Monophosphoryl lipid a prevents impairment of medullary thick ascending limb HCO- 3 absorption and improves plasma HCO- 3 concentration in septic mice

Bruns Watts, Thampi George, Edward R. Sherwood, David Good

Research output: Contribution to journalArticle

Abstract

Meta-bolic 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 medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic HCO- 3 absorptive capacity and 2) enhancing inhibition of HCO- 3 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 HCO3 - 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 HCO3 - 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 HCO3 - absorption were associated with marked improvement in plasma HCO- 3 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 HCO3 - absorption and attenuate metabolic acidosis during sepsis.

Original languageEnglish (US)
Pages (from-to)F711-F725
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number3
DOIs
StatePublished - Sep 6 2018

Fingerprint

Sepsis
Extremities
Lipids
Acidosis
Punctures
Ligation
Phosphatidylinositol 3-Kinase
Kidney
Toll-Like Receptor 4
Interleukin-1 Receptors
monophosphoryl lipid A
Immunologic Factors
Innate Immunity
Up-Regulation
Acids
Survival
Mortality

Keywords

  • Kidney
  • LPS
  • Metabolic acidosis
  • Monophosphoryl lipid A
  • Sepsis

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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title = "Monophosphoryl lipid a prevents impairment of medullary thick ascending limb HCO- 3 absorption and improves plasma HCO- 3 concentration in septic mice",
abstract = "Meta-bolic 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 medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic HCO- 3 absorptive capacity and 2) enhancing inhibition of HCO- 3 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 HCO3 - 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 HCO3 - 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 HCO3 - absorption were associated with marked improvement in plasma HCO- 3 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 HCO3 - absorption and attenuate metabolic acidosis during sepsis.",
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T1 - Monophosphoryl lipid a prevents impairment of medullary thick ascending limb HCO- 3 absorption and improves plasma HCO- 3 concentration in septic mice

AU - Watts, Bruns

AU - George, Thampi

AU - Sherwood, Edward R.

AU - Good, David

PY - 2018/9/6

Y1 - 2018/9/6

N2 - Meta-bolic 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 medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic HCO- 3 absorptive capacity and 2) enhancing inhibition of HCO- 3 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 HCO3 - 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 HCO3 - 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 HCO3 - absorption were associated with marked improvement in plasma HCO- 3 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 HCO3 - absorption and attenuate metabolic acidosis during sepsis.

AB - Meta-bolic 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 medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic HCO- 3 absorptive capacity and 2) enhancing inhibition of HCO- 3 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 HCO3 - 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 HCO3 - 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 HCO3 - absorption were associated with marked improvement in plasma HCO- 3 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 HCO3 - absorption and attenuate metabolic acidosis during sepsis.

KW - Kidney

KW - LPS

KW - Metabolic acidosis

KW - Monophosphoryl lipid A

KW - Sepsis

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U2 - 10.1152/ajprenal.00033.2018

DO - 10.1152/ajprenal.00033.2018

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SN - 0193-1849

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