-
《脓毒症和脓毒症休克的第三次国际共识定义》将脓毒症定义为由宿主对感染反应失调引起的危及生命的器官功能障碍[1]。肺极易在脓毒症时发生损伤，常导致急性呼吸窘迫综合征（ARDS）的发生[2]。脓毒症相关ALI/ARDS进展过程中，细胞因子可介导大量免疫细胞聚集、浸润入肺组织，激活多种细胞内信号转导通路。炎症细胞不断被激活，形成恶性循环，最终导致细胞因子风暴，破坏肺泡-毛细血管内皮屏障结构的完整性，引起中性粒细胞浸润和弥漫性肺水肿[3-4]。然而，其确切发病机制尚不清楚。研究发现，在引发ARDS病因中，脓毒症相关ARDS患者的死亡率高于其他原因[5]。有学者认为，脓毒症相关ARDS可能存在特异分子通路，并与如创伤、多次输血等原因激活的分子通路不同。因此，了解导致脓毒症相关肺损伤的分子机制至关重要。
-
1 Nrf2信号通路
-
氧化应激、免疫、炎症及自噬在脓毒症相关肺损伤的发生、发展中具有重要作用，NF-E2 p45相关因子2（NF-E2 p45-related factor 2，Nrf2）是一种生理上重要的转录因子[6]，在细胞中广泛表达[7]，是细胞氧化还原稳态的主要调节因子之一，相关信号通路与脓毒症相关肺损伤紧密相关[8]。
-
因Nrf2可触发对代谢、氧化和炎症应激源的快速反应，因此，以Nrf2为靶标对氧化应激和炎症疾病的研究具有重要意义。通过对新型冠状病毒肺炎（COVID-19）患者肺活检的研究显示，该病毒介导了Nrf2的抑制，并限制了宿主的抗炎反应[9]。Ma等[10]发现，5-甲氧基色氨酸可通过Nrf2/HO-1信号通路抑制NLRP3炎症小体介导的细胞焦亡，从而在体内外减轻内毒素诱导的急性肺损伤。Li等[11]经研究发现，川芎嗪可通过Nrf2/HO-1信号通路减轻高尔基体应激进而减轻内毒素性急性肺损伤。Nrf2相关通路激活后M1巨噬细胞产生的促炎因子肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL-6也显著减少[12]。
-
有学者认为脓毒症相关肺损伤与大量ROS产生密切相关，Nrf2依赖的基因诱导可修复这种损伤[13]。采用小鼠尾静脉给予脂多糖（LPS）建立肺损伤模型，Nrf2缺陷小鼠比野生型小鼠肺部炎症广泛，对ARDS的易感性显著增强，与对照组相比，经LPS处理的Nrf2缺陷小鼠的炎症生物标志物水平更高[14]。采用脓毒症兔模型的研究表明[15-16]，Nrf2介导和萝卜硫素诱导的机制对急性氧化性肺损伤具有保护作用，Nrf2缺乏可增加ARDS氧化性肺损伤的易感性，而Nrf2激活剂可预防ARDS相关氧化性损伤的发生。此外，一些类似Nrf2激活剂，也被证明可以改善脓毒症肺损伤，如Song等[17]研究发现，右美托咪定可通过激活Nrf2/HO-1信号通路调节线粒体动力学减轻内毒素性肺损伤。
-
2 PI3Ks信号通路
-
磷脂酰肌醇-3激酶（phosphatidylinositol3-kinase，PI3Ks）是一种异二聚酶[18]，激活状态的PI3Ks影响炎症反应中的关键事件，如细胞周期、分化、衰老和代谢等多种生物学过程[19]。在脓毒症相关ALI的肺纤维化中，从炎症反应开始至疾病发展的多个阶段，多种介质通过激活PI3K通路引发致病性肺重塑[20-21]。
-
脓毒症相关肺损伤发病的一个重要的病理变化是上皮/内皮屏障完整性受损。血管内皮生长因子（vascular endothelial growth factor，VEGF）可介导肺泡内皮细胞的血管通透性，通过药物抑制PI3K可抵消这一影响[22]。PI3Kγ的缺失可降低离体血管中AngII的反应，并使在体血管免受AngII诱导的损伤[23]。脓毒症相关肺损伤另一个重要的病理变化是肺泡内纤维化和弥漫性肺泡损伤（DAD）。在COVID-19重症患者中，ARDS伴有不受控制的成纤维细胞增殖，并激活PI3K/AKT/mTOR通路，该通路是细胞增殖的关键调控因子[24-25]。因此，肺成纤维细胞增殖、分化和细胞外基质生成的关键启动子转化生长因子-β（transforming growth factor-β，TGF-β）信号可以通过抑制PI3K进行调节[25]。研究表明，通过抑制PI3K，特别是PI3Kγ和PI3Kα，可以调节TGF-β刺激的下游信号传导，最终减少脓毒症相关肺损伤引发的肺泡内纤维化[26]。另外，余剑波教授团队研究发现，PI3K/Akt通路可介导血红素氧合酶-1（HO-1）调节线粒体质量控制并最终缓解内毒素急性肺损伤[27-29]，但其是否与成纤维细胞增殖相关，仍需进一步探索。
-
3 丝裂原活化蛋白激酶通路
-
丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）广泛存在于真核细胞中，是细胞中最重要的信号转导系统之一[30]。既往研究表明，MAPK通路可能在脓毒症诱导的ALI/ARDS相关的炎症过程中发挥重要的致病作用[31-33]。
-
MAPK磷酸化可诱导核因子-κB（nuclear factor-kappaB，NF-κB）的核转位并诱导细胞凋亡[34]，同时诱导黏附子的表达，刺激炎性因子产生，进而启动和放大感染过程中微血管内皮的炎症反应[35]。Hsieh等[36]发现p38/MAPK信号通路是介导细胞反应的重要系统，参与细胞生长和凋亡。激活的p38/MAPK可以通过增加体内中性粒细胞的募集和趋化以及调节巨噬细胞的免疫反应来调节肺组织的炎症反应[37]。Dong等[38]发现，一氧化碳可经p38/MAPK信号通路调节线粒体融合蛋白减轻脂多糖诱导的肺损伤。此外，p38/MAPK通路的激活可以与ERK、JNK和NF-κB信号通路产生正反馈，并级联放大炎症反应[39]。
-
通过阻断MAPK信号通路，可以有效降低肺组织的炎症反应，有效保护肺泡上皮细胞和毛细血管内皮细胞[40]。Wang等[41]报道Maresin1通过抑制MAPK/NF-κB信号通路的激活改善脓毒症相关的肺损伤。Chen等[42]报道四逆汤通过调节ACE2-Ang（1-7）-Mas轴，抑制MAPK信号通路改善脓毒症引起的急性肺损伤。Chen等[43]研究证明牛磺酸可减轻脓毒症引起的肺损伤，其机制与抑制p38/MAPK信号通路抑制炎症反应和氧化应激有关。
-
4 JAK2/STAT3通路
-
酪氨酸激酶2/信号转导和转录激活因子3（janus kinase-signal transducer and activitor of transcription，JAK2/STAT3）通路广泛参与免疫应答、炎症反应、细胞增殖和凋亡等多种生物学过程，是多种细胞因子信号转导的常见通路[44-45]。在脓毒症相关肺损伤过程中，JAK2/STAT3通路参与肺组织损伤修复[46]。
-
既往研究表明，JAK2/STAT3信号通路可被一系列细胞因子激活，包括TNF-α、IL-1β、IL-6等[47]。IL-6是细胞因子风暴的核心和重要标志物，它的分泌引发了一系列放大的炎症反应。多项研究表明，IL-6通过JAK-STAT途径与细胞膜上的受体结合，激活Janus激酶，磷酸化其下游的STAT3，从而启动STAT3靶基因的转录[48-49]。在脓毒症相关肺损伤的小鼠模型中，机体可能通过IL-6激活STAT3通路，促进炎症反应的发展[50]。
-
在LPS诱导的内毒素血症ALI模型中，STAT3的激活有助于肺保护[51-52]。有研究指出，STAT3抑制剂可增加NF-κB的活化，最终逆转右美托咪定对肺的保护作用，表明STAT3激活参与DEX对脓毒性ALI的作用的保护机制[53]。宫丽荣等[54]研究发现，电针刺可通过α7nAChR激活JAK2/STAT3信号通路减轻大鼠内毒素性急性肺损伤。然而，也有研究证明，抑制STAT3通路对肺损伤具有保护作用。例如，乌司他丁抑制JAK/STAT3通路与降低炎症介质水平相关，从而减少大鼠败血症期间的肺组织坏死和肿胀[55]。因此，JAK2-STAT3通路对脓毒症诱导的ALI/ARDS进展可能具有双重调节作用。
-
5 mTOR途径
-
哺乳动物类雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）是一种广泛表达的细胞内丝氨酸/苏氨酸蛋白激酶，通过调节许多细胞过程发挥重要作用，如细胞增殖、翻译、转录和自噬[56]。
-
研究表明，mTOR通路对脓毒症相关急性肺损伤调控具有两面性。自噬是一个重要的细胞内过程，其在脓毒症相关急性肺损伤中的作用存在争议，通过mTOR通路上下游调节因子既可以抑制自噬，也可以激活自噬，从而表现出不同的生理作用。有学者认为mTOR通路可以抑制自噬、减少促炎细胞浸润，对急性肺损伤发挥保护作用[57-58]。研究表明，铁死亡可以通过阻断mTOR信号和自噬来减弱脓毒症引起的急性肺损伤[59]。近期在对大鼠的脓毒症模型（CLP）研究中发现，PI3K/Akt/mTOR途径激活后可显著减少炎症因子释放、抑制细胞造成的自噬损伤和细胞凋亡，从而减轻肺水肿，提高存活率[60-61]。与之相反，也有学者认为mTOR信号通路激活可以诱发自噬，促使细胞凋亡以及炎症因子风暴的形成，从而导致肺损伤加重[62-63]。然而，最近的一项研究表明，间充质干细胞（mesenchymal stem cell，MSC）外泌体通过mTOR信号通路激活自噬显著改善内毒素诱导的ALI[64]。由此可见，虽然不同研究表明在脓毒症相关急性肺损伤中mTOR通路起到作用可能相反，但在不同的上下游分子调节下该通路可降低炎症因子水平。
-
6 小结
-
脓毒症所致ALI/ARDS发病机制非常复杂，涉及多种细胞因子和信号通路，如本文所述，脓毒症相关肺损伤有多个信号通路被激活。通过研究信号通路分析不同蛋白质和基因之间的相互作用，以及不同信号通路之间的关联性，能够加深研究者对相关机制的理解，对脓毒症相关肺损伤的诊断和治疗具有重要意义，可为开发治疗脓毒症引起的ALI/ARDS相关研究提供理论依据和启发。
-
参考文献
-
[1] Singer M,Deutschman CS,Seymour CW,et al.The third international consensus definitions for Sepsis and septic shock(Sepsis-3)[J].JAMA,2016,315(8):801-810.
-
[2] Bellani G,Laffey JG,Pham T,et al.Epidemiology,patterns of care,and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries[J].JAMA,2016,315(8):788-800.
-
[3] Lee C,Choi WJ.Overview of COVID-19 inflammatory pathogenesis from the therapeutic perspective[J].Arch Pharm Res,2021,44(1):99-116.
-
[4] Kim JS,Lee JY,Yang JW,et al.Immunopathogenesis and treatment of cytokine storm in COVID-19[J].Theranostics,2021,11(1):316-329.
-
[5] Stapleton RD,Wang BM,Hudson LD,et al.Causes and timing of death in patients with ARDS[J].Chest,2005,128(2):525-532.
-
[6] He F,Ru XL,Wen T.NRF2,a transcription factor for stress response and beyond[J].Int J Mol Sci,2020,21(13):4777.
-
[7] Robledinos-Antón N,Fernández-Ginés R,Manda G,et al.Activators and inhibitors of NRF2:a review of their potential for clinical development[J].Oxid Med Cell Longev,2019,2019:9372182.
-
[8] Cuadrado A,Pajares M,Benito C,et al.Can activation of NRF2 be a strategy against COVID-19?[J].Trends Pharmacol Sci,2020,41(9):598-610.
-
[9] McCord JM,Hybertson BM,Cota-Gomez A,et al.Nrf2 activator PB125® as a potential therapeutic agent against COVID-19[J].Antioxidants,2020,9(6):518.
-
[10] Ma Y,Wang ZX,Wu XY,et al.5-Methoxytryptophan ameliorates endotoxin-induced acute lung injury in vivo and in vitro by inhibiting NLRP3 inflammasome-mediated pyroptosis through the Nrf2/HO-1 signaling pathway[J].Inflamm Res,2023,72(8):1633-1647.
-
[11] Li SN,Xu YX,He SM,et al.Tetramethylpyrazine ameliorates endotoxin-induced acute lung injury by relieving Golgi stress via the Nrf2/HO-1 signaling pathway[J].BMC Pulm Med,2023,23(1):286.
-
[12] Calabrese EJ,Giordano JJ,Kozumbo WJ,et al.Hormesis mediates dose-sensitive shifts in macrophage activation patterns[J].Pharmacol Res,2018,137:236-249.
-
[13] Liu QM,Gao Y,Ci XX.Role of Nrf2 and its activators in respiratory diseases[J].Oxid Med Cell Longev,2019,2019:7090534.
-
[14] Chan K,Kan YW.Nrf2 is essential for protection against acute pulmonary injury in mice[J].Proc Natl Acad Sci USA,1999,96(22):12731-12736.
-
[15] Zhao B,Gao WW,Gao X,et al.Sulforaphane attenuates acute lung injury by inhibiting oxidative stress via Nrf2/HO-1 pathway in a rat sepsis model[J].Int J Clin Exp Pathol,2017,10(8):9021-9028.
-
[16] Sun ZJ,Niu ZQ,Wu SS,et al.Protective mechanism of sulforaphane in Nrf2 and anti-lung injury in ARDS rabbits[J].Exp Ther Med,2018:15(6):4911-4915.
-
[17] Song K,Shi J,Zhan LN,et al.Dexmedetomidine modulates mitochondrial dynamics to protect against endotoxin-induced lung injury via the protein kinase C-ɑ/haem oxygenase-1 signalling pathway[J].Biomarkers,2022,27(2):159-168.
-
[18] Chandrasekaran S,Funk CR,Kleber T,et al.Strategies to overcome failures in T-cell immunotherapies by targeting PI3K-δ and-Γ[J].Front Immunol,2021,12:718621.
-
[19] Deng CY,Lv M,Luo BH,et al.The role of the PI3K/AKT/mTOR signalling pathway in male reproduction[J].Curr Mol Med,2021,21(7):539-548.
-
[20] Fang L,Chen HT,Kong RY,et al.Endogenous tryptophan metabolite 5-Methoxytryptophan inhibits pulmonary fibrosis by downregulating the TGF-β/SMAD3 and PI3K/AKT signaling pathway[J].Life Sci,2020,260:118399.
-
[21] Huang EY,Peng N,Xiao F,et al.The roles of immune cells in the pathogenesis of fibrosis[J].Int J Mol Sci,2020,21(15):5203.
-
[22] Ourradi K,Blythe T,Jarrett C,et al.VEGF isoforms have differential effects on permeability of human pulmonary microvascular endothelial cells[J].Respir Res,2017,18(1):116.
-
[23] Vecchione C,Patrucco E,Marino G,et al.Protection from angiotensin II-mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma[J].J Exp Med,2005,201(8):1217-1228.
-
[24] Kindrachuk J,Ork B,Hart BJ,et al.Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis[J].Antimicrob Agents Chemother,2015,59(2):1088-1099.
-
[25] Conte E,Fruciano M,Fagone E,et al.Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts:the role of class I P110 isoforms[J].PLoS One,2011,6(10):e24663.
-
[26] Campa CC,Silva RL,Margaria JP,et al.Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis[J].Nat Commun,2018,9(1):5232.
-
[27] Shi J,Yu JB,Zhang Y,et al.PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury[J].Lab Invest,2019,99(12):1795-1809.
-
[28] Shi J,Yu JB,Zhang Y,et al.Phosphatidylinositol 3-kinase-mediated HO-1/CO represses Fis1 levels and alleviates lipopolysaccharide-induced oxidative injury in alveolar macrophages[J].Exp Ther Med,2018,16(3):2735-2742.
-
[29] 黄漫迎,史佳,张圆,等.PI3K/Akt信号通路在内毒素攻击大鼠肺泡上皮细胞时一氧化碳上调线粒体融合蛋白中的作用[J].中华麻醉学杂志,2018,38(6):728-731.
-
[30] Kong GQ,Huang X,Wang LP,et al.Astilbin alleviates LPS-induced ARDS by suppressing MAPK signaling pathway and protecting pulmonary endothelial glycocalyx[J].Int Immunopharmacol,2016,36:51-58.
-
[31] Fang W,Cai SX,Wang CL,et al.Modulation of mitogen‑activated protein kinase attenuates sepsis‑induced acute lung injury in acute respiratory distress syndrome rats[J].Mol Med Rep,2017,16(6):9652-9658.
-
[32] Cong ZK,Li D,Tao YF,et al.α2A-AR antagonism by BRL-44408 maleate attenuates acute lung injury in rats with downregulation of ERK1/2,p38MAPK,and p65 pathway[J].J Cell Physiol,2020,235(10):6905-6914.
-
[33] Liu YN,Mu ST,Li X,et al.Unfractionated heparin alleviates Sepsis-induced acute lung injury by protecting tight junctions[J].J Surg Res,2019,238:175-185.
-
[34] Walley KR.Sepsis-induced myocardial dysfunction[J].Curr Opin Crit Care,2018,24(4):292-299.
-
[35] Fiuza C,Bustin M,Talwar S,et al.Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells[J].Blood,2003,101(7):2652-2660.
-
[36] Hsieh CC,Papaconstantinou J.Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice[J].FASEB J,2006,20(2):259-268.
-
[37] Li XF,Zhou XK,Ye Y,et al.Lyn regulates inflammatory responses in Klebsiella pneumoniae infection via the p38/NF-κB pathway[J].Eur J Immunol,2014,44(3):763-773.
-
[38] Dong S,Zhang Y,Yu JB,et al.Carbon monoxide attenuates lipopolysaccharide-induced lung injury by mitofusin proteins via p38 MAPK pathway[J].J Surg Res,2018,228:201-210.
-
[39] Kang HE,Bang TS,Lee JW,et al.Protective effect of the methanol extract from Cryptotaenia japonica Hassk.against lipopolysaccharide-induced inflammation in vitro and in vivo[J].BMC Complement Altern Med,2012,12:199.
-
[40] Sim YS,Kim SY,Kim EJ,et al.Impaired expression of MAPK is associated with the downregulation of TNF-α,IL-6,and IL-10 in Mycobacterium abscessus lung disease[J].Tuberc Respir Dis,2012,72(3):275-283.
-
[41] Wang FQ,Wang M,Wang JX,et al.Maresin1 ameliorates sepsis-associated lung injury by inhibiting the activation of the JAK2/STAT3 and MAPK/NF-κB signaling pathways[J].Microb Pathog,2020,148:104468.
-
[42] Chen QH,Liu JJ,Wang WQ,et al.Sini Decoction ameliorates sepsis-induced acute lung injury via regulating ACE2-Ang(1-7)-Mas axis and inhibiting the MAPK signaling pathway[J].Biomed Pharmacother,2019,115:108971.
-
[43] Chen J,Xue X,Cai JQ,et al.Protective effect of taurine on sepsis‑induced lung injury via inhibiting the p38/MAPK signaling pathway[J].Mol Med Rep,2021,24(3):653.
-
[44] Zhang JF,Luo YF,Wang XL,et al.Global transcriptional regulation of STAT3-and MYC-mediated sepsis-induced ARDS[J].Ther Adv Respir Dis,2019,13:1753466619879840.
-
[45] Cai B,Cai JP,Luo YL,et al.The specific roles of JAK/STAT signaling pathway in Sepsis[J].Inflammation,2015,38(4):1599-1608.
-
[46] Paris AJ,Hayer KE,Oved JH,et al.STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury[J].Nat Cell Biol,2020,22(10):1197-1210.
-
[47] Jee SH,Chu CY,Chiu HC,et al.Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways[J].J Invest Dermatol,2004,123(6):1169-1175.
-
[48] Schaper F,Rose-John S.Interleukin-6:biology,signaling and strategies of blockade[J].Cytokine Growth Factor Rev,2015,26(5):475-487.
-
[49] Billing U,Jetka T,Nortmann L,et al.Robustness and information transfer within IL-6-induced JAK/STAT signalling[J].Commun Biol,2019,2:27.
-
[50] Severgnini M,Takahashi S,Rozo LM,et al.Activation of the STAT pathway in acute lung injury[J].Am J Physiol Lung Cell Mol Physiol,2004,286(6):L1282-L1292.
-
[51] Hilliard KL,Allen E,Traber KE,et al.Activation of hepatic STAT3 maintains pulmonary defense during endotoxemia[J].Infect Immun,2015,83(10):4015-4027.
-
[52] Wang L,Zhao YL,Liu NN,et al.Epithelial HO-1/STAT3 affords the protection of subanesthetic isoflurane against zymosan-induced lung injury in mice[J].Oncotarget,2017,8(33):54889-54903.
-
[53] Zhang HY,Sha JC,Feng XJ,et al.Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats[J].Int Immunopharmacol,2019,74:105717.
-
[54] 宫丽荣,史佳,张圆,等.α7nAChR在电针减轻大鼠内毒素性急性肺损伤中的作用:与JAK2/STAT3信号通路的关系[J].中华麻醉学杂志,2018,38(6):739-742.
-
[55] Wu JA,Yan X,Jin GQ.Ulinastatin protects rats from sepsis-induced acute lung injury by suppressing the JAK-STAT3 pathway[J].J Cell Biochem,2019,120(2):2554-2559.
-
[56] Liu GY,Sabatini DM.mTOR at the nexus of nutrition,growth,ageing and disease[J].Nat Rev Mol Cell Biol,2020,21(4):183-203.
-
[57] Nosaka N,Martinon D,Moreira D,et al.Autophagy protects against developing increased lung permeability and hypoxemia by down regulating inflammasome activity and IL-1β in LPS plus mechanical ventilation-induced acute lung injury[J].Front Immunol,2020,11:207.
-
[58] Wang QL,Yang L,Liu ZL,et al.Sirtuin 6 regulates macrophage polarization to alleviate sepsis-induced acute respiratory distress syndrome via dual mechanisms dependent on and independent of autophagy[J].Cytotherapy,2022,24(2):149-160.
-
[59] Li JH,Li MY,Li L,et al.Hydrogen sulfide attenuates ferroptosis and stimulates autophagy by blocking mTOR signaling in sepsis-induced acute lung injury[J].Mol Immunol,2022,141:318-327.
-
[60] Sui HS,Luo MJ,Miao YY,et al.Cystic fibrosis transmembrane conductance regulator ameliorates lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/AKT/mTOR pathway in mice[J].Respir Physiol Neurobiol,2020,273:103338.
-
[61] Wen H,Zhang H,Wang WN,et al.Tetrahydropalmatine protects against acute lung injury induced by limb ischemia/reperfusion through restoring PI3K/AKT/mTOR-mediated autophagy in rats[J].Pulm Pharmacol Ther,2020,64:101947.
-
[62] Zhang Y,Liu GJ,Dull RO,et al.Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation[J].Am J Physiol Lung Cell Mol Physiol,2014,307(2):L173-L185.
-
[63] Mizumura K,Cloonan SM,Haspel JA,et al.The emerging importance of autophagy in pulmonary diseases[J].Chest,2012,142(5):1289-1299.
-
[64] Wei XX,Yi XM,Lv HJ,et al.microRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy[J].Cell Death Dis,2020,11(8):657.
-
摘要
脓毒症是由宿主对感染反应失调引起的危及生命的器官功能障碍，作为人体重要器官，肺脏极易在脓毒症时发生损伤，导致急性呼吸窘迫综合征（ARDS）的发生。脓毒症引起的ARDS发病机制非常复杂，其确切发病机制尚不完全清楚，涉及多个信号通路被激活。本文通过介绍目前研究较多的信号通路在脓毒症相关肺损伤/ARDS中的作用及机制，分析信号通路不同蛋白质和基因之间的相互作用，以及不同信号通路之间的关联性，以期为探寻脓毒症相关肺损伤治疗靶点提供一定理论基础。