嗜中性白血球和新冠肺炎急性呼吸窘迫症的關係

cgust 2021-01-072021-01-07

由民生學院/黃聰龍於2020-01-07(星期四) 發表

長庚科技大學民生學院黃聰龍特聘教授

長庚科技大學健康產業科技研究所孔柏雄博士後研究員

新冠病毒(SARS-CoV-2)在感染宿主時會以血管收縮素轉化酶2 (human angiotensin-converting enzyme 2, hACE2) 做為入侵的媒介[1]。而血管收縮素轉化酶2廣泛分布在呼吸道、血管壁、腎臟以及腸胃道等處[2]。病毒RNA能以病原相關分子模式 (pathogen-associated molecular patterns) 作用在類鐸受體 (Toll-like receptors，TLRs)，如TLR3、TLR7、TLR8與TLR9；此一活化訊號會導致interferon α與β伴隨多種促炎性細胞因子的釋放[3]。肺部發炎的狀況始於促炎性巨噬細胞與嗜中性白血球的作用，最終進展成急性呼吸窘迫症 (acute respiratory distress syndrome，ARDS)，這也是SARS-CoV-2感染患者的一個非常致命的疾病[4]。SARS-CoV-2感染造成的新冠肺炎(COVID-19)嚴重病患往往有免疫調節失控的現象，例如淋巴球數目減少，但嗜中性白血球數目卻增加[5]。併發肺炎的COVID-19患者與輕微呼吸併發症的患著相比，嗜中性白血球數目也的確有增加的現象[6]。在25例因COVID-19造成的死亡患者的回顧性研究中發現，嗜中性白血球數量的顯著增加可以做為病患預後不良的生物標記 [7]。另一篇對95例COVID-19患者的回顧性分析中也指出，嗜中性白血球數目的增加與疾病的嚴重程度有關，並反映出其與發炎併發症的關聯性[8]。根據另一整合分析研究，重症COVID-19患者血液中，嗜中性白血球相對於淋巴球的數量有明顯的提升；嗜中性白血球與淋巴球的比例也可以作為生物標記來預測患者是否會產生較嚴重的併發症，例如ARDS [9]。所以，我們團隊和其他學者建議，嗜中性白血球可作為重症COVID-19患者併發症的治療靶標[10]。多項研究都指出COVID-19病人嗜中性白血球數目的增加與疾病嚴重程度有關，並且在治療COVID-19中有其重要性。嗜中性白血球數目的提升不僅僅是實驗室的異常發現，我們建議應該評估此現象作為感染SARS-CoV-2患者的治療方針。

SARS-CoV-2侵犯宿主細胞後，導致hACE2的表現量下降，引起嗜中性白血球的聚集[10]。開發SARS-CoV-2藥物的可行策略，包含拮抗ACE2受體、棘蛋白 (spike protein) 受體的結合區、細胞表面的微結構區 (macrodomain，Mac1) 或主要蛋白酶 (Mpro、3CLpro) [11-13]。嗜中性白血球廣泛分佈在COVID-19患者的肺泡中[14]。在實驗老鼠中，過量的嗜中性白血球移行到肺部會導致嚴重的肺出血和微血管通透性增加。因此，推測SARS-CoV-2感染老鼠所造成的呼吸道病理症狀來自於嗜中性白血球清除病毒的過程[15]。除此之外，嗜中性白血球在細胞因子風暴 (cytokine storm ) 也扮演重要的角色[16]。在COVID-19患者中，嗜中性白血球透過TLR8調控的機制促進介白素6 (interleukin-6) 分泌，從而導致細胞因子風暴和後續的肺損傷[17]。接著IL-1β和嗜中性白血球細胞外陷阱 (neutrophil extracellular trap, NETs) 會形成反饋迴路，導致COVID-19患者中ARDS的疾病進程[18]。SARS-CoV-2可能會侵襲神經並加劇呼吸衰竭[2]。在小鼠動物實驗中，嗜中性白血球所產生的活性氧類 (reactive oxygen species) 和NETs會參與SARS-CoV-2感染引起的中樞神經疾病[19]。因此，我們認為治療嗜中性白血球過度活化的現象，可以改善COVID-19相關的ARDS和神經疾病。本文摘錄自黃聰龍院長團隊發表之文章：Targeting Neutrophils to Treat Acute Respiratory Distress Syndrome in Coronavirus Disease. Front Pharmacol, 11(2020) 572009 [20]。

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