Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation.
Developing rat lung lipofibroblasts express leptin beginning on embryonic day (E) 17, increasing 7- to 10-fold by E20. Leptin and its receptor are expressed mutually exclusively by fetal lung fibroblasts and type II cells, suggesting a paracrine signaling "loop." This hypothesized mechanism is supported by the following experimental data: 1) leptin stimulates the de novo synthesis of surfactant phospholipid by both fetal rat type II cells (400% x 100 ng(-1) x ml(-1) x 24 h(-1)) and adult human airway epithelial cells (85% x 100 ng(-1) x 24 h(-1)); 2) leptin is secreted by lipofibroblasts in amounts that stimulate type II cell surfactant phospholipid synthesis in vitro; 3) epithelial cell secretions such as parathyroid hormone-related protein (PTHrP), PGE(2), and dexamethasone stimulate leptin expression by fetal rat lung fibroblasts; 4) PTHrP or leptin stimulate the de novo synthesis of surfactant phospholipid (2- to 2.5-fold/24 h) and the expression of surfactant protein B (SP-B; >25-fold/24 h) by fetal rat lung explants, an effect that is blocked by a leptin antibody; and 5) a PTHrP receptor antagonist inhibits the expression of leptin mRNA by explants but does not inhibit leptin stimulation of surfactant phospholipid or SP-B expression, indicating that PTHrP paracrine stimulation of type II cell maturation requires leptin expression by lipofibroblasts. This is the first demonstration of a paracrine loop that functionally cooperates to induce alveolar acinar lung development.
Torday
J S
JS
Department of Pediatrics and Obstetrics and Gynecology, Harbor-University of California Los Angeles Research and Education Institute, Torrance, California 90502, USA. jtorday@prl.humc.edu
Sun
H
H
Wang
L
L
Torres
E
E
Sunday
M E
ME
Rubin
L P
LP
D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D046508:Culture Techniques; D004347:Drug Interactions; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology; D005333:Fetus / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000494:pharmacology / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000196:embryology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D020738:Leptin; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger