CELLULAR-DISTRIBUTION OF INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEIN MESSENGER-RNAS AND PEPTIDES DURING RAT LUNG DEVELOPMENT

A role for IGF binding proteins (IGFBPs) in lung development is sugges ted by the identification of IGFBPs in lung tissue and production of I GFBPs by fetal lung cells in culture. To characterize the expression o f IGFBPs during lung development in the rat in vivo (16 days gestation through adulthood), the expression of IGFBP mRNAs (IGFBP-1 to IGFBP-6 ) was examined by Northern analysis and in situ hybridization, and IGF BP peptides (IGFBP-2, IGFBP-3, and IGFBP-5) were localized by immunohi stochemistry. IGFBP-1 mRNA was not detectable. IGFBP-2 mRNA (1.8 kb) w as expressed in both fetal and postnatal life with peak expression dur ing the fetal pseudoglandular stage. IGFBP-2 mRNA was localized mainly to airway epithelium. IGFBP-3 mRNA (2.4 kb) was maximally expressed p ostnatally in the saccular stage of lung development; it was identifie d in airway epithelium and interstitium in the fetal lung, but predomi nantly in airway epithelium after birth. IGFBP-4 (2.6 kb) and IGFBP-5 (6.0 kb) mRNA levels were maximal after birth, from 3 to 21 days postn atal (saccular and alveolar stage). IGFBP-4 mRNA was localized primari ly to the interstitium and blood vessels early in development, but was abundant in airway epithelium in the adult. IGFBP-5 mRNA was most abu ndant in the airway epithelium. IGFBP-3, IGFBP-4, IGFBP-5, and to a le sser extent IGFBP-6 were localized to the large cartilaginous airways in the adult. IGFBP-2, IGFBP-3, and IGFBP-5 peptides were distributed more widely than their respective mRNAs, with a temporal pattern of im munoreactivity following that of their mRNAs. Maximal staining was not ed in airway epithelium for IGFBP-2 in the newborn, for IGFBP-3 in the saccular stage (newborn to 3 days postnatal), and for IGFBP-5 in the alveolar stage (5 to 21 days postnatal). Our studies demonstrate that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 are synthesized and distributed in spatially and temporally different patterns in the developing lung . The widespread distribution of IGFBP immunoreactivity compared with their respective mRNAs suggests that IGFBPs are important paracrine fa ctors in the regulation of IGF action in the developing lung.