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The family of growth factors that includes epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are thought to play a role in the regulation of fetal lung development and epithelial repair after injury. To further elucidate the potential role of these growth factors and their receptor in normal human lung development and in response to injury, their distribution was determined by immunohistochemistry in normal fetal lung, as well as both normal and injured postnatal human lung. We studied 14 specimens of human lung tissue: from three fetuses, four normal infants, two preterm infants with hyaline membrane disease, and five infants with late bronchopulmonary dysplasia (BPD). EGF, TGF-alpha, and EGF receptor (EGF-R) colocalized in airway epithelium in normal fetal and in postnatal human lung. They were also colocalized in scattered alveolar epithelial cells in postnatal lung. Large numbers of alveolar macrophages immunostained for EGF, TGF-alpha, and EGF-R in lungs with late stages of BPD. The colocalization of these growth factors suggests parallel expression of EGF family members. Moreover, the colocalization of these growth factors with their receptor in developing lung suggests that they may act through an autocrine mechanism. The prominent expression of these growth factors in alveolar macrophages in BPD suggests they may be involved with the pathogenesis of this disease.

To define the distribution of transforming growth factor-alpha (TGF-alpha) and its relationship to epidermal growth factor (EGF) and EGF receptor in lung development and to determine whether epithelial cells produce TGF-alpha, we studied the expression of TGF-alpha, EGF, and their receptor in late-gestation fetal rat lung and in cultured fetal rat lung cells. TGF-alpha, EGF, and EGF receptor were colocalized in epithelial and smooth muscle cells of bronchioles and bronchi and in epithelial cells of saccules. Epithelial cells cultured from late-gestation fetal rat lung transcribe TGF-alpha and EGF receptor mRNA and produce TGF-alpha and EGF receptor proteins. Cultured fibroblasts contained EGF receptor mRNA, but no detectable TGF-alpha mRNA. These results demonstrate fetal lung epithelial cells are a source for TGF-alpha and suggest that TGF-alpha might act through an autocrine or paracrine mechanism with epithelial and mesenchymal cells. The colocalization of TGF-alpha and EGF suggests that these growth factors might act in parallel in lung development.