Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Vanderbilt University, Nashville, TN, USA.
Physiol Rep. 2020 Nov;8(21):e14589. doi: 10.14814/phy2.14589.
Cell-free hemoglobin (CFH) is associated with severe lung injury in human patients and is sufficient to induce airspace inflammation and alveolar-capillary barrier dysfunction in an experimental model of acute lung injury. The mechanisms through which this occurs are unknown. One key pathway which regulates inflammation during acute lung injury is the NLRP3 inflammasome. Because CFH can act as a damage-associated molecular pattern, we hypothesized that CFH may activate the NLRP3 inflammasome during acute lung injury. Primary mouse alveolar macrophages and cultured murine macrophages exposed to CFH (0-1 mg/ml) for 24 hr demonstrated robust upregulation of the NLRP3 inflammasome components NLRP3, caspase-1, and caspase-11. Maximal induction of the NLRP3 inflammasome by CFH required TLR4. Compared to wild-type controls, mice lacking NLRP3 developed less airspace inflammation (2.7 × 10 cells/ml in bronchoalveolar lavage fluid versus. 1.1 × 10 /ml, p = .006) after exposure to intratracheal CFH. Together, these data demonstrate that CFH can stimulate the NLRP3 inflammasome in macrophages and that this pathway may be important in the pathogenesis of CFH-induced acute lung injury.
无细胞血红蛋白 (CFH) 与人类患者的严重肺部损伤有关，足以在急性肺损伤的实验模型中诱导气腔炎症和肺泡毛细血管屏障功能障碍。其发生的机制尚不清楚。调节急性肺损伤期间炎症的一个关键途径是 NLRP3 炎性体。由于 CFH 可以作为损伤相关分子模式，我们假设 CFH 在急性肺损伤期间可能激活 NLRP3 炎性体。用 CFH（0-1 mg/ml）孵育 24 小时的原代小鼠肺泡巨噬细胞和培养的鼠巨噬细胞中，NLRP3 炎性体成分 NLRP3、半胱天冬酶-1 和半胱天冬酶-11 的表达明显上调。CFH 对 NLRP3 炎性体的最大诱导作用需要 TLR4。与野生型对照相比，缺乏 NLRP3 的小鼠在气管内给予 CFH 后，气腔炎症明显减少（支气管肺泡灌洗液中 2.7×10 个细胞/ml，而 1.1×10 个/ml，p=0.006）。这些数据表明，CFH 可以刺激巨噬细胞中的 NLRP3 炎性体，该途径可能在 CFH 诱导的急性肺损伤发病机制中起重要作用。
