Monitoring Early Inflammation in CF: Infant Pulmonary Function Testing

Sharp, Jack

doi:10.1385/criai:23:1:059

Cited by 6 publications

(3 citation statements)

References 51 publications

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“…These would become more apparent as the lung aged and was subjected to environmental insults. This is consistent with a growing body of evidence that CF patient lungs are abnormal at birth (Sharp, 2002;Farrell et al, 2003); that CFTR heterozygous and knockout lungs are different from homozygous normal mice (Cohen et al, 2004a); that in utero CFTR can reverse the CFTR knockout phenotype in the lungs (Fig. 9) and intestines (Larson et al, 1997); that CFTR is expressed at high levels in the developing lung (Broackes-Carter et al, 2002); and finally that transient in utero knockout of CFTR results in a CF phenotype in animals with a nor- mal CFTR genotype (Cohen and Larson, 2005).…”

Section: Discussionsupporting

confidence: 91%

“…However, there is increasing evidence that the lung may be functionally and structurally abnormal prior to the appearance of clinical infection. Recent data from several studies now document significant changes in pulmonary function in infants with CF (Sharp, 2002;Farrell et al, 2003). High-resolution computed tomography imaging has demonstrated that infants with CF have more dilated airways (Kadison et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Cohen

Larson

2006

Developmental Dynamics

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There is growing evidence for the role of CFTR (cystic fibrosis transmembrane conductance regulator) in lung development and differentiation. The mechanism by which the chloride channel could affect lung organogenesis, however, is unknown. In utero CFTR gene transfer in the fetal lungs of mice, rats, and non-human primates was shown previously to alter lung structure and function. A study of the genes altered in the fetal rat lung following CFTR overexpression was initiated in an effort to determine the molecular mechanism for CFTR-dependent differentiation. In utero gene transfer with recombinant adenoviruses carrying either a reporter gene or CFTR resulted in the increased expression of a number of genes upon microarray analysis. The majority of the genes overexpressed in the CFTR-treated lungs were primarily associated with muscle structure and function. Histological and biochemical characterization of these proteins including myosin heavy chain, heat shock protein 27, and isoforms of myosin light chain showed that CFTR overexpression had a profound effect on smooth muscle contraction-related proteins. The CFTR-dependent regulation of smooth muscle contraction related proteins was shown to be related to chloride and extracellular ATP and was dependent upon the PI3 Kinase and Phospholipase C pathways. The changes in smooth muscle proteins were consistent with CFTR-dependent contractions of the embryonic airway smooth muscle. An assay was developed using fluorescent polystyrene beads to show that CFTR did indeed increase amniotic fluid flow into the fetal lung. Increased amniotic fluid pressure was shown previously to be associated with stretch-induced differentiation of the lung. Evaluation of neonatal respiratory function showed that CFTR-dependent muscle contractions and increased amniotic fluid pressure resulted in accelerated maturation of the neonatal rat lung. In addition, these CFTR-dependent changes were shown to be sufficient to reverse the lung phenotype of the CFTR knockout mouse. Mechanical forces influence lung development through pulmonary distension. CFTR overexpression in the fetal lung altered differentiation and development in the lung. These results are consistent with CFTR influencing lung development by regulating the muscle contractions associated with cytoskeletal tension and stretch induced differentiation. Deficiency of CFTR altering lung development would contribute significantly to the Cystic Fibrosis disease phenotype.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Cohen

Larson

2006

Developmental Dynamics

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“…Several studies have shown changes in lung volumes and maximal flows indicating early obstruction in the small airways. However, lack of standardized equipment and technique currently prevents routine use of these measurements [41,42].…”

Section: Pulmonary Function Testsmentioning

confidence: 99%

Standards of care for patients with cystic fibrosis: a European consensus

Kerem¹,

Conway²,

Elborn³

et al. 2005

Journal of Cystic Fibrosis

399

332

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Developmental Paradigm for Early Features of Cystic Fibrosis

Larson

Cohen

2005

Pediatr. Pulmonol.

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Cystic fibrosis (CF) is a progressive disease in which the lung is perceived to be normal at birth and is injured by recurrent infection. However, there is increasing evidence that the lung is functionally and structurally abnormal prior to the appearance of clinical infection. The cystic fibrosis transmembrane regulator (CFTR) is highly expressed in fetal tissues, and this review examines the role of CFTR in regulatory cascades during lung development. Early changes in the CF lung are examined from a perspective of disrupted fetal development, explaining a number of paradoxes seen with the disease.

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Monitoring Early Inflammation in CF: Infant Pulmonary Function Testing

Cited by 6 publications

References 51 publications

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Cystic fibrosis transmembrane conductance regulator (CFTR) dependent cytoskeletal tension during lung organogenesis

Standards of care for patients with cystic fibrosis: a European consensus

Developmental Paradigm for Early Features of Cystic Fibrosis

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