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Am J Physiol Lung Cell Mol Physiol 282: L457-L467, 2002; doi:10.1152/ajplung.00050.2001
1040-0605/02 $5.00
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Vol. 282, Issue 3, L457-L467, March 2002

SPECIAL TOPIC
Pre- and Postnatal Lung Development, Maturation, and Plasticity
Insulin-like growth factor I receptor is downregulated after alveolarization in an apoptotic fibroblast subset

Suseela Srinivasan1, Jennifer Strange2, Feyisola Awonusonu1, and Margaret C. Bruce1

Departments of 1 Pediatrics and 2 Immunology, University of Kentucky Medical School, Lexington, Kentucky 40536

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.

lung development; PI 3-kinase; ras-raf-MAP kinase; flow cytometry; lipid interstitial fibroblasts


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