Ikegami Machiko, Le Cras Timothy D, Hardie William D, Stahlman Mildred T, Whitsett Jeffrey A, Korfhagen Thomas R
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, OH 45229-3039, USA.
Am J Physiol Lung Cell Mol Physiol. 2005 Jul;289(1):L34-43. doi: 10.1152/ajplung.00407.2004. Epub 2005 Mar 11.
To determine potential relationships between transforming growth factor (TGF)-alpha and surfactant homeostasis, the metabolism, function, and composition of surfactant phospholipid and proteins were assessed in transgenic mice in which TGF-alpha was expressed in respiratory epithelial cells. Secretion of saturated phosphatidylcholine was decreased 40-60% by expression of TGF-alpha. Although SP-A, SP-B, and SP-C mRNA levels were unchanged by expression of TGF-alpha, SP-A and SP-B content in bronchoalveolar lavage fluid was decreased. The minimum surface tension of surfactant isolated from the transgenic mice was significantly increased. Incubation of cultured normal mice type II cells with TGF-alpha in vitro did not change secretion of surfactant phosphatidylcholine and SP-B, indicating that TGF-alpha does not directly influence surfactant secretion. Expression of a dominant negative (mutant) EGF receptor in the respiratory epithelium blocked the TGF-alpha-induced changes in lung morphology and surfactant secretion, indicating that EGF receptor signaling in distal epithelial cells was required for TGF-alpha effects on surfactant homeostasis. Because many epithelial cells were embedded in fibrotic lesions caused by TGF-alpha, changes in surfactant homeostasis may at least in part be influenced by tissue remodeling that results in decreased surfactant secretion. The number of nonembedded type II cells was decreased 30% when TGF-alpha was expressed during development and was increased threefold by TGF-alpha expression in adulthood, suggesting possible alteration of type II cells on surfactant metabolism in the adult lung. Abnormalities in surfactant function and decreased surfactant level in the airways may contribute to the pathophysiology induced by TGF-alpha in both the developing and adult lung.
为了确定转化生长因子（TGF）-α与表面活性剂稳态之间的潜在关系，我们在呼吸道上皮细胞中表达TGF-α的转基因小鼠中评估了表面活性剂磷脂和蛋白质的代谢、功能及组成。TGF-α的表达使饱和磷脂酰胆碱的分泌减少了40%-60%。尽管TGF-α的表达未改变SP-A、SP-B和SP-C的mRNA水平，但支气管肺泡灌洗液中SP-A和SP-B的含量却降低了。从转基因小鼠分离的表面活性剂的最小表面张力显著增加。体外将培养的正常小鼠II型细胞与TGF-α孵育并未改变表面活性剂磷脂酰胆碱和SP-B的分泌，这表明TGF-α不会直接影响表面活性剂的分泌。呼吸道上皮中显性负性（突变型）表皮生长因子受体的表达阻断了TGF-α诱导的肺形态和表面活性剂分泌的变化，这表明远端上皮细胞中的表皮生长因子受体信号传导是TGF-α影响表面活性剂稳态所必需的。由于许多上皮细胞嵌入由TGF-α引起的纤维化病变中，表面活性剂稳态的变化可能至少部分受到导致表面活性剂分泌减少的组织重塑的影响。在发育过程中表达TGF-α时，未嵌入的II型细胞数量减少了30%，而成年期TGF-α的表达使其增加了三倍，这表明成年肺中II型细胞可能对表面活性剂代谢产生了改变。表面活性剂功能异常和气道中表面活性剂水平降低可能导致TGF-α在发育中和成年肺中诱导的病理生理学变化。
