Fighting Bacterial Pathogens in the Lung: Platelets to the Rescue?
Fighting Bacterial Pathogens in the Lung: Platelets to the Rescue?
复制标题
对抗肺部细菌病原体：血小板来拯救？
DOI：
10.1165/rcmb.2017-0349ed
复制
发表时间：
2018
影响因子：
6.4
通讯作者：
Lee,JanetS
中科院分区：
文献类型：
--
作者：
Olonisakin,TolaniF;Lee,JanetS
铜绿假单胞菌是一种利用免疫功能低下宿主的细胞外革兰氏阴性细菌条件致病菌。尽管铜绿假单胞菌因其在囊性纤维化肺中持续存在并建立慢性感染的能力而臭名昭著，但它也是危重患者急性下呼吸道感染的常见原因。事实上，铜绿假单胞菌在75个国家的ICU感染的多中心国际合作研究中被确定为最常见的革兰氏阴性菌感染（1），并且铜绿假单胞菌感染与ICU死亡率增加独立相关（2）。在本期杂志中，Amison及其同事（pp. 331-340）提供了令人信服的证据，表明血小板是宿主防御铜绿假单胞菌所必需的（3）。这可能是令人惊讶的，因为血小板通常被视为主要止血的介质;然而，血小板越来越多地被认为是对抗感染的先天防御中的关键角色（4）。Amison及其同事证明，急性肺内铜绿假单胞菌感染可诱导外周血小板减少症，并伴有肺组织中活化血小板的积聚。在空气中发现的血小板显示出脱颗粒的证据，感染小鼠的BAL液中血小板因子4水平升高。他们进一步表明，在铜绿假单胞菌感染期间，肺中活化血小板的积累是保护性的而不是有害的，因为小鼠中的血小板耗竭导致铜绿假单胞菌的致病性增强，肺细菌负荷更高，体重减轻增加，死亡率增加。血小板的消耗也会导致白细胞的募集受损，最明显的是嗜中性白细胞对铜绿假单胞菌的应答。尽管感染后中性粒细胞募集受损可能是血小板耗竭小鼠中观察到的表型恶化的原因，但作者还认为血小板可以限制体外细菌生长。这一发现提出了血小板可能具有直接防御细菌病原体的额外功能。血小板是唯一适合调查主机的威胁，并通过模式识别受体迅速应对入侵者（5）。它们大量存在于血液中，并且富含颗粒，其内容物可以被动员以潜在地促进大量的宿主防御功能（4）。虽然血小板可以在无菌肺损伤的实验模型中加重炎症和损伤（6），但越来越多的证据表明在感染期间相反（4）。活化的血小板已被证明可以直接结合并内化特定亚细胞区室中的感染性生物体，类似于吞噬体（7）。还显示血小板Toll样受体4响应于微生物触发物而被激活，导致血小板与粘附的中性粒细胞结合，随后中性粒细胞活化，形成中性粒细胞胞外陷阱（NET）（8）。此外，活化的血小板可以通过P-选择素束缚募集的中性粒细胞，导致中性粒细胞整合素活化和诱导嗜中性粒细胞炎性表型（9）。在腹膜内大肠杆菌感染模型中，通过消耗血小板或中性粒细胞破坏血小板-中性粒细胞相互作用可防止肝窦内NET的释放，并增强细菌传播（10）。在急性肺炎克雷伯菌肺内感染模型中，血小板耗竭也导致细菌生长和传播增加（11）。然而，血小板似乎并不是肺中性粒细胞募集或NET形成所必需的K。pneumoniae模型，and differences差异in the.
Pseudomonas aeruginosa is an extracellular Gram-negative, bacterial, opportunistic pathogen that exploits immunocompromised hosts. Although it is notorious for its ability to persist in the cystic fibrosis lung and establish chronic infection, P. aeruginosa is also a common cause of acute lower-respiratory-tract infections in critically ill patients. Indeed, P. aeruginosa was identified as the most common Gram-negative infection in a multicenter, international collaborative study of ICU infections in 75 countries (1), and P. aeruginosa infection is independently associated with increased ICU mortality (2). In this issue of the Journal, Amison and colleagues (pp. 331–340) provide compelling evidence that platelets are required in host defense against P. aeruginosa (3). This may be surprising because platelets are conventionally viewed as mediators of primary hemostasis; yet, platelets are increasingly being recognized as key players in the innate defense against infection (4). Amison and colleagues demonstrate that acute intrapulmonary P. aeruginosa infection induces peripheral thrombocytopenia with accumulation of activated platelets in lung tissue. Platelets found in the airspaces showed evidence of degranulation, with elevated platelet factor 4 levels in the BAL fluid of infected mice. They further show that the accumulation of activated platelets in the lungs is protective rather than deleterious during P. aeruginosa infection, as platelet depletion in mice results in enhanced pathogenicity of P. aeruginosa with a higher lung bacterial burden, increased weight loss, and increased mortality. Depletion of platelets also results in impaired leukocyte recruitment—most notably, neutrophils—in response to P. aeruginosa. Although the impaired neutrophil recruitment after infection may account for the worsened phenotype observed in platelet-depleted mice, the authors also suggest that platelets can limit bacterial growth in vitro. This finding invites the possibility that platelets serve an additional function of direct host defense against bacterial pathogens. Platelets are uniquely suited to survey the host for threats and rapidly respond to invaders via pattern recognition receptors (5). They are abundantly present in the bloodstream and are rich in granules, the contents of which can be mobilized to potentially facilitate a vast array of host-defense functions (4). Although platelets can worsen inflammation and injury in experimental models of sterile lung injury (6), there is a growing body of evidence that suggests the contrary during infection (4). Activated platelets have been shown to directly bind and internalize infectious organisms within specific subcellular compartments analogous to phagosomes (7). It has also been shown that platelet Toll-like receptor 4 is activated in response to a microbial trigger, resulting in platelet binding to adherent neutrophils and subsequent neutrophil activation with formation of neutrophil extracellular traps (NETs)(8). Moreover, activated platelets can tether recruited neutrophils via P-selectin, leading to neutrophil integrin activation and induction of a neutrophilic inflammatory phenotype (9). Disruption of platelet–neutrophil interactions by depletion of either platelets or neutrophils was shown to prevent the release of NETs within liver sinusoids and enhance bacterial dissemination in an intraperitoneal Escherichia coli infection model (10). Depletion of platelets also resulted in increased bacterial growth and dissemination in an acute Klebsiella pneumoniae intrapulmonary infection model (11). However, platelets did not appear to be essential for pulmonary neutrophil recruitment or NET formation in the K. pneumoniae model, and differences in the …