Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Cardiac Surgery, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Front Immunol. 2023 Jun 12;14:1114129. doi: 10.3389/fimmu.2023.1114129. eCollection 2023.
Acute respiratory distress syndrome (ARDS) is associated with high mortality rates in patients admitted to the intensive care unit (ICU) patients with overwhelming inflammation considered to be an internal cause. The authors' previous study indicated a potential correlation between phenylalanine levels and lung injury. Phenylalanine induces inflammation by enhancing the innate immune response and the release of pro-inflammatory cytokines. Alveolar macrophages (AMs) can respond to stimuli synthesis and release of inflammatory mediators through pyroptosis, one form of programmed cell death acting through the nucleotide-binging oligomerization domain-like receptors protein 3 (NLRP3) signaling pathway, resulting in the cleavage of caspase-1 and gasdermin D (GSDMD) and the release of interleukin (IL) -1β and IL-18, aggravating lung inflammation and injury in ARDS. In this study, phenylalanine promoted pyroptosis of AMs, which exacerbated lung inflammation and ARDS lethality in mice. Furthermore, phenylalanine initiated the NLRP3 pathway by activating the calcium-sensing receptor (CaSR). These findings uncovered a critical mechanism of action of phenylalanine in the context of ARDS and may be a new treatment target for ARDS.
急性呼吸窘迫综合征（ARDS）与重症监护病房（ICU）中炎症反应过度的患者的高死亡率相关，被认为是内部原因。作者之前的研究表明，苯丙氨酸水平与肺损伤之间可能存在相关性。苯丙氨酸通过增强先天免疫反应和促炎细胞因子的释放来引发炎症。肺泡巨噬细胞（AMs）可以通过细胞焦亡对刺激作出反应，通过核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）信号通路合成和释放炎症介质，导致半胱氨酸天冬氨酸蛋白酶-1（caspase-1）和 Gasdermin D（GSDMD）的切割以及白细胞介素（IL）-1β和 IL-18 的释放，从而加重 ARDS 中的肺炎症和损伤。在这项研究中，苯丙氨酸促进了 AMs 的细胞焦亡，加剧了小鼠的肺炎症和 ARDS 致死率。此外，苯丙氨酸通过激活钙敏感受体（CaSR）启动 NLRP3 途径。这些发现揭示了苯丙氨酸在 ARDS 中的关键作用机制，可能成为 ARDS 的新治疗靶点。
