血小板介導的免疫血栓在慢性阻塞性肺疾病相關肺動脈高壓中的作用機制_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

QIN Yu ¹ ,  YUE Hongmei ^1,2 , WANGY ongqing ¹ , ZHU Zhangfan ¹ , YANG Fan ¹

1. ;
2. ;

Corresponding?author：

YUE Hongmei, Email: yuehongmei18@sina.com

Keywords：

DOI：

10.7507/1671-6205.202512092

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Citation： QIN Yu, YUE Hongmei, WANGY ongqing, ZHU Zhangfan, YANG Fan. 血小板介導的免疫血栓在慢性阻塞性肺疾病相關肺動脈高壓中的作用機制. Chinese Journal of Respiratory and Critical Care Medicine, 2026, 25(7): 532-536. doi: 10.7507/1671-6205.202512092 Copy

1.	Venkatesan P. GOLD COPD report: 2024 update. Lancet Respir Med, 2024, 12(1): 15-16.
2.	Shlobin OA, Adir Y, Barbera JA, et al. Pulmonary hypertension associated with lung diseases. Eur Respir J, 2024, 64(4).
3.	Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax, 2016, 71(9): 830.
4.	Lin P, Huang H, Hu M, et al. Prostate tissue-induced platelet activation and platelet–neutrophil aggregation following transurethral resection of the prostate surgery: an in vitro study. Biomedicines, 2025, 13(4): 1006.
5.	Duler L, Visser L, Nguyen N, et al. Platelet hyperresponsiveness and increased platelet‐neutrophil aggregates in dogs with myxomatous mitral valve disease and pulmonary hypertension. J Vet Intern Med, 2024, 38(4): 2052-2063.
6.	Chaurasia SN, Kushwaha G, Kulkarni PP, et al. Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release. Haematologica, 2019, 104(12): 2482-2492.
7.	Tyagi T, Ahmad S, Gupta N, et al. Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype. Blood, 2014, 123(8): 1250-1260.
8.	Wang M, McGraw KR, Monticone R E, et al. Unraveling elastic fiber-derived signaling in arterial aging and related arterial diseases. Biomolecules, 2025, 15(2): 153.
9.	Marques P, Bocigas I, Domingo E, et al. Key role of activated platelets in the enhanced adhesion of circulating leucocyte-platelet aggregates to the Front. Immunol, 2024, 15: 1441637.
10.	Hardy M, Douxfils J, Xhaet O, et al. Development and validation of an in vitro model to study thrombin generation on the surface of catheters in platelet-poor and platelet-rich plasma. Thromb Res, 2024, 244: 109194.
11.	Smith CW. Release of α-granule contents during platelet activation. Platelets, 2022, 33(4): 491-502.
12.	Flieder T, von Bargen K, Zimmermann M, et al. Investigating platelet-leukocyte-aggregate formation under shear stress conditions in vitro and in vivo. H? mostaseologie, 2024, 44(S01): 3.
13.	Wallis S, Wolska N, Englert H, et al. A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes. J Thromb Haemost, 2022, 20(3): 729-741.
14.	Jin R, Yu S, Song Z, et al. Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst. PLoS One, 2013, 8(6): e64631.
15.	Wang Y, Gao H, Shi C, et al. Corrigendum: Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun, 2017, 8: 16124.
16.	Li H, Shan W, Zhao X, et al. Neutrophils: Linking Inflammation to Thrombosis and Unlocking New Treatment Horizons. Int J Mol Sci, 2025, 26(5).
17.	Na? J, Terglane J, Gerke V. Weibel Palade bodies: unique secretory organelles of endothelial cells that control blood vessel homeostasis. Cell Dev Biol, 2021, 9: 813995.
18.	Zhang J, DeMeo DL, Silverman EK, et al. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors. BMC Pulm Med, 2021, 21(1): 235.
19.	Trivedi A, Khan MA, Bade G, et al. Orchestration of neutrophil extracellular traps (Nets), a unique innate immune function during chronic obstructive pulmonary disease (COPD) development. Biomedicines, 2021, 9(1): 53.
20.	Aldabbous L, Abdul-Salam V, McKinnon T, et al. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2016, 36(10): 2078-2087.
21.	Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018, 18(2): 134-147.
22.	Li Z, Wang S, Bai Y, et al. Neutrophil extravasation and NETosis in decompression illness lung injury: A P-selectin/PSGL-1/NOX2/PAD4 axis governed pathway validated by multi-model interrogation. A Free Radic Biol Med, 2025, 239: 14-26.
23.	Matsumoto K, Yasuoka H, Yoshimoto K, et al. Platelet CXCL4 mediates neutrophil extracellular traps formation in ANCA-associated vasculitis. Sci Rep, 2021, 11(1): 222.
24.	Zhan Y, Ling Y, Deng Q, et al. HMGB1-mediated neutrophil extracellular trap formation exacerbates intestinal ischemia/reperfusion-induced acute lung injury. J Immunol, 2022, 208(4): 968-978.
25.	Wienkamp A, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol, 2022, 13: 953129.
26.	Sennett C, Pula G. Trapped in the NETs: multiple roles of platelets in the vascular complications associated with neutrophil extracellular traps. Cells, 2025, 14(5): 335.
27.	Zhang Z, Hu J, Bai Y, et al. Emerging molecular targets in deep vein thrombosis: from inflammation to coagulation. Hematology, 2025, 30(1): 2548735.
28.	Bun M, Kawano M, Yamamoto G, et al. G-CSF induces neutrophil extracellular traps formation and promotes ovarian cancer peritoneal dissemination. J Leukoc Biol, 2024, 116(5): 1157-1168.
29.	Sharma S, Hofbauer TM, Ondracek AS, et al. Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis. Blood, 2021, 137(8): 1104-1116.
30.	Sweatt AJ, Miyagawa K, Rhodes CJ, et al. Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency. Chest, 2021, 160(4): 1442-1458.
31.	Chang C, Hsu H, Ho W, et al. Cathepsin S promotes the development of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol, 2019, 317(1): L1-L13.
32.	Taylor S, Isobe S, Cao A, et al. Endogenous retroviral elements generate pathologic neutrophils in pulmonary arterial hypertension. Am J Respir Crit Care Med, 2022, 206(8): 1019-1034.
33.	Zimmer A, Teixeira RB, Constantin RL, et al. The progression of pulmonary arterial hypertension induced by monocrotaline is characterized by lung nitrosative and oxidative stress, and impaired pulmonary artery reactivity. Eur J Pharmacol, 2021, 891: 173699.
34.	Tiyerili V, Camara B, Becher MU, et al. Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice. Int J Cardiol, 2016, 204: 29-36.
35.	Le Page A, Khalil A, Vermette P, et al. The role of elastin-derived peptides in human physiology and diseases. Matrix Biol, 2019, 84: 81-96.
36.	Carmona-Rivera C, Zhao W, Yalavarthi S, et al. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis, 2015, 74(7): 1417-1424.
37.	Wang Y, Du C, Zhang Y, et al. Composition and function of neutrophil extracellular traps. Biomolecules, 2024, 14(4): 416.
38.	Dutzmann J, Daniel J M, Korte L, et al. Adventitial fibroblasts release interleukin 6 after vascular injury and induce smooth muscle cell proliferation and neointima formation. J Am Heart Assoc, 2025, 14(14): e40143.
39.	Schwiening M, Swietlik EM, Pandya D, et al. Direct influence of BMPR2 mutations on cytokine patterns and biomarker effectiveness in pulmonary arterial hypertension. medRxiv, 2021: 2021-2025.
40.	Xu W, Wu Q, He W, et al. Interleukin-6 and pulmonary hypertension: from physiopathology to therapy. Front Immunol, 2023, 14: 1181987.
41.	Rong W, Liu C, Li X, et al. Caspase-8 promotes pulmonary hypertension by activating macrophage-associated inflammation and IL-1β (interleukin 1β) production. Arterioscler Thromb Vasc Biol, 2022, 42(5): 613-631.
42.	Dinc R, Ardic N. Molecular and cellular mechanisms of neutrophil extracellular traps in cardiovascular diseases: from NET formation to mechanistic therapeutic targeting. Biocell, 2026, 50(1): 0327-9545.
43.	Wang J, Li L, Xu J, et al. Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury. Theranostics, 2025, 15(17): 9221-9239.
44.	Sun H, Du Z, Zhang X, et al. Neutrophil extracellular traps promote proliferation of pulmonary smooth muscle cells mediated by CCDC25 in pulmonary arterial hypertension. Respir Res, 2024, 25(1): 183.
45.	Chen WA, Boskovic DS. Neutrophil extracellular DNA traps in response to infection or inflammation, and the roles of platelet interactions. Int J Mol Sci, 2024, 25(5): 3025.
46.	徐婉婷, 江曉琴, 朱濤. 肺動脈高壓的治療進展. 中國呼吸與危重監護雜志, 2024, 23(4): 287-292.
47.	Escopy S, Chaikof EL. Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation. Blood Vessels Thromb Hemost, 2024, 1(3): 100015.
48.	Li X, Ma Y, Wang D. The role of P-selectin/PSGL-1 in regulating NETs as a novel mechanism in cerebral ischemic injury. Front Neurol, 2024, 15: 1442613.
49.	Jiménez-Alcázar M, Rangaswamy C, Panda R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science, 2017, 358(6367): 1202-1206.
50.	Bonilha CS, Veras FP, de Queiroz Cunha F. NET-targeted therapy: effects, limitations, and potential strategies to enhance treatment efficacy. Trends Pharmacol Sci, 2023, 44(9): 622-634.
51.	王敏, 劉子雯, 張苗條, 等. 新型納米藥物遞送系統在低氧性肺動脈高壓治療中的研究進展. 心臟雜志, 2025, 37(6): 708-715.
52.	Baptista De Barros Ribeiro Dourado LP, Santos M, Moreira-Gon?alves D. Nets, pulmonary arterial hypertension, and thrombo-inflammation. J Mol Med, 2022, 100(5): 713-722.

1. Venkatesan P. GOLD COPD report: 2024 update. Lancet Respir Med, 2024, 12(1): 15-16.
2. Shlobin OA, Adir Y, Barbera JA, et al. Pulmonary hypertension associated with lung diseases. Eur Respir J, 2024, 64(4).
3. Coste F, Dournes G, Dromer C, et al. CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension. Thorax, 2016, 71(9): 830.
4. Lin P, Huang H, Hu M, et al. Prostate tissue-induced platelet activation and platelet–neutrophil aggregation following transurethral resection of the prostate surgery: an in vitro study. Biomedicines, 2025, 13(4): 1006.
5. Duler L, Visser L, Nguyen N, et al. Platelet hyperresponsiveness and increased platelet‐neutrophil aggregates in dogs with myxomatous mitral valve disease and pulmonary hypertension. J Vet Intern Med, 2024, 38(4): 2052-2063.
6. Chaurasia SN, Kushwaha G, Kulkarni PP, et al. Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release. Haematologica, 2019, 104(12): 2482-2492.
7. Tyagi T, Ahmad S, Gupta N, et al. Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype. Blood, 2014, 123(8): 1250-1260.
8. Wang M, McGraw KR, Monticone R E, et al. Unraveling elastic fiber-derived signaling in arterial aging and related arterial diseases. Biomolecules, 2025, 15(2): 153.
9. Marques P, Bocigas I, Domingo E, et al. Key role of activated platelets in the enhanced adhesion of circulating leucocyte-platelet aggregates to the Front. Immunol, 2024, 15: 1441637.
10. Hardy M, Douxfils J, Xhaet O, et al. Development and validation of an in vitro model to study thrombin generation on the surface of catheters in platelet-poor and platelet-rich plasma. Thromb Res, 2024, 244: 109194.
11. Smith CW. Release of α-granule contents during platelet activation. Platelets, 2022, 33(4): 491-502.
12. Flieder T, von Bargen K, Zimmermann M, et al. Investigating platelet-leukocyte-aggregate formation under shear stress conditions in vitro and in vivo. H? mostaseologie, 2024, 44(S01): 3.
13. Wallis S, Wolska N, Englert H, et al. A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes. J Thromb Haemost, 2022, 20(3): 729-741.
14. Jin R, Yu S, Song Z, et al. Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ) in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst. PLoS One, 2013, 8(6): e64631.
15. Wang Y, Gao H, Shi C, et al. Corrigendum: Leukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα. Nat Commun, 2017, 8: 16124.
16. Li H, Shan W, Zhao X, et al. Neutrophils: Linking Inflammation to Thrombosis and Unlocking New Treatment Horizons. Int J Mol Sci, 2025, 26(5).
17. Na? J, Terglane J, Gerke V. Weibel Palade bodies: unique secretory organelles of endothelial cells that control blood vessel homeostasis. Cell Dev Biol, 2021, 9: 813995.
18. Zhang J, DeMeo DL, Silverman EK, et al. Secondary polycythemia in chronic obstructive pulmonary disease: prevalence and risk factors. BMC Pulm Med, 2021, 21(1): 235.
19. Trivedi A, Khan MA, Bade G, et al. Orchestration of neutrophil extracellular traps (Nets), a unique innate immune function during chronic obstructive pulmonary disease (COPD) development. Biomedicines, 2021, 9(1): 53.
20. Aldabbous L, Abdul-Salam V, McKinnon T, et al. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol, 2016, 36(10): 2078-2087.
21. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol, 2018, 18(2): 134-147.
22. Li Z, Wang S, Bai Y, et al. Neutrophil extravasation and NETosis in decompression illness lung injury: A P-selectin/PSGL-1/NOX2/PAD4 axis governed pathway validated by multi-model interrogation. A Free Radic Biol Med, 2025, 239: 14-26.
23. Matsumoto K, Yasuoka H, Yoshimoto K, et al. Platelet CXCL4 mediates neutrophil extracellular traps formation in ANCA-associated vasculitis. Sci Rep, 2021, 11(1): 222.
24. Zhan Y, Ling Y, Deng Q, et al. HMGB1-mediated neutrophil extracellular trap formation exacerbates intestinal ischemia/reperfusion-induced acute lung injury. J Immunol, 2022, 208(4): 968-978.
25. Wienkamp A, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol, 2022, 13: 953129.
26. Sennett C, Pula G. Trapped in the NETs: multiple roles of platelets in the vascular complications associated with neutrophil extracellular traps. Cells, 2025, 14(5): 335.
27. Zhang Z, Hu J, Bai Y, et al. Emerging molecular targets in deep vein thrombosis: from inflammation to coagulation. Hematology, 2025, 30(1): 2548735.
28. Bun M, Kawano M, Yamamoto G, et al. G-CSF induces neutrophil extracellular traps formation and promotes ovarian cancer peritoneal dissemination. J Leukoc Biol, 2024, 116(5): 1157-1168.
29. Sharma S, Hofbauer TM, Ondracek AS, et al. Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis. Blood, 2021, 137(8): 1104-1116.
30. Sweatt AJ, Miyagawa K, Rhodes CJ, et al. Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency. Chest, 2021, 160(4): 1442-1458.
31. Chang C, Hsu H, Ho W, et al. Cathepsin S promotes the development of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol, 2019, 317(1): L1-L13.
32. Taylor S, Isobe S, Cao A, et al. Endogenous retroviral elements generate pathologic neutrophils in pulmonary arterial hypertension. Am J Respir Crit Care Med, 2022, 206(8): 1019-1034.
33. Zimmer A, Teixeira RB, Constantin RL, et al. The progression of pulmonary arterial hypertension induced by monocrotaline is characterized by lung nitrosative and oxidative stress, and impaired pulmonary artery reactivity. Eur J Pharmacol, 2021, 891: 173699.
34. Tiyerili V, Camara B, Becher MU, et al. Neutrophil-derived myeloperoxidase promotes atherogenesis and neointima formation in mice. Int J Cardiol, 2016, 204: 29-36.
35. Le Page A, Khalil A, Vermette P, et al. The role of elastin-derived peptides in human physiology and diseases. Matrix Biol, 2019, 84: 81-96.
36. Carmona-Rivera C, Zhao W, Yalavarthi S, et al. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis, 2015, 74(7): 1417-1424.
37. Wang Y, Du C, Zhang Y, et al. Composition and function of neutrophil extracellular traps. Biomolecules, 2024, 14(4): 416.
38. Dutzmann J, Daniel J M, Korte L, et al. Adventitial fibroblasts release interleukin 6 after vascular injury and induce smooth muscle cell proliferation and neointima formation. J Am Heart Assoc, 2025, 14(14): e40143.
39. Schwiening M, Swietlik EM, Pandya D, et al. Direct influence of BMPR2 mutations on cytokine patterns and biomarker effectiveness in pulmonary arterial hypertension. medRxiv, 2021: 2021-2025.
40. Xu W, Wu Q, He W, et al. Interleukin-6 and pulmonary hypertension: from physiopathology to therapy. Front Immunol, 2023, 14: 1181987.
41. Rong W, Liu C, Li X, et al. Caspase-8 promotes pulmonary hypertension by activating macrophage-associated inflammation and IL-1β (interleukin 1β) production. Arterioscler Thromb Vasc Biol, 2022, 42(5): 613-631.
42. Dinc R, Ardic N. Molecular and cellular mechanisms of neutrophil extracellular traps in cardiovascular diseases: from NET formation to mechanistic therapeutic targeting. Biocell, 2026, 50(1): 0327-9545.
43. Wang J, Li L, Xu J, et al. Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury. Theranostics, 2025, 15(17): 9221-9239.
44. Sun H, Du Z, Zhang X, et al. Neutrophil extracellular traps promote proliferation of pulmonary smooth muscle cells mediated by CCDC25 in pulmonary arterial hypertension. Respir Res, 2024, 25(1): 183.
45. Chen WA, Boskovic DS. Neutrophil extracellular DNA traps in response to infection or inflammation, and the roles of platelet interactions. Int J Mol Sci, 2024, 25(5): 3025.
46. 徐婉婷, 江曉琴, 朱濤. 肺動脈高壓的治療進展. 中國呼吸與危重監護雜志, 2024, 23(4): 287-292.
47. Escopy S, Chaikof EL. Targeting the P-selectin/PSGL-1 pathway: discovery of disease-modifying therapeutics for disorders of thromboinflammation. Blood Vessels Thromb Hemost, 2024, 1(3): 100015.
48. Li X, Ma Y, Wang D. The role of P-selectin/PSGL-1 in regulating NETs as a novel mechanism in cerebral ischemic injury. Front Neurol, 2024, 15: 1442613.
49. Jiménez-Alcázar M, Rangaswamy C, Panda R, et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science, 2017, 358(6367): 1202-1206.
50. Bonilha CS, Veras FP, de Queiroz Cunha F. NET-targeted therapy: effects, limitations, and potential strategies to enhance treatment efficacy. Trends Pharmacol Sci, 2023, 44(9): 622-634.
51. 王敏, 劉子雯, 張苗條, 等. 新型納米藥物遞送系統在低氧性肺動脈高壓治療中的研究進展. 心臟雜志, 2025, 37(6): 708-715.
52. Baptista De Barros Ribeiro Dourado LP, Santos M, Moreira-Gon?alves D. Nets, pulmonary arterial hypertension, and thrombo-inflammation. J Mol Med, 2022, 100(5): 713-722.

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慢性阻塞性肺疾病合并肌少癥的診斷及治療進展

Chinese Journal of Respiratory and Critical Care Medicine

血小板介導的免疫血栓在慢性阻塞性肺疾病相關肺動脈高壓中的作用機制

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