Monophosphoryl lipid A prevents impairment of medullary thick ascending LIMB HCO absorption and improves plasma HCO concentration in septic mice.

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 HCO absorption in the MTAL by: 1) decreasing the intrinsic HCO absorptive capacity, and 2) enhancing inhibition of HCO absorption by LPS through upregulation of TLR4 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 HCO absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Mice were administered vehicle or MPLA 48 h before sham or CLP surgery. MTALs were studied in vitro 18 h post-surgery. Pretreatment with MPLA prevented both the effects of sepsis to decrease the basal HCO absorption rate and to enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a TRIF-dependent PI3K-Akt pathway that prevents sepsis- and LPS-induced ERK activation. The effects of MPLA to improve MTAL HCO absorption were associated with marked improvement in the plasma HCO 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 HCO absorption and attenuate metabolic acidosis during sepsis.