Division of General Pediatric Surgery, Johns Hopkins University and Johns Hopkins Children's Center, Johns Hopkins Hospital, Baltimore, Maryland.
Shock. 2019 Aug;52(2):215-223. doi: 10.1097/SHK.0000000000001255.
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants, and is associated with the development of severe lung inflammation. The pathogenesis of NEC-induced lung injury remains unknown, yet infiltrating immune cells may play a role. In support of this possibility, we now show that NEC in mice and humans was associated with the development of profound lung injury that was characterized by an influx of Th17 cells and a reduction in T regulatory lymphocytes (Tregs). Importantly, the adoptive transfer of CD4 T cells isolated from lungs of mice with NEC into the lungs of immune incompetent mice (Rag1 mice) induced profound inflammation in the lung, while the depletion of Tregs exacerbated NEC induced lung injury, demonstrating that imbalance of Th17/Treg in the lung is required for the induction of injury. In seeking to define the mechanisms involved, the selective deletion of toll-like receptor 4 (TLR4) from the Sftpc1 pulmonary epithelial cells reversed lung injury, while TLR4 activation induced the Th17 recruiting chemokine (C-C motif) ligand 25 (CCL25) in the lungs of mice with NEC. Strikingly, the aerosolized inhibition of both CCL25 and TLR4 and the administration of all trans retinoic acid restored Tregs attenuated NEC-induced lung injury. In summary, we show that TLR4 activation in Surfactant protein C-1 (Sftpc1) cells disrupts the Treg/Th17 balance in the lung via CCL25 leading to lung injury after NEC and reveal that inhibition of TLR4 and stabilization of Th17/Treg balance in the neonatal lung may prevent this devastating complication of NEC.
坏死性小肠结肠炎（NEC）是早产儿胃肠道疾病死亡的主要原因，与严重肺部炎症的发展有关。NEC 诱导的肺损伤的发病机制尚不清楚，但浸润的免疫细胞可能起作用。支持这种可能性，我们现在表明，NEC 在小鼠和人类中与严重肺损伤的发展相关，其特征是 Th17 细胞的浸润和 T 调节性淋巴细胞（Tregs）的减少。重要的是，从患有 NEC 的小鼠肺部分离的 CD4 T 细胞的过继转移到免疫无能的小鼠（Rag1 小鼠）的肺部中，诱导肺部严重炎症，而 Tregs 的耗竭加剧了 NEC 诱导的肺损伤，表明肺中 Th17/Treg 的失衡是诱导损伤所必需的。在寻求定义所涉及的机制时，从 Sftpc1 肺上皮细胞中选择性删除 Toll 样受体 4（TLR4）逆转了肺损伤，而 TLR4 激活在患有 NEC 的小鼠的肺部诱导了 Th17 募集趋化因子（C-C 基序）配体 25（CCL25）。引人注目的是，CCL25 和 TLR4 的雾化抑制以及全反式视黄酸的给药恢复了 Tregs 减弱了 NEC 诱导的肺损伤。总之，我们表明 TLR4 在 Surfactant protein C-1（Sftpc1）细胞中的激活通过 CCL25 破坏了肺中的 Treg/Th17 平衡，导致 NEC 后肺损伤，并表明抑制 TLR4 和稳定新生儿肺中的 Th17/Treg 平衡可能预防这种毁灭性的 NEC 并发症。
