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

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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.	雷凱春, 岳紅梅, 周婷婷. 特發性肺纖維化治療新進展. 中國呼吸與危重監護雜志, 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.	楊瑩, 徐凱峰, 魏麗娟. 吡非尼酮和尼達尼布在新型冠狀病毒感染后肺纖維化中的應用進展. 中國呼吸與危重監護雜志, 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, 何榮伶, 鄒麗君, 等. 生物標志物在特發性肺纖維化中的臨床價值. 南方醫科大學學報, 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.	呂長俊, 李洪波, 王曉芝, 等. 特發性肺纖維化與非特異性間質性肺炎的非創傷性鑒別診斷方程. 中華內科雜志, 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.	吳亞娜, 劉東玲, 宋忠陽, 等. 特發性肺纖維化中上皮-間質轉化的研究現狀. 中國臨床藥理學雜志, 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.	鄧艷, 趙紅玉, 朱麗萍, 等. 硫酸羥氯喹通過PI3K/AKt/mTOR信號通路對百草枯致小鼠肺纖維化影響. 中國呼吸與危重監護雜志, 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, 艾承錦, 等. 肺纖維化血清 KL-6, TGF-β, CXCL13 水平與病變程度的關系及其聯合預測價值. 醫學研究生學報, 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.	魯未, 趙卉, 魏紅. 血清KL-6、SP-A、SP-D及MMP-7對特發性肺纖維化的診斷意義及與肺功能的關系. 安徽醫科大學學報, 2016, 51(6): 868-872.
28.	蘇文瑤, 陳鏗鏗, 黃永順, 等. 表面活性蛋白A、D在肺纖維化中的作用研究進展. 中國職業醫學, 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, 關為群, 張楊安, 等. 骨膜蛋白和 p53 在口腔白斑及鱗狀細胞癌組織中的表達及意義. 國際口腔醫學雜志, 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.	劉勝菲, 李龍, 陳鳳, 等. 骨膜蛋白在特發性肺纖維化中的研究進展. 中國呼吸與危重監護雜志, 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. 雷凱春, 岳紅梅, 周婷婷. 特發性肺纖維化治療新進展. 中國呼吸與危重監護雜志, 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. 楊瑩, 徐凱峰, 魏麗娟. 吡非尼酮和尼達尼布在新型冠狀病毒感染后肺纖維化中的應用進展. 中國呼吸與危重監護雜志, 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, 何榮伶, 鄒麗君, 等. 生物標志物在特發性肺纖維化中的臨床價值. 南方醫科大學學報, 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. 呂長俊, 李洪波, 王曉芝, 等. 特發性肺纖維化與非特異性間質性肺炎的非創傷性鑒別診斷方程. 中華內科雜志, 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. 吳亞娜, 劉東玲, 宋忠陽, 等. 特發性肺纖維化中上皮-間質轉化的研究現狀. 中國臨床藥理學雜志, 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. 鄧艷, 趙紅玉, 朱麗萍, 等. 硫酸羥氯喹通過PI3K/AKt/mTOR信號通路對百草枯致小鼠肺纖維化影響. 中國呼吸與危重監護雜志, 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, 艾承錦, 等. 肺纖維化血清 KL-6, TGF-β, CXCL13 水平與病變程度的關系及其聯合預測價值. 醫學研究生學報, 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. 魯未, 趙卉, 魏紅. 血清KL-6、SP-A、SP-D及MMP-7對特發性肺纖維化的診斷意義及與肺功能的關系. 安徽醫科大學學報, 2016, 51(6): 868-872.
28. 蘇文瑤, 陳鏗鏗, 黃永順, 等. 表面活性蛋白A、D在肺纖維化中的作用研究進展. 中國職業醫學, 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, 關為群, 張楊安, 等. 骨膜蛋白和 p53 在口腔白斑及鱗狀細胞癌組織中的表達及意義. 國際口腔醫學雜志, 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. 劉勝菲, 李龍, 陳鳳, 等. 骨膜蛋白在特發性肺纖維化中的研究進展. 中國呼吸與危重監護雜志, 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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