Mouse as a Model of Growth Retardation in Cystic Fibrosis

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease that results in lung failure and premature death. A long recognized symptom of CF is growth failure, which is clinically relevant because it correlates with the severity of lung disease. We describe growth retardation in a mouse model of CF and discuss its potential for modeling certain aspects of human growth retardation. Mice with a null mutation in Cftr (cystic fibrosis transmembrance conductance regulator) were compared with wild-type (WT) mice at 31, 45, and 84 d of age. CF mice were severely growth retarded in weight and length compared with wild-type controls. Serum insulin like growth factor I (Igf-1) was lower in CF mice by 31-55% (depending on age and sex) and it significantly correlated with the size of mice after controlling for gender, age, and Cftr genotype. There was a marginally significant deficiency of serum growth hormone (Gh) in CF females, but not males. Our findings were consistent with models of an energy deficit in rodents. We, therefore, assessed food intake and found no difference between CF and WT mice, suggesting that CF mice had a malabsorption-mediated energy deficit. We argue that CF mice are suited to study the effects of intestinal disease on growth as well as other proposed growth-modulating processes. (Pediatr Res 59: [191][192][193][194][195] 2006)

IGF Binding Protein-3 Treatment Alters Intestinal Cell Proliferation But Not Body Weight of Adult Cystic Fibrosis Transmembrane Conductance Regulator Deficient Mice

“…To determine whether rhIGFBP-3 treatment affected systemic levels of Igf-I or Igfbp-3, the serum levels of these proteins were measured. As shown in Figure 5A, Igf-I was lower in serum from CF versus non-CF mice (p ϭ 0.003) as has been reported for CF patients (17) and CF mice (18), whereas Igfbp-3 levels were significantly increased (p ϭ 0.002). Serum levels of Igfbp-3 have not been reported for CF mice, whereas in CF patients, these measures have been shown to be lower (17) or unaltered (19); neither measure was significantly altered by rhIGFBP-3 treatment.…”

Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium

“…The reduced growth in the CF mouse without PI supports observations in CF patients, suggesting additional causes of CF growth reduction. Although reduced dietary intake in the mice has also been suggested (22), we found no evidence of reduced caloric intake by these animals (45). One hypothesized origin for the reduced growth of the CF mouse is the intestine.…”

“…Similar to CF patients, the CF mouse experiences growth retardation, typically displaying a 20 -50% reduction in weight compared with normal littermates (9,20,21,35,39,45,46,48,53,56). Interestingly, the CF mouse displays only mild pancreatic pathology with little to no exocrine pancreatic dysfunction (12,22), suggesting an origin other than PI for the observed growth reduction.…”

Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR −/− mice

“…2A), similar to observations in CFTR −/− mice (24,28), CFTR −/− pigs (29), and humans with CF (30,31). These results suggest that the growth defect may not be due solely to reduced or absent CFTR in intestinal epithelium, a result consistent with findings in CF pigs and humans with CF (29).…”