Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
Am J Physiol Renal Physiol. 2018 Sep 1;315(3):F711-F725. doi: 10.1152/ajprenal.00033.2018. Epub 2018 May 9.
Metabolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously, we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs [Formula: see text] absorption in the medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic [Formula: see text] absorptive capacity and 2) enhancing inhibition of [Formula: see text] absorption by LPS through upregulation of Toll-like receptor (TLR) 4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis. Pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of [Formula: see text] absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Vehicle or MPLA was administered to mice 48 h before sham or CLP surgery, and MTALs were studied in vitro 18 h postsurgery. Pretreatment with MPLA prevented the effects of sepsis to decrease the basal [Formula: see text] absorption rate and enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β-(TRIF)-dependent phosphatidylinositol 3-kinase-Akt pathway that prevents sepsis- and LPS-induced ERK activation. The effects of MPLA to improve MTAL [Formula: see text] absorption were associated with marked improvement in plasma [Formula: see text] concentration, supporting a role for the kidneys in the pathogenesis of sepsis-induced metabolic acidosis. These studies support detoxified TLR4-based immunomodulators, such as MPLA, that enhance antimicrobial responses as a safe and effective approach to prevent or treat sepsis-induced renal tubule dysfunction and identify cell signaling pathways that can be targeted to preserve MTAL [Formula: see text] absorption and attenuate metabolic acidosis during sepsis.
代谢性酸中毒是脓毒症患者最常见的酸碱紊乱类型，与死亡率增加有关。之前，我们已经证明，盲肠结扎穿孔（CLP）诱导的脓毒症通过以下两种方式损害髓袢升支粗段（MTAL）中的[Formula: see text]吸收：1）降低固有[Formula: see text]吸收能力，2）通过上调 Toll 样受体（TLR）4 信号增强 LPS 对[Formula: see text]吸收的抑制作用。这两种效应都依赖于 ERK 激活。单磷酰脂质 A（MPLA）是一种 TLR4 激动剂的解毒形式，可增强先天抗菌免疫，并改善脓毒症后的存活率。在体外用 MPLA 预处理 MTAL 可防止 LPS 抑制[Formula: see text]吸收。在此，我们研究了 MPLA 预处理是否可以保护 MTAL 免受脓毒症的影响。在假手术或 CLP 手术前 48 小时给小鼠注射载体或 MPLA，术后 18 小时研究 MTAL 体外情况。MPLA 预处理可防止脓毒症降低基础[Formula: see text]吸收速率和增强 LPS 抑制的作用。这些保护作用是通过 MPLA 刺激 Toll/IL-1 受体域包含衔接蛋白诱导 IFN-β-（TRIF）依赖性磷酸肌醇 3-激酶-Akt 途径介导的，该途径可防止脓毒症和 LPS 诱导的 ERK 激活。MPLA 改善 MTAL[Formula: see text]吸收的作用与血浆[Formula: see text]浓度的显著改善相关，这支持肾脏在脓毒症诱导的代谢性酸中毒发病机制中的作用。这些研究支持使用基于 TLR4 解毒的免疫调节剂，如 MPLA，增强抗菌反应，作为预防或治疗脓毒症诱导的肾小管功能障碍的安全有效方法，并确定可以靶向的细胞信号通路以维持 MTAL[Formula: see text]吸收并减轻脓毒症期间的代谢性酸中毒。
