Monophosphoryl lipid A prevents impairment of medullary thick ascending LIMB HCO3- absorption and improves plasma HCO3- concentration in septic mice.

Monophosphoryl lipid A prevents impairment of medullary thick ascending LIMB HCO3- absorption and improves plasma HCO3- concentration in septic mice. Am J Physiol Renal Physiol. 2018 May 09;: Authors: Watts BA, George T, Sherwood ER, Good DW Abstract 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 HCO3- absorption in the MTAL by: 1) decreasing the intrinsic HCO3- absorptive capacity, and 2) enhancing inhibition of HCO3- 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 HCO3- 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 HCO3- 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 HCO3- ab...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research