6-O-desulfated heparin protects lung injury in septic mice by inhibiting the degradation of endothelial glycocalyx degradation_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIN Xuerong ¹ , WANG Jia ¹ , SHEN Xiaoxing ¹ , WU Yanan ² , ZHANG Qiang ¹ , HAN Ying ¹ ,  XUE Qianlong ¹

1. Department of Emergency Medicine, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P. R. China;
2. Medical Department, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei 075000, P. R. China;

Corresponding?author：

XUE Qianlong, Email: 535999464@qq.com

Keywords：

Sepsis; lung injury; endothelial glycocalyx; 6-o-desulfated heparin; angiopoietin; tyrosine kinase receptor 2

DOI：

10.7507/1671-6205.202510007

Video：

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Objective To investigate the protective effects of 6-O-desulfated heparin (6-DeH) on lung injury in septic mice by inhibiting the degradation of endothelial glycocalyx degradation. Methods BALB/c mice were divided into a sham group, a sepsis group, and a sepsis+6-DeH group. Cecal perforation surgery was used to establish sepsis model. After modeling, the sepsis+6-DeH group was given 2 mL of 5 g/L 6-DeH solution for nebulized inhalation, while the sham group and the sepsis group were given 2 mL of normal saline for nebulized inhalation, once every other day. Lung wet/dry weight ratio, protein concentration in bronchoalveolar lavage fluid (BALF), pathological changes of lung tissue, protein expression levels of CD31, thromboxomodulin (TM), hyaluronic acid (HA), heparan sulfate (HS), syndecan-1, glypican, angiopoietin 1 (Ang1), angiopoietin 2 (Ang2), Tie2 in lung tissue, co-localization of CD31 and syndecan-1 were detected at 14 days of intervention. Results Lung wet/dry weight ratio, protein concentration in BALF, protein expression level of Ang2 in lung tissue of the sepsis group were all significantly higher than those of the sham group, while protein expression levels of CD31, TM, HA, HS, syndecan-1, glypican, Ang1 and Tie2 in lung tissue were significantly lower than those of the sham group (all P<0.05). Lung wet/dry weight ratio, protein concentration in BALF, protein expression level of Ang2 in lung tissue of the sepsis+6-DeH group were all lower than those of the sepsis group, while protein expression levels of CD31, TM, HA, HS, syndecan-1, glypican, Ang1 and Tie2 in lung tissue were all higher than those of the sepsis group (all P<0.05). Immunofluorescence revealed co-localization of CD31 and syndecan-1 in lung tissue. Conclusions 6-DeH alleviates lung injury and inhibits degradation of endothelial glycocalyx in pulmonary blood vessels in septic mice. This effect is related to the regulation of the Ang/Tie2 pathway.

Citation： LIN Xuerong, WANG Jia, SHEN Xiaoxing, WU Yanan, ZHANG Qiang, HAN Ying, XUE Qianlong. 6-O-desulfated heparin protects lung injury in septic mice by inhibiting the degradation of endothelial glycocalyx degradation. Chinese Journal of Respiratory and Critical Care Medicine, 2026, 25(5): 336-341. doi: 10.7507/1671-6205.202510007 Copy

1.	Zhu Z, Zhang Y, Chen H, et al. Cell-cell crosstalk in the pathogenesis of acute lung injury and acute respiratory distress syndrome. Tissue Barriers, 2025, 11: 2452082.
2.	Qiao X, Yin J, Zheng Z, et al. Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications. Cell Commun Signal, 2024, 22(1): 241.
3.	陳加弟, 龔迪, 易玉虎, 等. 血管內皮糖萼在膿毒癥急性肺損傷病理機制及診斷治療中的作用. 解放軍醫學雜志, 2021, 46(4): 398-403.
4.	Lu Z, Fang P, Li S, et al. Lactylation of histone H3k18 and Egr1 promotes endothelial glycocalyx degradation in sepsis-induced acute lung injury. Adv Sci, 2025, 12(7): e2407064.
5.	de Oliveira JGCG, Miranda CH. Doxycycline protects against sepsis-induced endothelial glycocalyx shedding. Sci Rep, 2024, 14(1): 10477.
6.	楊晶, 劉曉妮, 吳青青, 等. 6-O-脫硫酸化肝素通過Syndecan-1/c-Met/Akt途徑延緩博來霉素誘導的肺損傷. 中國藥理學通報, 2022, 38(8): 1147-1155.
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8.	Witzemann A, Uzun G, Wolska N, et al. Intravenous immunoglobulin prevents thrombosis in an endothelialized disease model of heparin-induced thrombocytopenia. J Thromb Haemost, 2025, 23(5): 1657-1666.
9.	Liu Y, Zhou M, Cheng H, et al. Effect of low-molecular-weight heparin calcium combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function and pregnancy outcome in early-onset severe preeclampsia. Eur J Clin Pharmacol, 2024, 80(10): 1495-1501.
10.	Wang Y, Li T, Li N, et al. 6-O-desulfated heparin attenuates myocardial ischemia/reperfusion injury in mice through the regulation of miR-199a-5p/klotho axis. Glycoconj J, 2022, 39(6): 747-758.
11.	Wang Y, Qu R, Du W, et al. In Situ bioorthogonal repair of the vascular endothelium glycocalyx to treat acute lung injury. Small, 2024, 20(49): e2405092.
12.	Machin DR, Sabouri M, Zheng X, et al. Therapeutic strategies targeting the endothelial glycocalyx. Curr Opin Clin Nutr Metab Care, 2023, 26(6): 543-550.
13.	Li Z, Jiang X, Li J, et al. Correlation of hyaluronic acid (HA), syndecan-1 (SDC-1), heparan sulfate (HS) with early stage end organ dysfunction in sepsis patients. J Cardiovasc Pharmacol, 2025, 85(2): 129-136.
14.	Qian X, Lui KY, Hu X, et al. Dynamic changes and prognosis value of plasma syndecan-1 and different microcirculatory parameters in sepsis: A prospective observational study. World J Surg, 2025, 49(2): 353-363.
15.	Yin J, Chi Y, Liu D, et al. Unfractionated heparin attenuated histone-induced pulmonary endothelial glycocalyx injury through Ang/Tie2 pathway. J Inflamm, 2025, 22(1): 9.
16.	Qiu Y, Buffonge S, Ramnath R, et al. Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice. Diabetologia, 2022, 65(5): 879-894.
17.	Wang R, Li H, Xie Z, et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice. Sci Adv, 2025, 11(3): eads1796.
18.	Suzuki T, Loyde E, Chen S, et al. Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis. J Clin Invest, 2025, 135(8): e174135.

1. Zhu Z, Zhang Y, Chen H, et al. Cell-cell crosstalk in the pathogenesis of acute lung injury and acute respiratory distress syndrome. Tissue Barriers, 2025, 11: 2452082.
2. Qiao X, Yin J, Zheng Z, et al. Endothelial cell dynamics in sepsis-induced acute lung injury and acute respiratory distress syndrome: pathogenesis and therapeutic implications. Cell Commun Signal, 2024, 22(1): 241.
3. 陳加弟, 龔迪, 易玉虎, 等. 血管內皮糖萼在膿毒癥急性肺損傷病理機制及診斷治療中的作用. 解放軍醫學雜志, 2021, 46(4): 398-403.
4. Lu Z, Fang P, Li S, et al. Lactylation of histone H3k18 and Egr1 promotes endothelial glycocalyx degradation in sepsis-induced acute lung injury. Adv Sci, 2025, 12(7): e2407064.
5. de Oliveira JGCG, Miranda CH. Doxycycline protects against sepsis-induced endothelial glycocalyx shedding. Sci Rep, 2024, 14(1): 10477.
6. 楊晶, 劉曉妮, 吳青青, 等. 6-O-脫硫酸化肝素通過Syndecan-1/c-Met/Akt途徑延緩博來霉素誘導的肺損傷. 中國藥理學通報, 2022, 38(8): 1147-1155.
7. Yang R, Zhang X. A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Front Cell Infect Microbiol, 2022, 15(12): 984835.
8. Witzemann A, Uzun G, Wolska N, et al. Intravenous immunoglobulin prevents thrombosis in an endothelialized disease model of heparin-induced thrombocytopenia. J Thromb Haemost, 2025, 23(5): 1657-1666.
9. Liu Y, Zhou M, Cheng H, et al. Effect of low-molecular-weight heparin calcium combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function and pregnancy outcome in early-onset severe preeclampsia. Eur J Clin Pharmacol, 2024, 80(10): 1495-1501.
10. Wang Y, Li T, Li N, et al. 6-O-desulfated heparin attenuates myocardial ischemia/reperfusion injury in mice through the regulation of miR-199a-5p/klotho axis. Glycoconj J, 2022, 39(6): 747-758.
11. Wang Y, Qu R, Du W, et al. In Situ bioorthogonal repair of the vascular endothelium glycocalyx to treat acute lung injury. Small, 2024, 20(49): e2405092.
12. Machin DR, Sabouri M, Zheng X, et al. Therapeutic strategies targeting the endothelial glycocalyx. Curr Opin Clin Nutr Metab Care, 2023, 26(6): 543-550.
13. Li Z, Jiang X, Li J, et al. Correlation of hyaluronic acid (HA), syndecan-1 (SDC-1), heparan sulfate (HS) with early stage end organ dysfunction in sepsis patients. J Cardiovasc Pharmacol, 2025, 85(2): 129-136.
14. Qian X, Lui KY, Hu X, et al. Dynamic changes and prognosis value of plasma syndecan-1 and different microcirculatory parameters in sepsis: A prospective observational study. World J Surg, 2025, 49(2): 353-363.
15. Yin J, Chi Y, Liu D, et al. Unfractionated heparin attenuated histone-induced pulmonary endothelial glycocalyx injury through Ang/Tie2 pathway. J Inflamm, 2025, 22(1): 9.
16. Qiu Y, Buffonge S, Ramnath R, et al. Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice. Diabetologia, 2022, 65(5): 879-894.
17. Wang R, Li H, Xie Z, et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice. Sci Adv, 2025, 11(3): eads1796.
18. Suzuki T, Loyde E, Chen S, et al. Cathepsin K cleavage of angiopoietin-2 creates detrimental Tie2 antagonist fragments in sepsis. J Clin Invest, 2025, 135(8): e174135.

Chinese Journal of Respiratory and Critical Care Medicine

6-O-desulfated heparin protects lung injury in septic mice by inhibiting the degradation of endothelial glycocalyx degradation

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