Calabrese F, Lunardi F, Giacometti C, Marulli G, Gnoato M, Pontisso P, Saetta M, Valente M, Rea F, Perissinotto E, Agostini C
Department of Diagnostic Medical Sciences and Special Therapies, University of Padua Medical School, Via Gabelli, 61 Padua, Italy.
Thorax. 2008 Sep;63(9):795-802. doi: 10.1136/thx.2007.088583. Epub 2008 Mar 14.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder with a poor prognosis. Epithelial instability is a crucial step in the development and progression of the disease, including neoplastic transformation. Few tissue markers for epithelial instability have been reported in IPF. Squamous cell carcinoma antigen (SCCA) is a serine protease inhibitor typically expressed by dysplastic and neoplastic cells of epithelial origin, more often in squamous cell tumours. At present, no information is available on its expression in IPF.
SCCA and transforming growth factor beta (TGFbeta) expression in surgical lung biopsies from 22 patients with IPF and 20 control cases was examined. An in vitro study using A549 pneumocytes was also conducted to investigate the relationship between SCCA and TGFbeta expression. SCCA and TGFbeta epithelial expression was evaluated by immunohistochemistry and reverse transcription-PCR (RT-PCR). SCCA values were correlated with different pathological and clinical parameters. Time course analysis of TGFbeta expression in A549 pneumocytes incubated with different SCCA concentrations was assessed by real time RT-PCR.
SCCA was expressed in many metaplastic alveolar epithelial cells in all IPF cases with a mean value of 24.9% while it was seen in only two control patients in up to 5% of metaplastic cells. In patients with IPF, SCCA correlated positively with extension of fibroblastic foci (r = 0.49, p = 0.02), expression of TGFbeta (r = 0.78, p<0.0001) and with carbon monoxide transfer factor decline after 9 months of follow-up (r = 0.59, p = 0.01). In vitro experiments showed that incubation of cultured cells with SCCA induced TGFbeta expression, with a peak at 24 h.
Our findings provide for the first time a potential mechanism by which SCCA secreted from metaplastic epithelial cells may exert a profibrotic effect in IPF. SCCA could be an important biomarker in this incurable disease.
特发性肺纤维化（IPF）是一种预后较差的慢性进行性疾病。上皮细胞不稳定是该疾病发生发展包括肿瘤转化的关键步骤。在IPF中，鲜有关于上皮细胞不稳定的组织标志物的报道。鳞状细胞癌抗原（SCCA）是一种丝氨酸蛋白酶抑制剂，通常由上皮来源的发育异常和肿瘤细胞表达，更常见于鳞状细胞肿瘤。目前，尚无关于其在IPF中表达情况的信息。
检测了22例IPF患者和20例对照者手术肺活检组织中SCCA和转化生长因子β（TGFβ）的表达。还进行了一项使用A549肺细胞的体外研究，以探讨SCCA与TGFβ表达之间的关系。通过免疫组织化学和逆转录 - 聚合酶链反应（RT-PCR）评估SCCA和TGFβ的上皮表达。SCCA值与不同的病理和临床参数相关。通过实时RT-PCR评估在不同SCCA浓度下孵育的A549肺细胞中TGFβ表达的时间进程分析。
在所有IPF病例中，许多化生的肺泡上皮细胞中都有SCCA表达，平均值为24.9%，而在对照患者中，仅在2例患者中可见，化生细胞中比例高达5%。在IPF患者中，SCCA与成纤维细胞灶的范围呈正相关（r = 0.49，p = 0.02），与TGFβ的表达呈正相关（r = 0.78，p<0.0001），并与随访9个月后一氧化碳转运因子下降呈正相关（r = 0.59，p = 0.01）。体外实验表明，用SCCA孵育培养细胞可诱导TGFβ表达，在24小时达到峰值。
我们的研究结果首次提供了一种潜在机制，化生上皮细胞分泌的SCCA可能在IPF中发挥促纤维化作用。SCCA可能是这种无法治愈疾病的重要生物标志物。
