Our objective is to determine if growth factors can be related to the physiology of intraparenchymal airway development and response to injury in the human lung. In the future, new biologial strategies for the treatment of newborn lung disease may involve the use of growth factors. Precise information about the synthesis of growth factors and the availability of their receptors may contribute to the design of such therapies. The emphasis of this project is to define the cellular sites of synthesis and changes in the synthesis of epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha) and the EGF receptor (EGF-R) during lung development and the perturbed response to injury seen in bronchopulmonary dysplasia (BPD). Three major hypotheses will be tested: (1) select cell populations of the intraparenchymal conducting airways produce EGF, TGFalpha and EGF-R; (2) EGF, or a similar ligand for EGF-R, exerts autocrine or paracrine effects contributing to the development (and repair) of pulmonary epithelium; (3) changes in the production of EGF, or growth factor ligands for EGF-R, may occur during lung development and BPD. These hypotheses will be tested with the following specific aims. (1) Changes in the morphological differentiation of airway epithelium during lung development will be defined by light and electron microscopy. (2) Sensitive immunocytochemistry (IC) will be used to identify the specific cell types containing immunoreactive EGF, TGFalpha and EGF-R. Since neuroendocrine cells may uptake and store peptide hormones and the EGF: receptor complex is rapidly internalized and degraded after EGF binding, IC alone does not establish the sites of synthesis (or lack of synthesis) of these products. (3) The more direct method of nucleic acid in situ hybridization histochemistry (IHH) will be used to identify the cellular sites of transcription of EGF, TGFalpha and EGF-R mRNA. IHH alone does not establish that the target mRNA is translated and processed to the peptide. Hence, identification of both the mRNA for a peptide and the immunoreactive peptide in the same or morphologically identical (and phenotypically defined) cell increases the probability that this cell is synthesizing the peptide product. (4) Since EGF may be involved in the repair response, the sites of synthesis of EGF, TGFalpha and EGF-R will be identified in BPD lungs. Growth factor gene expression may be under developmental control and/or altered during the response to injury, therefore (5) relative changes in the gene expression of EGF, TGFalpha and EGF-R will be defined by quantitative hybridization studies of lung during normal development and BPD. (6) Additional studies will identify the sites of and changes in the synthesis of other promising growth-related peptides. These studies will determine the in vivo sites of EGF synthesis and provide in vivo evidence of a physiological role for EGF during lung development and the response to injury found in BPD.
| Johnson, M D; Gray, M E; Carpenter, G et al. (1990) Ontogeny of epidermal growth factor receptor and lipocortin-1 in fetal and neonatal human lungs. Hum Pathol 21:182-91 |
| Johnson, M D; Gray, M E; Pepinsky, R B et al. (1990) Lipocortin-1 immunoreactivity in the human pituitary gland. J Histochem Cytochem 38:1841-5 |
| Johnson, M D; Gray, M E; Carpenter, G et al. (1989) Ontogeny of epidermal growth factor receptor/kinase and of lipocortin-1 in the ovine lung. Pediatr Res 25:535-41 |
| Stahlman, M T; Orth, D N; Gray, M E (1989) Immunocytochemical localization of epidermal growth factor in the developing human respiratory system and in acute and chronic lung disease in the neonate. Lab Invest 60:539-47 |
