The expression levels and clinical significance of cold-inducible RNA-binding protein and MUC5AC in interstitial lung disease_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

HUANG Lihui ¹ , DONG Jing ² , LIU Xiaoju ² , TAO Huihui ¹ , ZHANG Yi ² ,  BAO Hairong ²

1. First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Pulmonary and Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

BAO Hairong, Email: baohr9301@163.com

Keywords：

Interstitial lung disease; cold-inducible RNA-binding protein; mucin5AC; lung function; blood gas analysis; 6-minute walk distance

DOI：

10.7507/1671-6205.202406072

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Objective To investigate the levels and clinical significance of cold-inducible RNA-binding protein (CIRBP) and mucin 5AC (MUC5AC) in serum and bronchoalveolar lavage fluid (BALF) of patients with interstitial lung disease (ILD). Methods A total of 63 ILD patients who were hospitalized in the Department of Pulmonary and Critical Care Medicine, The First Hospital of Lanzhou University from January 2022 to February 2024 were collected, including 22 patients with idiopathic pulmonary fibrosis (IPF), 20 patients with connective tissue disease-related interstitial lung disease (CTD-ILD), and 21 patients with other types of ILD. Thirty healthy individuals with matching demographic characteristics during the same time period were selected as the healthy group. Enzyme linked immunosorbent assay was used to detect the levels of CIRBP and MUC5AC in serum of healthy group, the levels of CIRBP and MUC5AC in serum and BLAF of ILD patients. The levels of CIRBP and MUC5AC in serum were compared between the healthy group and the ILD group, and the levels of CIRBP and MUC5AC in serum and BALF were compared among the patients with different types of ILD. The correlations were analyzed between the levels of CIRBP and MUC5AC and the lung function, blood gas analysis, and 6-minute walk distance (6MWD) in the patients with different types of ILD. The receiver operating characteristic curve was drawn according to the levels of CIRBP and MUC5AC in serum. The optimal cut-off value, sensitivity and specificity of serum CIRBP and MUC5AC for diagnosis of ILD were determined. Results The serum CIRBP level in the three groups of ILD patients was higher than that of the healthy group (P<0.01), but there was no significant difference in the serum CIRBP level among the three groups of ILD patients (P>0.05). There was no significant difference in serum MUC5AC levels between the three groups of ILD patients and the healthy group, as well as among the three groups of ILD patients (P>0.05). There was no significant difference in the levels of CIRBP and MUC5AC in BALF among the three groups of ILD patients (P>0.05). CIRBP in BALF of the IPF patients was negatively correlated with 6MWD, while CIRBP in serum of the CTD-ILD patients was negatively correlated with partial pressure of oxygen and arterial oxygen saturation. CIRBP in serum of other ILD patients was negatively correlated with total lung capacity as a percentage of predicted value (TLC%pred), forced vital capacity as a percentage of predicted value (FVC%pred), diffusion capacity of carbon monoxide of lung as a percentage of predicted value (D_LCO%pred), and 6MWD, while CIRBP in BALF was negatively correlated with D_LCO%pred. The MUC5AC in BALF of IPF patients was negatively correlated with D_LCO%pred, while the MUC5AC in BALF of CTD-ILD patients was negatively correlated with TLC%pred, D_LCO%pred, and 6MWD. The serum MUC5AC in other ILD patients was negatively correlated with FVC%pred, D_LCO% pred, and 6MWD. The sensitivity was 77.6%, and the specificity was 96.7% for diagnosing ILD with serum CIRBP. Sensitivity was 55.1%, and specificity was 76.7% for diagnosing ILD with serum MUC5AC. The combination of the two indicators resulted in a sensitivity of 87.8% and a specificity of 86.7% for the diagnosis of ILD. Conclusion The high expression levels of CIRBP and MUC5AC have certain diagnostic efficacy and disease assessment effects on ILD, and may serve as potential biomarkers for ILD.

Citation： HUANG Lihui, DONG Jing, LIU Xiaoju, TAO Huihui, ZHANG Yi, BAO Hairong. The expression levels and clinical significance of cold-inducible RNA-binding protein and MUC5AC in interstitial lung disease. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(5): 326-335. doi: 10.7507/1671-6205.202406072 Copy

1.	Pagano AM, Vu T, Berkowitz EA, et al. Evaluation of interstitial lung disease: an algorithmic review using ILD-RADS. Clin Imaging, 2022, 88: 45-52.
2.	Bolourani S, Sari E, Brenner M, et al. Extracellular CIRP induces an inflammatory phenotype in pulmonary fibroblasts via TLR4. Front Immunol, 2021, 12: 721970.
3.	Ballester B, Milara J, Cortijo J. Mucins as a new frontier in pulmonary fibrosis. J Clin Med, 2019, 8(9): 1447.
4.	Chen L, Ran D, Xie W, et al. Cold-inducible RNA-binding protein mediates cold air inducible airway mucin production through TLR4/NF-κB signaling pathway. Int Immunopharmacol, 2016, 39: 48-56.
5.	Juan Y, Haiqiao W, Xie W, et al. Cold-inducible RNA-binding protein mediates airway inflammation and mucus hypersecretion through a post-transcriptional regulatory mechanism under cold stress. Int J Biochem Cell Biol, 2016, 78: 335-348.
6.	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.
7.	Kondoh Y, Makino S, Ogura T, et al. 2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease. Respir Investig, 2021, 59(6): 709-740.
8.	ATS/ERS. American thoracic society/European respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 2002, 165: 277-304.
9.	刘梦影, 王天真, 曹孟淑. 间质性肺疾病的治疗进展. 国际呼吸杂志, 2021, 41(21): 1616-1624.
10.	方楚玲, 徐作军. 特发性肺纤维化的细胞和分子生物学标志的研究进展. 中华结核和呼吸杂志, 2018, 41(4): 303-303.
11.	杨红娇, 董昭兴, 王颖. 特发性肺纤维化生物标志物的研究进展. 中国呼吸与危重监护杂志, 2019, 18(2): 204-208.
12.	中华医学会呼吸病学分会, 中国医师协会呼吸医师分会. 间质性肺疾病多学科讨论规范中国专家共识. 中华结核和呼吸杂志, 2023, 46(12): 1176-1188.
13.	Zhong P, Huang H. Recent progress in the research of cold-inducible RNA-binding protein. Future Sci OA, 2017, 3(4): Fso246.
14.	Qiang X, Yang WL, Wu R, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med, 2013, 19(11): 1489-1495.
15.	Denning NL, Aziz M, Murao A, et al. Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight, 2020, 5(5): e134172.
16.	Hozumi H, Kataoka K, Kondoh Y, et al. Clinical significance of cold-inducible RNA-binding protein in idiopathic pulmonary fibrosis. Chest, 2021, 160(6): 2149-2157.
17.	Omori I, Sumida H, Sugimori A, et al. Serum cold-inducible RNA-binding protein levels as a potential biomarker for systemic sclerosis-associated interstitial lung disease. Sci Rep, 2023, 13(1): 5017.
18.	Ma J, Rubin BK, Voynow JA. Mucins, mucus, and goblet cells. Chest, 2018, 154(1): 169-176.
19.	Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med, 2021, 9(11): 1241-1254.
20.	Cho HY, Park S, Miller L, et al. Role for mucin-5AC in upper and lower airway pathogenesis in mice. Toxicol Pathol, 2021, 49(5): 1077-1099.
21.	Lorenzo-Salazar JM, Ma SF, Jou J, et al. Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing. ERJ Open Res, 2019, 5(2): 00071-2019.
22.	Peng Y, Wang ZN, Xu AR, et al. Mucus hypersecretion and ciliary impairment in conducting airway contribute to alveolar mucus plugging in idiopathic pulmonary fibrosis. Front Cell Dev Biol, 2021, 9: 810842.
23.	Wei L, Zhao J, Bao J, et al. The characteristics and clinical significance of mucin levels in bronchoalveolar lavage fluid of patients with interstitial lung disease. J Investig Med, 2019, 67(4): 761-766.
24.	Weng L, Liu W, Wang L, et al. Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions. Front Immunol, 2022, 13: 987723.

1. Pagano AM, Vu T, Berkowitz EA, et al. Evaluation of interstitial lung disease: an algorithmic review using ILD-RADS. Clin Imaging, 2022, 88: 45-52.
2. Bolourani S, Sari E, Brenner M, et al. Extracellular CIRP induces an inflammatory phenotype in pulmonary fibroblasts via TLR4. Front Immunol, 2021, 12: 721970.
3. Ballester B, Milara J, Cortijo J. Mucins as a new frontier in pulmonary fibrosis. J Clin Med, 2019, 8(9): 1447.
4. Chen L, Ran D, Xie W, et al. Cold-inducible RNA-binding protein mediates cold air inducible airway mucin production through TLR4/NF-κB signaling pathway. Int Immunopharmacol, 2016, 39: 48-56.
5. Juan Y, Haiqiao W, Xie W, et al. Cold-inducible RNA-binding protein mediates airway inflammation and mucus hypersecretion through a post-transcriptional regulatory mechanism under cold stress. Int J Biochem Cell Biol, 2016, 78: 335-348.
6. 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.
7. Kondoh Y, Makino S, Ogura T, et al. 2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease. Respir Investig, 2021, 59(6): 709-740.
8. ATS/ERS. American thoracic society/European respiratory society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 2002, 165: 277-304.
9. 刘梦影, 王天真, 曹孟淑. 间质性肺疾病的治疗进展. 国际呼吸杂志, 2021, 41(21): 1616-1624.
10. 方楚玲, 徐作军. 特发性肺纤维化的细胞和分子生物学标志的研究进展. 中华结核和呼吸杂志, 2018, 41(4): 303-303.
11. 杨红娇, 董昭兴, 王颖. 特发性肺纤维化生物标志物的研究进展. 中国呼吸与危重监护杂志, 2019, 18(2): 204-208.
12. 中华医学会呼吸病学分会, 中国医师协会呼吸医师分会. 间质性肺疾病多学科讨论规范中国专家共识. 中华结核和呼吸杂志, 2023, 46(12): 1176-1188.
13. Zhong P, Huang H. Recent progress in the research of cold-inducible RNA-binding protein. Future Sci OA, 2017, 3(4): Fso246.
14. Qiang X, Yang WL, Wu R, et al. Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis. Nat Med, 2013, 19(11): 1489-1495.
15. Denning NL, Aziz M, Murao A, et al. Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis. JCI Insight, 2020, 5(5): e134172.
16. Hozumi H, Kataoka K, Kondoh Y, et al. Clinical significance of cold-inducible RNA-binding protein in idiopathic pulmonary fibrosis. Chest, 2021, 160(6): 2149-2157.
17. Omori I, Sumida H, Sugimori A, et al. Serum cold-inducible RNA-binding protein levels as a potential biomarker for systemic sclerosis-associated interstitial lung disease. Sci Rep, 2023, 13(1): 5017.
18. Ma J, Rubin BK, Voynow JA. Mucins, mucus, and goblet cells. Chest, 2018, 154(1): 169-176.
19. Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med, 2021, 9(11): 1241-1254.
20. Cho HY, Park S, Miller L, et al. Role for mucin-5AC in upper and lower airway pathogenesis in mice. Toxicol Pathol, 2021, 49(5): 1077-1099.
21. Lorenzo-Salazar JM, Ma SF, Jou J, et al. Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing. ERJ Open Res, 2019, 5(2): 00071-2019.
22. Peng Y, Wang ZN, Xu AR, et al. Mucus hypersecretion and ciliary impairment in conducting airway contribute to alveolar mucus plugging in idiopathic pulmonary fibrosis. Front Cell Dev Biol, 2021, 9: 810842.
23. Wei L, Zhao J, Bao J, et al. The characteristics and clinical significance of mucin levels in bronchoalveolar lavage fluid of patients with interstitial lung disease. J Investig Med, 2019, 67(4): 761-766.
24. Weng L, Liu W, Wang L, et al. Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions. Front Immunol, 2022, 13: 987723.

Chinese Journal of Respiratory and Critical Care Medicine

The expression levels and clinical significance of cold-inducible RNA-binding protein and MUC5AC in interstitial lung disease

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