Mason R J, Leslie C C, McCormick-Shannon K, Deterding R R, Nakamura T, Rubin J S, Shannon J M
Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
Am J Respir Cell Mol Biol. 1994 Nov;11(5):561-7. doi: 10.1165/ajrcmb.11.5.7524567.
Proliferation of alveolar type II cells is thought to be critical for restoration of gas exchange units after diffuse alveolar damage. However, the factors that regulate type II cell proliferation are not well understood. Hepatocyte growth factor (HGF) is a potentially important mitogen because it causes epithelial cells but not fibroblasts to proliferate and is found in the lung. We used rat alveolar type II cells in primary culture to demonstrate that HGF stimulates DNA synthesis in a concentration-dependent manner. The half maximal effect on stimulation of thymidine incorporation was less than 1 ng/ml. By autoradiography, HGF increased nuclear labeling from 1.3% of type II cells with medium alone to 9.4% with 5 ng/ml HGF. During this time, HGF modestly increased cell number in comparison to control media. However, in an assay of colony formation in low-density cultures, HGF did not consistently increase colony formation by alveolar type II cells and was less effective than acidic fibroblast growth factor or bronchoalveolar lavage fluid in this assay. The receptor for HGF (c-met proto-oncogene) was expressed in rat type II cells and whole lung but not in macrophages. In contrast, the mRNA for HGF was detected in rat macrophages and lung but not in type II cells. However, HGF message was not detected in human alveolar macrophages under conditions in which the HGF message was detected in rat alveolar macrophages and in human fibroblasts. Hence, HGF is a potential paracrine growth factor for alveolar type II cells, but there may be important species differences in the relative level of expression.
肺泡II型细胞的增殖被认为对弥漫性肺泡损伤后气体交换单位的恢复至关重要。然而，调节II型细胞增殖的因素尚未完全明确。肝细胞生长因子（HGF）是一种潜在的重要促有丝分裂原，因为它能使上皮细胞而非成纤维细胞增殖，且在肺中存在。我们使用原代培养的大鼠肺泡II型细胞来证明HGF以浓度依赖的方式刺激DNA合成。对胸苷掺入刺激的半数最大效应小于1 ng/ml。通过放射自显影，HGF使核标记从仅用培养基时II型细胞的1.3%增加到用5 ng/ml HGF时的9.4%。在此期间，与对照培养基相比，HGF适度增加了细胞数量。然而，在低密度培养的集落形成试验中，HGF并未持续增加肺泡II型细胞的集落形成，且在该试验中其效果不如酸性成纤维细胞生长因子或支气管肺泡灌洗液。HGF的受体（c-met原癌基因）在大鼠II型细胞和全肺中表达，但在巨噬细胞中不表达。相反，HGF的mRNA在大鼠巨噬细胞和肺中检测到，但在II型细胞中未检测到。然而，在大鼠肺泡巨噬细胞和人成纤维细胞中能检测到HGF信息的条件下，在人肺泡巨噬细胞中未检测到HGF信息。因此，HGF是肺泡II型细胞潜在的旁分泌生长因子，但在相对表达水平上可能存在重要的种属差异。
