescence and reduced weight and length occurred independent of gastrointestinal CF issues [97]. As chronic inflammation in CF patients could lower IGF-1 concentration, NO production could be influenced as well as the possibility that respiratory impairment might rise as IGF-1 levels decrease [98].…”

Origins of growth deficiencies in cystic fibrosis

“…Of note, there were no differences in IGF-1 levels in late gestation or at birth; levels of CF mice did not diverge from control mice until 3 weeks’ postnatal age 14. Thus, while reductions in IGF-1 in CF are observed among humans, pigs and mice, the timing of these changes is not necessarily consistent between humans and various animal models.…”

“…In CF mice and also in a Cftr invfl10 +villin-Cre mice (a model with correctable intestinal obstruction), adult CF mice had lower IGF-1 compared with wild-type littermates; these lower IGF-1 levels were correlated with decreased weight and length 14. Of note, there were no differences in IGF-1 levels in late gestation or at birth; levels of CF mice did not diverge from control mice until 3 weeks’ postnatal age 14.…”

“…In a study comparing Italian newborns with and without CF, birth weight was not significantly different in infants born prematurely, but among those born at 37 weeks’ gestational age or later, CF infants were approximately 205 g smaller12; this weight divergence beginning later in gestation has also been confirmed in a CF mouse model 14. There are limited data available on intrauterine growth in CF, but effects on birth length have also been noted 6 13.…”

“…However, lower aquaporin expression in CF mice as compared with control mice did not correlate with decreased fluid exchange,14 leaving the contribution of placental CFTR derangements to intrauterine growth unresolved. Intestinal obstruction and meconium ileus may be seen in neonates with CF.…”