In the present study we demonstrated that circulating levels of napsin A are increased in patients with IPF, as compared with healthy controls, and correlate with those of KL-6, SP-A, SP-D, and the severity of disease. In addition, the serum napsin A levels were not elevated in patients with pulmonary adenocarcinoma without ILD or in kidney disease. These findings suggest that serum napsin A may be a candidate biomarker for IPF.
Our findings demonstrating elevated serum levels of KL-6, SP-A, and SP-D in IPF are consistent with those reported previously [4–6], as well as the cut-off levels in this study for KL-6, SP-A and SP-D were similar to those in previous reports [17–19]. Compared to these serum markers, napsin A showed the largest AUC for distinguishing IPF from controls. A comparison of KL-6, SP-A, and SP-D for the diagnostic values in patients with ILD including IPF previously demonstrated that KL-6 was superior to other markers , and the findings of present study for IPF regarding the order of the AUC values obtained from ROC curves is the same as that study , in which KL-6 preceded SP-A and SP-D. In our findings, serum napsin A levels showed greater diagnostic accuracy for distinguishing IPF from controls.
The mechanism by which the circulating levels of napsin A are elevated in IPF is not known. It is probably due to a combination of a loss of integrity of the epithelial barrier caused by lung injury and an increased mass of type II cells due to hyperplasia as SP-A and SP-D . The molecular weights of SP-A and SP-D are 26–38 kDa and 43 kDa, respectively [20–22]; that of napsin A is approximately 38 kDa , while that of KL-6 is estimated to be greater than 200 kD [20, 23]. Serum KL-6 possibly requires cleavage by a proteinase to liberate its extracellular domain in order to leak into the bloodstream [20, 24]. These differences may account for differences in the detected levels of these markers in IPF.
Serum napsin A levels were correlated with serum KL-6, SP-A, and SP-D in patients with IPF. Moreover, we found that napsin A levels were more strongly correlated with SP-A, and SP-D levels than with KL-6 levels, and this is supported by previous findings that napsin A is protease that relates to maturation of SP-B and SP-C . Consequently, napsin A is also a useful type II pneumocytes marker, as it the case with existing biomarker for IPF: KL-6, SP-A, and SP-D. The serum markers for IPF are similar to those for type II pneumocytes; it is possible that these biomarkers reflect type II pneumocyte activity.
A concern regarding serum biomarkers is that elevated levels of some markers can be found in IPF as well as in malignancies, while these diseases may coincide. Serum levels of KL-6 or VEGF were reported to be increased in patients with IPF but also in lung cancer patients [25, 26]. The production of SP-A and SP-D by lung adenocarcinoma cells obtained from malignant pleural effusions has also been previously reported . In lung tumors, the sensitivity and specificity of napsin A immunostaining are high for identifying adenocarcinomas [12, 13, 28–30]. We compared the serum levels of napsin A, KL-6, SP-A, and SP-D in patients with IPF and primary pulmonary adenocarcinomas. The ROC curves demonstrated that napsin A, KL-6 and SP-D were superior to SP-A as serum markers distinguishing IPF from adenocarcinomas. The limitation in falsely positive cases with lung cancer may be able to be corrected by using in combination.
In addition to type II pneumocytes, napsin A is expressed in the epithelium of the proximal and convoluted tubules of the kidney . In this study, none of the subjects with IPF, lung cancer, or controls exhibited any signs of renal dysfunction or renal cell carcinoma. Serum napsin A levels of patients with kidney disease indicated no elevation compared with those of control subjects. Therefore, it is unlikely that our data were influenced by kidney disease.
There were some limitations in this study. The study was retrospective and included only limited numbers of patients. The role of napsin A in the pathogenesis of lung disease is unknown, and it is possible that several other diseases including other types of ILD and pneumonia can cause an increase in serum napsin A levels. Therefore, a large cohort study will be required to confirm our results. We will also need to clarify the relationship of these markers to the histological patterns of ILD.