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

Rebecca Darrah,Ilya Bederman,Megan Vitko,Craig A. Hodges,Mitchell L. Drumm,Dana M. Valerio,Jeffrey M. Beekman

doi:10.1371/journal.pone.0175467

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.

Highlights

Cystic fibrosis (CF) is a complex, systemic, and lethal disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR)
Using conditional Cftr mouse alleles, we previously reported that inactivation of Cftr in the intestinal epithelium of mice produced an intestinal obstruction phenotype, but did not reduce growth, while activation of Cftr in the intestinal epithelium of mice resulted in no evidence of intestinal obstruction, and no improvement in growth [30]
The CF and gut-corrected CF mice were similar in all measured aspects of growth, the incidence of lethal intestinal obstruction differed significantly with 75% of CF affected but none of the gut-corrected CF mice succumbing to obstruction by 6 weeks of age (Fig 1D; P35 mice per group)

Summary

Introduction

Cystic fibrosis (CF) is a complex, systemic, and lethal disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Reduced growth in CF patients continues throughout life, with approximately 25% of CF children reported below the 10th percentile for weight-for-age and sex, and CF adults typically display reduced body mass index [5]. Improvement in these traits has been observed in recent years due to increased focus on nutrition and improved pancreatic enzyme replacement therapy [6,7,8]. These observations indicate that growth deficits in CF patients have significant clinical importance and highlight the necessity of understanding the origins for CF-associated growth reduction

Methods

Results

Conclusion