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

View Article: PubMed Central - PubMed

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.

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Intestinal correction of CFTR does not improve growth.(A) Weight of CF mice, gut-corrected CF mice and control littermates was assessed up to 40 days of age (n≥10 of each sex). Weight was significantly decreased in CF and gut-corrected CF mice compared to control animals at every age measured (P<0.001) with equal numbers of each sex used. (B) Length and (C) inguinal fat weight of CF mice, gut-corrected CF mice and control littermates was assessed between 6–7 weeks of age (n≥10 of each sex). Both length and inguinal fat weight was significantly decreased in CF and gut-corrected CF mice compared to control animals independent of sex (* = P<0.05; data represent mean±SE). (D) Survival of CF and gut-corrected CF between 10–42 days of age. All deaths were the result of intestinal obstruction as verified by postmortem examination.
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pone.0175467.g001: Intestinal correction of CFTR does not improve growth.(A) Weight of CF mice, gut-corrected CF mice and control littermates was assessed up to 40 days of age (n≥10 of each sex). Weight was significantly decreased in CF and gut-corrected CF mice compared to control animals at every age measured (P<0.001) with equal numbers of each sex used. (B) Length and (C) inguinal fat weight of CF mice, gut-corrected CF mice and control littermates was assessed between 6–7 weeks of age (n≥10 of each sex). Both length and inguinal fat weight was significantly decreased in CF and gut-corrected CF mice compared to control animals independent of sex (* = P<0.05; data represent mean±SE). (D) Survival of CF and gut-corrected CF between 10–42 days of age. All deaths were the result of intestinal obstruction as verified by postmortem examination.

Mentions: To reduce the possibility of genetic heterogeneity as a confounding variable, we backcrossed the conditional Cftr allele and the Cre recombinase transgene necessary to produce the gut-corrected CF mouse to the C57BL/6 background for 10 generations. On the C57BL/6 inbred background, the CF mice and gut-corrected CF mice continued to show very similar growth deficiencies compared to normal littermates (Fig 1). Specifically, the weight of both CF and gut-corrected CF mice was significantly reduced compared to wildtype littermates’ weight measured between 10 and 40 days of age, with both groups in the range of 60–80% of normal mouse weight (Fig 1A). Length was significantly reduced in CF and gut-corrected CF mice independent of sex, with both groups’ length reduced by 5–10% of wildtype littermates’ length. Reduction in fat accumulation is common in CF patients and CF mice and is observed in the gut-corrected CF model as well. Both CF and gut-corrected CF mice display a 50% reduction in inguinal fat (Fig 1C). Although 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; P<0.0001 up to 6 weeks of age; n>35 mice per group). In addition, no signs of intestinal obstruction were observed in any gut-corrected CF mice following sacrifice and postmortem examination. These data clearly show that restoration of CFTR in the intestinal epithelium and prevention of intestinal obstruction in CF mice does not improve growth.


Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction
Intestinal correction of CFTR does not improve growth.(A) Weight of CF mice, gut-corrected CF mice and control littermates was assessed up to 40 days of age (n≥10 of each sex). Weight was significantly decreased in CF and gut-corrected CF mice compared to control animals at every age measured (P<0.001) with equal numbers of each sex used. (B) Length and (C) inguinal fat weight of CF mice, gut-corrected CF mice and control littermates was assessed between 6–7 weeks of age (n≥10 of each sex). Both length and inguinal fat weight was significantly decreased in CF and gut-corrected CF mice compared to control animals independent of sex (* = P<0.05; data represent mean±SE). (D) Survival of CF and gut-corrected CF between 10–42 days of age. All deaths were the result of intestinal obstruction as verified by postmortem examination.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5383306&req=5

pone.0175467.g001: Intestinal correction of CFTR does not improve growth.(A) Weight of CF mice, gut-corrected CF mice and control littermates was assessed up to 40 days of age (n≥10 of each sex). Weight was significantly decreased in CF and gut-corrected CF mice compared to control animals at every age measured (P<0.001) with equal numbers of each sex used. (B) Length and (C) inguinal fat weight of CF mice, gut-corrected CF mice and control littermates was assessed between 6–7 weeks of age (n≥10 of each sex). Both length and inguinal fat weight was significantly decreased in CF and gut-corrected CF mice compared to control animals independent of sex (* = P<0.05; data represent mean±SE). (D) Survival of CF and gut-corrected CF between 10–42 days of age. All deaths were the result of intestinal obstruction as verified by postmortem examination.
Mentions: To reduce the possibility of genetic heterogeneity as a confounding variable, we backcrossed the conditional Cftr allele and the Cre recombinase transgene necessary to produce the gut-corrected CF mouse to the C57BL/6 background for 10 generations. On the C57BL/6 inbred background, the CF mice and gut-corrected CF mice continued to show very similar growth deficiencies compared to normal littermates (Fig 1). Specifically, the weight of both CF and gut-corrected CF mice was significantly reduced compared to wildtype littermates’ weight measured between 10 and 40 days of age, with both groups in the range of 60–80% of normal mouse weight (Fig 1A). Length was significantly reduced in CF and gut-corrected CF mice independent of sex, with both groups’ length reduced by 5–10% of wildtype littermates’ length. Reduction in fat accumulation is common in CF patients and CF mice and is observed in the gut-corrected CF model as well. Both CF and gut-corrected CF mice display a 50% reduction in inguinal fat (Fig 1C). Although 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; P<0.0001 up to 6 weeks of age; n>35 mice per group). In addition, no signs of intestinal obstruction were observed in any gut-corrected CF mice following sacrifice and postmortem examination. These data clearly show that restoration of CFTR in the intestinal epithelium and prevention of intestinal obstruction in CF mice does not improve growth.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus