Comparative study of serum POSTN, KL-6, SP-A, and SP-D as biomarkers of idiopathic pulmonary fibrosis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WU Shi ¹ , LIU Hua ² , YIN Shijia ¹ ,  DING Zhen ¹

1. Department of Respiratory and Critical Care Medicine, The Third Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230061, P. R. China;
2. Anhui Institutes for Food and Drug Control, Hefei, Anhui 230051, P. R. China;

Corresponding author：

DING Zhen, Email: imdzh@163.com

Keywords：

Idiopathic pulmonary fibrosis; periostin; Krebs von den lungen-6; surfactant protein A; surfactant protein D; biomarkers

DOI：

10.7507/1671-6205.202405076

Video：

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Objective To investigate the impact and mechanisms of periostin (POSTN), Krebs von den Lungen-6 (KL-6), pulmonary surfactant protein A (SP-A), and pulmonary surfactant protein D (SP-D) on the diagnosis and disease assessment of idiopathic pulmonary fibrosis (IPF), and conduct a comparative analysis. Methods From October 2022 to October 2023, a total of 55 patients diagnosed with IPF and treated at the Third Affiliated Hospital of Anhui Medical University were enrolled as an IPF group. Additionally, 30 patients with bacterial pneumonia and 30 healthy individuals undergoing concurrent health examinations during the same period were selected as a pneumonia control group and a healthy control group, respectively. All participants underwent enzyme-linked immunosorbent assay to measure serum levels of POSTN, KL-6, SP-A, and SP-D, along with pulmonary function tests. The IPF patients also underwent high-resolution computed tomography (HRCT) and echocardiography to quantify HRCT scores and pulmonary artery systolic pressure (PASP). Receiver operating characteristic (ROC) curves were plotted to analyze the significance of serum POSTN, KL-6, SP-A, and SP-D levels in IPF diagnosis. Pearson and Spearman correlation tests were used to analyze the relationships between these biomarkers and pulmonary function, PASP, and HRCT scores. Results Serum concentrations of POSTN, KL-6, SP-A, and SP-D were significantly elevated in the IPF group compared with the pneumonia group and the healthy controls (P<0.05), while serum levels of SP-A and SP-D were notably higher in the pneumonia group compared with the healthy control group (P<0.05). Within the IPF group, serum POSTN levels were negatively correlated with forced expiratory volume in the first second as a percentage of predicted value (FEV₁%pred) and diffusion capacity of the lung for carbon monoxide as a percentage of predicted value (D_LCO%pred) (P<0.05); KL-6 and SP-D levels were also negatively correlated with FEV₁%pred, forced vital capacity as a percentage of predicted value (FVC%pred), and D_LCO%pred (P<0.05); and the concentration of SP-A was negatively correlated with D_LCO%pred and positively correlated with PASP (P<0.05). Additionally, serum levels of POSTN, KL-6, and SP-A in the IPF group showed significant positive associations with HRCT scores (P<0.01). Conclusions POSTN is a valuable serum biomarker for IPF, exhibiting the highest sensitivity and specificity among the four serum markers, with diagnostic performance superior to KL-6, SP-A, and SP-D. POSTN, KL-6, SP-A, and SP-D can all be used for the diagnosis and assessment of IPF.

Citation： WU Shi, LIU Hua, YIN Shijia, DING Zhen. Comparative study of serum POSTN, KL-6, SP-A, and SP-D as biomarkers of idiopathic pulmonary fibrosis. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(3): 179-185. doi: 10.7507/1671-6205.202405076 Copy

1.	Richeldi L, Azuma A, Cottin V, et al. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med, 2022, 386(23): 2178-2187. DOI: 10.1056/NEJMoa 2201737.
2.	Esposito DB, Lanes S, Donneyong M, et al. Idiopathic pulmonary fibrosis in United States automated claims. Incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med, 2015, 192(10): 1200-1207.
3.	Harari S, Madotto F, Caminati A, et al. Epidemiology of idiopathic pulmonary fibrosis in Northern Italy. PLoS One, 2016, 11(2): e0147072.
4.	雷凯春, 岳红梅, 周婷婷. 特发性肺纤维化治疗新进展. 中国呼吸与危重监护杂志, 2019, 18(2): 199-203.
5.	Selvarajah B, Platé M, Chambers RC. Pulmonary fibrosis: emerging diagnostic and therapeutic strategies. Mol Aspects Med, 2023, 94: 101227.
6.	杨莹, 徐凯峰, 魏丽娟. 吡非尼酮和尼达尼布在新型冠状病毒感染后肺纤维化中的应用进展. 中国呼吸与危重监护杂志, 2024, 23(8): 593-598.
7.	Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med, 2022, 205(9): e18-e47.
8.	Drakopanagiotakis F, Wujak L, Wygrecka M, et al. Biomarkers in idiopathic pulmonary fibrosis. Matrix Biol, 2018, 68: 404-421.
9.	Stainer A, Faverio P, Busnelli S, et al. Molecular biomarkers in idiopathic pulmonary fibrosis: state of the art and future directions. Int J Mol Sci, 2021, 22(12): 6255.
10.	范宇斌, 何荣伶, 邹丽君, 等. 生物标志物在特发性肺纤维化中的临床价值. 南方医科大学学报, 2020, 40(7): 1062-1065.
11.	O’dwyer DN, Moore BB. The role of periostin in lung fibrosis and airway remodeling. Cell Mol Life Sci, 2017, 74: 4305-4314.
12.	Ono J, Takai M, Kamei A, et al. Pathological roles and clinical usefulness of periostin in type 2 inflammation and pulmonary fibrosis. Biomolecules, 2021, 11(8): 1084.
13.	吕长俊, 李洪波, 王晓芝, 等. 特发性肺纤维化与非特异性间质性肺炎的非创伤性鉴别诊断方程. 中华内科杂志, 2010, 49(5): 376-379.
14.	Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet, 2017, 389(10082): 1941-1952.
15.	Singh S, Natalini JG, Segal LN. Lung microbial-host interface through the lens of multi-omics. Mucosal Immunol, 2022, 15(5): 837-845.
16.	吴亚娜, 刘东玲, 宋忠阳, 等. 特发性肺纤维化中上皮-间质转化的研究现状. 中国临床药理学杂志, 2023, 39(23): 3499-3503.
17.	Salton F, Volpe MC, Confalonieri M. Epithelial–mesenchymal transition in the pathogenesis of idiopathic pulmonary fibrosis. Medicina, 2019, 55(4): 83.
18.	邓艳, 赵红玉, 朱丽萍, 等. 硫酸羟氯喹通过PI3K/AKt/mTOR信号通路对百草枯致小鼠肺纤维化影响. 中国呼吸与危重监护杂志, 2024, 23(3): 192-199.
19.	Gao Y, Du T, Yang L, et al. Research progress of KL-6 in respiratory system diseases. Crit Rev Clin Lab Sci, 2024: 1-17.
20.	D’alessandro M, Bergantini L, Cameli P, et al. Krebs von den Lungen-6 as a biomarker for disease severity assessment in interstitial lung disease: a comprehensive review. Biomark Med, 2020, 14(8): 665-674.
21.	Okamoto T, Fujii M, Furusawa H, et al. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir Med, 2015, 109(12): 1576-1581.
22.	Xu L, Bian W, Gu X, et al. Differing expression of cytokines and tumor markers in combined pulmonary fibrosis and emphysema compared to emphysema and pulmonary fibrosis. COPD, 2017, 14(2): 245-250.
23.	廖明星, 潘瑞琪, 艾承锦, 等. 肺纤维化血清 KL-6, TGF-β, CXCL13 水平与病变程度的关系及其联合预测价值. 医学研究生学报, 2021, 34(1): 62-67.
24.	Sánchez-Díez S, Munoz X, Ojanguren I, et al. YKL-40 and KL-6 levels in serum and sputum of patients diagnosed with hypersensitivity pneumonitis. J Allergy Clin Immunol Pract, 2022, 10(9): 2414-2423.
25.	Mulugeta S, Nureki SI, Beers MF. Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol, 2015, 309(6): L507-L525.
26.	Katzen J, Beers MF. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. J Clin Invest, 2020, 130(10): 5088-5099.
27.	鲁未, 赵卉, 魏红. 血清KL-6、SP-A、SP-D及MMP-7对特发性肺纤维化的诊断意义及与肺功能的关系. 安徽医科大学学报, 2016, 51(6): 868-872.
28.	苏文瑶, 陈铿铿, 黄永顺, 等. 表面活性蛋白A、D在肺纤维化中的作用研究进展. 中国职业医学, 2021, 48(4): 451-456.
29.	Confalonieri P, Volpe MC, Jacob J, et al. Regeneration or repair? The role of alveolar epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cells, 2022, 11(13): 2095.
30.	Hamai K, Iwamoto H, Ishikawa N, et al. Comparative study of circulating MMP -7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis. Dis Markers, 2016, 2016: 4759040.
31.	Guagliardo R, Perez-Gil J, De SS, et al. Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins. J Control Release, 2018, 291: 116-126.
32.	Dare A, King SD, Chen SY. Surfactant protein A promotes western diet-induced hepatic steatosis and fibrosis in mice. Sci Rep, 2024, 14(1): 7464.
33.	李群, 关为群, 张杨安, 等. 骨膜蛋白和 p53 在口腔白斑及鳞状细胞癌组织中的表达及意义. 国际口腔医学杂志, 2019, 46(1): 5-11.
34.	Yoshihara T, Nanri Y, Nunomura S, et al. Periostin plays a critical role in the cell cycle in lung fibroblasts. Respir Res, 2020, 21: 1-12.
35.	刘胜菲, 李龙, 陈凤, 等. 骨膜蛋白在特发性肺纤维化中的研究进展. 中国呼吸与危重监护杂志, 2023, 22(6): 448-451.
36.	Carpagnano GE, Soccio P, Scioscia G, et al. The potential role of airways periostin in the clinical Practice of patients affected by idiopathic pulmonary fibrosis. Rejuvenation Res, 2021, 24(4): 302-306.

1. Richeldi L, Azuma A, Cottin V, et al. Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis. N Engl J Med, 2022, 386(23): 2178-2187. DOI: 10.1056/NEJMoa 2201737.
2. Esposito DB, Lanes S, Donneyong M, et al. Idiopathic pulmonary fibrosis in United States automated claims. Incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med, 2015, 192(10): 1200-1207.
3. Harari S, Madotto F, Caminati A, et al. Epidemiology of idiopathic pulmonary fibrosis in Northern Italy. PLoS One, 2016, 11(2): e0147072.
4. 雷凯春, 岳红梅, 周婷婷. 特发性肺纤维化治疗新进展. 中国呼吸与危重监护杂志, 2019, 18(2): 199-203.
5. Selvarajah B, Platé M, Chambers RC. Pulmonary fibrosis: emerging diagnostic and therapeutic strategies. Mol Aspects Med, 2023, 94: 101227.
6. 杨莹, 徐凯峰, 魏丽娟. 吡非尼酮和尼达尼布在新型冠状病毒感染后肺纤维化中的应用进展. 中国呼吸与危重监护杂志, 2024, 23(8): 593-598.
7. Raghu G, Remy-Jardin M, Richeldi L, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med, 2022, 205(9): e18-e47.
8. Drakopanagiotakis F, Wujak L, Wygrecka M, et al. Biomarkers in idiopathic pulmonary fibrosis. Matrix Biol, 2018, 68: 404-421.
9. Stainer A, Faverio P, Busnelli S, et al. Molecular biomarkers in idiopathic pulmonary fibrosis: state of the art and future directions. Int J Mol Sci, 2021, 22(12): 6255.
10. 范宇斌, 何荣伶, 邹丽君, 等. 生物标志物在特发性肺纤维化中的临床价值. 南方医科大学学报, 2020, 40(7): 1062-1065.
11. O’dwyer DN, Moore BB. The role of periostin in lung fibrosis and airway remodeling. Cell Mol Life Sci, 2017, 74: 4305-4314.
12. Ono J, Takai M, Kamei A, et al. Pathological roles and clinical usefulness of periostin in type 2 inflammation and pulmonary fibrosis. Biomolecules, 2021, 11(8): 1084.
13. 吕长俊, 李洪波, 王晓芝, 等. 特发性肺纤维化与非特异性间质性肺炎的非创伤性鉴别诊断方程. 中华内科杂志, 2010, 49(5): 376-379.
14. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet, 2017, 389(10082): 1941-1952.
15. Singh S, Natalini JG, Segal LN. Lung microbial-host interface through the lens of multi-omics. Mucosal Immunol, 2022, 15(5): 837-845.
16. 吴亚娜, 刘东玲, 宋忠阳, 等. 特发性肺纤维化中上皮-间质转化的研究现状. 中国临床药理学杂志, 2023, 39(23): 3499-3503.
17. Salton F, Volpe MC, Confalonieri M. Epithelial–mesenchymal transition in the pathogenesis of idiopathic pulmonary fibrosis. Medicina, 2019, 55(4): 83.
18. 邓艳, 赵红玉, 朱丽萍, 等. 硫酸羟氯喹通过PI3K/AKt/mTOR信号通路对百草枯致小鼠肺纤维化影响. 中国呼吸与危重监护杂志, 2024, 23(3): 192-199.
19. Gao Y, Du T, Yang L, et al. Research progress of KL-6 in respiratory system diseases. Crit Rev Clin Lab Sci, 2024: 1-17.
20. D’alessandro M, Bergantini L, Cameli P, et al. Krebs von den Lungen-6 as a biomarker for disease severity assessment in interstitial lung disease: a comprehensive review. Biomark Med, 2020, 14(8): 665-674.
21. Okamoto T, Fujii M, Furusawa H, et al. The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respir Med, 2015, 109(12): 1576-1581.
22. Xu L, Bian W, Gu X, et al. Differing expression of cytokines and tumor markers in combined pulmonary fibrosis and emphysema compared to emphysema and pulmonary fibrosis. COPD, 2017, 14(2): 245-250.
23. 廖明星, 潘瑞琪, 艾承锦, 等. 肺纤维化血清 KL-6, TGF-β, CXCL13 水平与病变程度的关系及其联合预测价值. 医学研究生学报, 2021, 34(1): 62-67.
24. Sánchez-Díez S, Munoz X, Ojanguren I, et al. YKL-40 and KL-6 levels in serum and sputum of patients diagnosed with hypersensitivity pneumonitis. J Allergy Clin Immunol Pract, 2022, 10(9): 2414-2423.
25. Mulugeta S, Nureki SI, Beers MF. Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. Am J Physiol Lung Cell Mol Physiol, 2015, 309(6): L507-L525.
26. Katzen J, Beers MF. Contributions of alveolar epithelial cell quality control to pulmonary fibrosis. J Clin Invest, 2020, 130(10): 5088-5099.
27. 鲁未, 赵卉, 魏红. 血清KL-6、SP-A、SP-D及MMP-7对特发性肺纤维化的诊断意义及与肺功能的关系. 安徽医科大学学报, 2016, 51(6): 868-872.
28. 苏文瑶, 陈铿铿, 黄永顺, 等. 表面活性蛋白A、D在肺纤维化中的作用研究进展. 中国职业医学, 2021, 48(4): 451-456.
29. Confalonieri P, Volpe MC, Jacob J, et al. Regeneration or repair? The role of alveolar epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cells, 2022, 11(13): 2095.
30. Hamai K, Iwamoto H, Ishikawa N, et al. Comparative study of circulating MMP -7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis. Dis Markers, 2016, 2016: 4759040.
31. Guagliardo R, Perez-Gil J, De SS, et al. Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins. J Control Release, 2018, 291: 116-126.
32. Dare A, King SD, Chen SY. Surfactant protein A promotes western diet-induced hepatic steatosis and fibrosis in mice. Sci Rep, 2024, 14(1): 7464.
33. 李群, 关为群, 张杨安, 等. 骨膜蛋白和 p53 在口腔白斑及鳞状细胞癌组织中的表达及意义. 国际口腔医学杂志, 2019, 46(1): 5-11.
34. Yoshihara T, Nanri Y, Nunomura S, et al. Periostin plays a critical role in the cell cycle in lung fibroblasts. Respir Res, 2020, 21: 1-12.
35. 刘胜菲, 李龙, 陈凤, 等. 骨膜蛋白在特发性肺纤维化中的研究进展. 中国呼吸与危重监护杂志, 2023, 22(6): 448-451.
36. Carpagnano GE, Soccio P, Scioscia G, et al. The potential role of airways periostin in the clinical Practice of patients affected by idiopathic pulmonary fibrosis. Rejuvenation Res, 2021, 24(4): 302-306.

Chinese Journal of Respiratory and Critical Care Medicine

Comparative study of serum POSTN, KL-6, SP-A, and SP-D as biomarkers of idiopathic pulmonary fibrosis

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