Korfhagen T R, Swantz R J, Wert S E, McCarty J M, Kerlakian C B, Glasser S W, Whitsett J A
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229.
J Clin Invest. 1994 Apr;93(4):1691-9. doi: 10.1172/JCI117152.
Increased production of EGF or TGF-alpha by the respiratory epithelial cells has been associated with the pathogenesis of various forms of lung injury. Growth factors and cytokines are thought to act locally, via paracrine and autocrine mechanisms, to stimulate cell proliferation and matrix deposition by interstitial lung cells resulting in pulmonary fibrosis. To test whether TGF-alpha mediates pulmonary fibrotic responses, we have generated transgenic mice expressing human TGF-alpha under control of regulatory regions of the human surfactant protein C (SP-C) gene. Human TGF-alpha mRNA was expressed in pulmonary epithelial cells in the lungs of the transgenic mice. Adult mice bearing the SP-C-TGF-alpha transgene developed severe pulmonary fibrosis. Fibrotic lesions were observed in peribronchial, peribronchiolar, and perivascular regions, as well as subjacent to pleural surfaces. Lesions consisted of fibrous tissue that included groups of epithelial cells expressing endogenous SP-C mRNA, consistent with their identification as distal respiratory epithelial cells. Peripheral fibrotic regions consisted of thickened pleura associated with extensive collagen deposition. Alveolar architecture was disrupted in the transgenic mice with loss of alveoli in the lung parenchyma. Pulmonary epithelial cell expression of TGF-alpha in transgenic mice disrupts alveolar morphogenesis and produces fibrotic lesions mediated by paracrine signaling between respiratory epithelial and interstitial cells of the lung.
呼吸道上皮细胞中表皮生长因子（EGF）或转化生长因子-α（TGF-α）产量的增加与多种形式的肺损伤发病机制有关。生长因子和细胞因子被认为通过旁分泌和自分泌机制在局部发挥作用，刺激肺间质细胞的细胞增殖和基质沉积，从而导致肺纤维化。为了测试TGF-α是否介导肺纤维化反应，我们构建了在人表面活性蛋白C（SP-C）基因调控区控制下表达人TGF-α的转基因小鼠。人TGF-α mRNA在转基因小鼠肺的肺上皮细胞中表达。携带SP-C-TGF-α转基因的成年小鼠出现严重的肺纤维化。在支气管周围、细支气管周围和血管周围区域以及胸膜表面下方观察到纤维化病变。病变由纤维组织组成，其中包括表达内源性SP-C mRNA的上皮细胞群，这与其作为远端呼吸道上皮细胞的身份一致。周围纤维化区域由与大量胶原沉积相关的增厚胸膜组成。转基因小鼠的肺泡结构被破坏，肺实质中的肺泡丧失。转基因小鼠肺上皮细胞中TGF-α的表达破坏了肺泡形态发生，并产生由肺呼吸上皮细胞和间质细胞之间的旁分泌信号介导的纤维化病变。
