Division of Surgical Research, Department of Surgery, Brown University, Rhode Island Hospital, Providence, RI, United States.
Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.
Front Immunol. 2024 May 7;15:1365174. doi: 10.3389/fimmu.2024.1365174. eCollection 2024.
Sepsis remains a major source of morbidity and mortality in neonates, and characterization of immune regulation in the neonatal septic response remains limited. HVEM is a checkpoint regulator which can both stimulate or inhibit immune responses and demonstrates altered expression after sepsis. We hypothesized that signaling via HVEM would be essential for the neonatal response to sepsis, and that therefore blockade of this pathway would improve survival to septic challenge.
To explore this, neonatal mice were treated with cecal slurry (CS), CS with Anti-HVEM antibody (CS-Ab) or CS with isotype (CS-IT) and followed for 7-day survival. Mice from all treatment groups had thymus, lung, kidney and peritoneal fluid harvested, weighed, and stained for histologic evaluation, and changes in cardiac function were assessed with echocardiography.
Mortality was significantly higher for CS-Ab mice (72.2%) than for CS-IT mice (22.2%). CS resulted in dysregulated alveolar remodeling, but CS-Ab lungs demonstrated significantly less dysfunctional alveolar remodeling than CS alone (MCL 121.0 CS vs. 87.6 CS-Ab), as well as increased renal tubular vacuolization. No morphologic differences in alveolar septation or thymic karyorrhexis were found between CS-Ab and CS-IT. CS-Ab pups exhibited a marked decrease in heart rate (390.3 Sh vs. 342.1 CS-Ab), stroke volume (13.08 CS-IT vs. 8.83 CS-Ab) and ultimately cardiac output (4.90 Sh vs. 3.02 CS-Ab) as well as a significant increase in ejection fraction (73.74 Sh vs. 83.75 CS-Ab) and cardiac strain (40.74 Sh vs. 51.16 CS-Ab) as compared to CS-IT or Sham animals.
While receptor ligation of aspects of HVEM signaling, via antibody blockade, appears to mitigate aspects of lung injury and thymic involution, stimulatory signaling via HVEM still seems to be necessary for vascular and hemodynamic resilience and overall neonatal mouse survival in response to this experimental polymicrobial septic insult. This dissonance in the activity of anti-HVEM neutralizing antibody in neonatal animals speaks to the differences in how septic cardiac dysfunction should be considered and approached in the neonatal population.
败血症仍然是新生儿发病和死亡的主要原因，而对新生儿败血症反应中免疫调节的特征仍然有限。HVEM 是一种检查点调节剂，既能刺激又能抑制免疫反应，并在败血症后表现出改变的表达。我们假设 HVEM 的信号传导对于新生儿对败血症的反应至关重要，因此阻断该途径将提高对败血症挑战的存活率。
为了探索这一点，用盲肠浆（CS）、CS 与抗 HVEM 抗体（CS-Ab）或 CS 与同型（CS-IT）处理新生小鼠，并进行 7 天的生存随访。所有治疗组的小鼠均采集胸腺、肺、肾和腹腔液，称重，并进行组织学评估，用超声心动图评估心脏功能的变化。
CS-Ab 小鼠（72.2%）的死亡率明显高于 CS-IT 小鼠（22.2%）。CS 导致肺泡重塑失调，但 CS-Ab 肺显示出比 CS 单独治疗（MCL 121.0 CS 与 87.6 CS-Ab）更少的功能失调的肺泡重塑，以及肾小管空泡化增加。CS-Ab 和 CS-IT 之间在肺泡间隔或胸腺核溶解方面没有形态学差异。CS-Ab 幼鼠心率（390.3 Sh 与 342.1 CS-Ab）、每搏量（13.08 CS-IT 与 8.83 CS-Ab）和心输出量（4.90 Sh 与 3.02 CS-Ab）明显下降，射血分数（73.74 Sh 与 83.75 CS-Ab）和心脏应变（40.74 Sh 与 51.16 CS-Ab）显著增加，与 CS-IT 或假手术动物相比。
虽然通过抗体阻断 HVEM 信号转导的某些方面的受体结合似乎减轻了肺损伤和胸腺萎缩的某些方面，但 HVEM 的刺激信号转导似乎仍然是血管和血液动力学弹性以及整体新生小鼠对这种实验性多微生物败血症的反应中存活所必需的。抗 HVEM 中和抗体在新生动物中的这种活性差异说明了在新生儿人群中应如何考虑和处理败血症性心脏功能障碍。
