During the previous grant period, we focused on (a) effects of lung distention on fetal lung growth and development and (b) apoptosis in the fetal lung. The current project extends our observation on fetal lung distention and relates them to the clinical problem of congenital diaphragmatic hernia (CDH) and new methods of treating CDH prenatally. Congenital anomalies are a leading cause of neonatal death, with pulmonary hypoplasia the most common anomaly in infants dying the neonatal period. CDH, a major cause of pulmonary hypoplasia, occurs once in 2400 births and has a high mortality rate. Fetal lung growth depends primarily on physical, or mechanical factors, which influence lung growth by changes in lung distension, or stretch, a potent stimulus for diverse cellular effects. With CDH, pulmonary hypoplasia results from alteration of several of these factors. Occluding the fetal trachea distends the lung with fluid and stimulates lung growth, findings that have led to clinical efforts to treat CDH prenatally by tracheal occlusion. Although preliminary results have been encouraging, little is known about effects of tracheal conclusion on some aspect of lung development crucial to adequate pulmonary function, including quantitative lung morphology, the pulmonary vasculature, and lung water balance. Also, tracheal occlusion produces potentially adverse effects, such as decreases in surfactant and alveolar type II cells. Administration of the pesticide of the pesticide, nitrofen, to pregnant rats causes CDH and pulmonary hypoplasia in 60% of the fetuses; the condition resembles CDH in human infants. We propose to distend, by tracheal occlusion, the lungs in fetal rats with nitrofen-induced CDH and to study the effects on lung growth and maturation, on differentiation of the distal pulmonary epithelium, on quantitative pulmonary and vascular morphology. on lung water transport and on components of the cytoskeleton, which is involved in cellular transduction of mechanical stimuli. We will also examine effects on maternal (a) glucocorticoids, which accelerate lung maturation, but which may adversely affect septation and lung growth, and of (b) retinoic acid, which postnatally increases septation and reverses the decreased septation due to dexamethasone. We have shown that apoptosis is a normal process in fetal lung development. How3ever, because changes in lung distension have little effect on apoptosis, further studies of that process are not included in the current project. Results of the proposed studies will increase our knowledge of fetal pulmonary biology and provide new information that may have direct bearing on the clinical problem of CDH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL024075-23
Application #
6501906
Study Section
Project Start
2001-07-01
Project End
2002-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
23
Fiscal Year
2001
Total Cost
$88,647
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Barrette, Anne Marie; Roberts, Jessica K; Chapin, Cheryl et al. (2016) Antiinflammatory Effects of Budesonide in Human Fetal Lung. Am J Respir Cell Mol Biol 55:623-632
Gonzales, Linda W; Gonzalez, Robert; Barrette, Anne Marie et al. (2015) Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease. J Histochem Cytochem 63:908-21
Raymond, Wilfred W; Xu, Xiang; Nimishakavi, Shilpa et al. (2015) Regulation of hepatocyte growth factor in mice with pneumonia by peptidases and trans-alveolar flux. PLoS One 10:e0125797
Danhaive, Olivier; Chapin, Cheryl; Horneman, Hart et al. (2015) Surface film formation in vitro by infant and therapeutic surfactants: role of surfactant protein B. Pediatr Res 77:340-6
Vanderbilt, Jeff N; Gonzalez, Robert F; Allen, Lennell et al. (2015) High-efficiency type II cell-enhanced green fluorescent protein expression facilitates cellular identification, tracking, and isolation. Am J Respir Cell Mol Biol 53:14-21
LaFemina, Michael J; Sutherland, Katherine M; Bentley, Trevor et al. (2014) Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol 51:550-8
Gonzalez, Robert F; Dobbs, Leland G (2013) Isolation and culture of alveolar epithelial Type I and Type II cells from rat lungs. Methods Mol Biol 945:145-59
Chapin, Cheryl; Bailey, Nicole A; Gonzales, Linda W et al. (2012) Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung. Am J Physiol Lung Cell Mol Physiol 302:L216-25
Heine, Vivi M; Griveau, Amelie; Chapin, Cheryl et al. (2011) A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury. Sci Transl Med 3:105ra104
Gonzalez, Robert F; Allen, Lennell; Gonzales, Linda et al. (2010) HTII-280, a biomarker specific to the apical plasma membrane of human lung alveolar type II cells. J Histochem Cytochem 58:891-901

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