Insulin-like growth factor I receptor is downregulated after alveolarization in an apoptotic fibroblast subset.
After alveolar formation, >20% of interstitial lung fibroblasts undergo apoptosis, a process that is of critical importance for normal lung maturation. The immature lung contains two morphologically distinct fibroblast populations, lipid-filled interstitial fibroblasts (LIF) and non-LIF (NLIF), which differ with respect to contractile protein content, proliferative capacity, and expression of mRNAs for fibronectin and types I and III collagen, but not tropoelastin. After alveolarization, apoptosis occurs in only one fibroblast population, the LIF. Using flow cytometry to analyze fibroblasts stained with a lipophilic, fluorescent dye, we identified a subset, designated LIF(-), that contained fewer lipid droplets. Unlike LIF that retain lipid, LIF(+), the LIF(-) do not undergo apoptosis after alveolarization. In LIF(+), apoptosis was correlated with downregulation of insulin-like growth factor I receptor (IGF-IR) mRNA and cell surface protein expression. Treatment with anti-IGF-IR decreased total lung fibroblast survival (P = 0.05) as did treatment with the phosphatidylinositol 3-kinase inhibitor LY-294002 and the ras-raf-mitogen-activated protein kinase inhibitor PD-98059 (P < 0.002), which block IGF-I/insulin receptor survival pathways. These observations implicate downregulation of IGF-IR expression in fibroblast apoptosis after alveolar formation.
Srinivasan
Suseela
S
Department of Pediatrics, University of Kentucky Medical School, Lexington, Kentucky 40536, USA.
Strange
Jennifer
J
Awonusonu
Feyisola
F
Bruce
Margaret C
MC
D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D005314:Embryonic and Fetal Development; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000145:classification / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D007425:Intracellular Membranes / Q000378:metabolism; D050356:Lipid Metabolism; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology* / Q000254:growth & development*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors
D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017526:Receptor, IGF Type 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one