张金婷,王卓亚

低氧性肺动脉高压（HPH）是一种常见的肺血管疾病，多发生在罹患慢性肺部疾病或长期生活于慢性低氧环境中，如高原地区，随着病情的发展可导致右心室功能衰竭而危及生命。然而，参与该疾病的机制很多，主要包括缺氧诱导的血管收缩、血小板活化和炎症反应。血小板在低氧环境下参与了肺动脉平滑肌细胞的增殖和迁移，促进炎症反应的发生，通过释放血小板源性生长因子和血管活性物质来调节炎症细胞的活化和迁移，这些发现为HPH的发病机制提供了新的认识。本综述将对低氧诱导因子、血小板及炎症反应在HPH中的扮演的角色进行深入探讨，挖掘对HPH有效的、新型的治疗靶点。

低氧性肺动脉高压；血小板；炎症反应；低氧诱导因子

[1] HUMBERT M,KOVACS G,HOEPER M M,et al.2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension[J].Eur Heart J,2022,43(38):3618-731. [2] ZEIDAN E M,HOSSAIN M A,EL-DALY M,et al.Mitochondrial Regulation of the Hypoxia-Inducible Factor in the Development of Pulmonary Hypertension[J].J Clin Med,2022,11(17). [3] ALBANESE A,DALY L A,MENNERICH D,et al.The Role of Hypoxia-Inducible Factor Post-Translational Modifications in Regulating Its Localisation,Stability,and Activity[J].Int J Mol Sci,2020,22(1). [4] KIERANS S J,TAYLOR C T.Regulation of glycolysis by the hypoxia-inducible factor(HIF):implications for cellular physiology[J].J Physiol,2021,599(1):23-37. [5] NISAR A,KHAN S,LI W,et al.Hypoxia and aging:molecular mechanisms,diseases,and therapeutic targets[J].MedComm(2020),2024,5(11):e786. [6] DAI Z,CHENG J,LIU B,et al.Loss of Endothelial Hypoxia Inducible Factor-Prolyl Hydroxylase 2 Induces Cardiac Hypertrophy and Fibrosis[J].J Am Heart Assoc,2021,10(22):e022077. [7] ELAMAA H,KAAKINEN M,NäTYNKI M,et al.PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis[J].Angiogenesis,2022,25(2):259-74. [8] LIU H,WANG Y,ZHANG Q,et al.Macrophage-derived inflammation promotes pulmonary vascular remodeling in hypoxia-induced pulmonary arterial hypertension mice[J].Immunol Lett,2023,263:113-22. [9] ZHANG G,MA L,BAI L,et al.Inflammatory microenvironment-targeted nanotherapies[J].J Control Release,2021,334:114-26. [10] HEO J,KANG H.Platelet-derived growth factor-stimulated pulmonary artery smooth muscle cells regulate pulmonary artery endothelial cell dysfunction through extracellular vesicle miR-409-5p[J].Biol Chem,2024,405(3):203-15. [11] LIU C,CHEN J,HUANG X,et al.lncRNA VELRP Modulates Pulmonary Arterial Smooth Muscle Cell Proliferation and Promotes Vascular Remodeling in Pulmonary Hypertension[J].Arterioscler Thromb Vasc Biol,2024,44(12):2560-76. [12] SONG J L,ZHENG S Y,HE R L,et al.Serotonin and chronic hypoxic pulmonary hypertension activate a NADPH oxidase 4 and TRPM2 dependent pathway for pulmonary arterial smooth muscle cell proliferation and migration[J].Vascul Pharmacol,2021,138:106860. [13] DELANEY C,DAVIZON-CASTILLO P,ALLAWZI A,et al.Platelet activation contributes to hypoxia-induced inflammation[J].Am J Physiol Lung Cell Mol Physiol,2021,320(3):L413-l21. [14] JURK K,KEHREL B E.Platelets:Physiology and Biochemistry[J].Semin Thromb Hemost,2024,50(5):794-803. [15] LI H,ZHANG S,HUANG X,et al.Genetic recording of transient endothelial activation in distinct alveolar capillary cells during pulmonary fibrosis[J].Cell Discov,2024,10(1):119. [16] YU B,WANG X,SONG Y,et al.The role of hypoxia-inducible factors in cardiovascular diseases[J].Pharmacol Ther,2022,238:108186. [17] GU W,QI J,ZHANG S,et al.Inhibition of Hypoxia-Inducible Factor Prolyl-Hydroxylase Modulates Platelet Function[J].Thromb Haemost,2022,122(10):1693-705. [18] WU L,GUO N,XU Z,et al.Low arterial oxygen partial pressure induces pulmonary thrombocytopenia in patients and a mouse model[J].BMC Pulm Med,2021,21(1):3. [19] GE X,ZHANG W,ZHU T,et al.Hypoxia-activated platelets stimulate proliferation and migration of pulmonary arterial smooth muscle cells by phosphatidylserine/LOX-1 signaling-impelled intercellular communication[J].Cell Signal,2021,87:110149. [20] LIANG S,DESAI A A,BLACK S M,et al.Cytokines,Chemokines,and Inflammation in Pulmonary Arterial Hypertension[J].Adv Exp Med Biol,2021,1303:275-303. [21] MACKAY C D A,MEECHEM M B,PATEL V B.Macrophages in vascular disease:Roles of mitochondria and metabolic mechanisms[J]. Vascul Pharmacol,2024,156:107419. [22] LI C,LIU P,YAO H,et al.Regulatory B cells protect against chronic hypoxia-induced pulmonary hypertension by modulating the Tfh/Tfr immune balance[J].Immunology,2023,168(4):580-96. [23] EL ALAM S,PENA E,AGUILERA D,et al.Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure[J].Int J Mol Sci,2022,23(20). [24] MA W,MA Y,BAI Y,et al.Changes in Macrophages in Pulmonary Hypertension:A Focus on High-altitude Pulmonary Hypertension[J]. Anatol J Cardiol,2025. [25] SUN Y,ZHANG C,TIAN D,et al.Application of 7.0 T ultra-high-field MRI in evaluating the structure and function of the right ventricle of the heart in rats under a chronic hypoxic environment at high altitude[J].Ann Transl Med,2021,9(20):1585. [26] KNOPP T,JUNG R,WILD J,et al.Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation[J].Eur Heart J Open,2024,4(4):oeae046. [27] HUANG W,LIU H,PAN Y,et al.Mechanical stretching of the pulmonary vein mediates pulmonary hypertension due to left heart disease by regulating SAC/MAPK pathway and the expression of IL-6 and TNF-α[J].J Cardiothorac Surg,2021,16(1):127. [28] ROGER I,MILARA J,MONTERO P,et al.The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension[J].Int J Mol Sci,2021,22(9). [29] BEGUM R,THOTA S,ABDULKADIR A,et al.NADPH oxidase family proteins:signaling dynamics to disease management[J]. [30] ZHANG Z,ZHANG Y,CAI Y,et al.NAT10 regulates the LPS-induced inflammatory response via the NOX2-ROS-NF-κB pathway in macrophages[J].Biochim Biophys Acta Mol Cell Res,2023,1870(7):119521. [31] BAI B,YANG Y,WANG Q,et al.NLRP3 inflammasome in endothelial dysfunction[J].Cell Death Dis,2020,11(9):776. [32] FU J,WU H.Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation[J].Annu Rev Immunol,2023,41:301-16. [33] MEZGER M,NORDING H,SAUTER R,et al.Platelets and Immune Responses During Thromboinflammation[J].Front Immunol, 2019,10:1731. [34] BAPTISTA DE BARROS RIBEIRO DOURADO L P,SANTOS M,MOREIRA-GONçALVES D.Nets,pulmonary arterial hypertension, and thrombo-inflammation[J].J Mol Med(Berl),2022,100(5):713-22. [35] WIENKAMP A K,ERPENBECK L,ROSSAINT J.Platelets in the NETworks interweaving inflammation and thrombosis[J].Front Immunol,2022,13:953129. [36] HERRE M,CEDERVALL J,MACKMAN N,et al.Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases[J].Physiol Rev,2023,103(1):277-312. [37] 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[J].Respir Res,2024,25(1):183. [38] LI Y,CHEN K,WANG Q F.Immunological face of megakaryocytes[J].Front Med,2024,18(6):988-1001. [39] NI C,ZHOU L,YANG S,et al.Oxymatrine,a novel TLR2 agonist,promotes megakaryopoiesis and thrombopoiesis through the STING/NF-κB pathway[J].J Pharm Anal,2025,15(1):101054. [40] THEOFILIS P,SAGRIS M,OIKONOMOU E,et al.Inflammatory Mechanisms Contributing to Endothelial Dysfunction[J]. Biomedicines,2021,9(7). [41] YUN E,KOOK Y,YOO K H,et al.Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases[J].Biomedicines,2020,8(12). [42] HUANG N,ZHU T T,LIU T,et al.Aspirin ameliorates pulmonary vascular remodeling in pulmonary hypertension by dampening endothelial-to-mesenchymal transition[J].Eur J Pharmacol,2021,908:174307. [43] WU S,HOANG H B,YANG J Z,et al.Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension[J]. Chest,2022,162(6):1360-72. [44] FLORENTIN J,ZHAO J,TAI Y Y,et al.Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension[J].Cell Mol Immunol,2021,18(2):374-84. [45] OU M,ZHANG C,CHEN J,et al.Overexpression of MicroRNA-340-5p Inhibits Pulmonary Arterial Hypertension Induced by APE by Downregulating IL-1βand IL-6[J].Mol Ther Nucleic Acids,2020,21:542-54.

点击下载PDF