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

Srinivasan, Suseela, Jennifer Strange, Feyisola Awonusonu, and Margaret C. Bruce. Insulin-like growth factor I receptor is downregulated after alveolarization in an apoptotic fibroblast subset. Am J Physiol Lung Cell Mol Physiol 282: L457–L467, 2002; 10.1152/ajplung.00050. 2001.—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.