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Early-age-related changes in proteostasis augment immunopathogenesis of sepsis and acute lung injury

Manish Bodas1, Taehong Min, Neeraj Vij

  • 1Department of Pediatric Respiratory Sciences, Johns Hopkins University, Baltimore, Maryland, United States of America.

Plos One
|November 19, 2010
PubMed

Insights

Early age-related proteostasis imbalance exacerbates inflammation in sepsis and acute lung injury. Salubrinal shows therapeutic potential by reducing NFκB-mediated inflammation in adult subjects.

Area of Science:

  • Immunology
  • Cellular Biology
  • Aging Research

Background:

  • Proteasomal activity decline is linked to age-related disorders, but early mechanisms remain unclear.
  • Investigated early-age-related mechanisms augmenting sepsis and acute lung injury immunopathogenesis.

Purpose of the Study:

  • To elucidate age-related changes in proteostasis and their impact on inflammation in pediatric versus adult mice.
  • To assess the therapeutic potential of salubrinal in mitigating age-associated inflammatory responses.

Main Methods:

  • Compared pediatric and adult C57BL/6 mice subjected to sepsis (CLP) or acute lung injury (ALI) models.
  • Analyzed inflammatory markers (IL-6, MPO), proteasomal subunit PSMB6, ubiquitinated proteins, unfolded protein response (UPR), and NFκB signaling.
  • Utilized in vitro cell models and in vivo salubrinal treatment to evaluate therapeutic efficacy.

Main Results:

  • Adult mice exhibited higher basal IL-6 and MPO levels, indicating increased inflammation.
  • Reduced PSMB6 expression in adults led to protein ubiquitination, UPR activation, and elevated NFκB.
  • Salubrinal effectively controlled IL-6 secretion and pro-inflammatory cell recruitment in adult mice.

Conclusions:

  • Early-age-related proteostasis imbalance is a novel mechanism driving NFκB-mediated inflammation in sepsis and ALI.
  • Salubrinal demonstrates therapeutic efficacy in reducing NFκB-mediated inflammation in adult and older individuals.
Abstract

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