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Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice
06:40

Cecal Ligation and Puncture-induced Sepsis as a Model To Study Autophagy in Mice

Published on: February 9, 2014

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PICK1 Deficiency Induces Autophagy Dysfunction via Lysosomal Impairment and Amplifies Sepsis-Induced Acute Lung

Yunchang Mo1, Yingying Lou1, Anqi Zhang1

  • 1Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Wenzhou City, Zhejiang Province 325000, China.

Mediators of Inflammation
|November 8, 2018
PubMed

Insights

Protein interacting with C-kinase 1 (PICK1) deficiency worsens sepsis-induced acute lung injury by disrupting autophagy. Impaired lysosomal function blocks autophagic flux, highlighting PICK1's role in sepsis treatment.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathophysiology

Background:

  • Sepsis triggers systemic inflammation, leading to multi-organ failure and high mortality.
  • Current sepsis therapies are limited by insufficient understanding of its pathophysiology.
  • Protein interacting with C-kinase 1 (PICK1) has known functions, but its role in sepsis-induced acute lung injury (ALI) is unknown.

Purpose of the Study:

  • To investigate the role of PICK1 in sepsis-induced ALI.
  • To elucidate the mechanisms underlying PICK1's involvement in sepsis pathophysiology.

Main Methods:

  • Established a mouse model of sepsis using cecal ligation and puncture (CLP).
  • Analyzed autophagy markers (LC3-II/LC3-I) in wild-type and PICK1 knockout (PICK1-/-) septic mice.
  • Utilized transmission electron microscopy (TEM) to examine autophagosome accumulation in bone marrow-derived macrophages (BMDMs).
  • Investigated the role of lysosomal function and the PI3K-Akt-mTOR pathway.

Main Results:

  • PICK1-/- septic mice exhibited decreased LC3-II/LC3-I ratios, indicating autophagy dysfunction.
  • TEM revealed autophagosome accumulation in BMDMs from PICK1-/- mice, suggesting impaired autophagic flux.
  • PICK1 deficiency exacerbated sepsis-induced ALI, demonstrating that disrupted autophagic flux is detrimental.
  • Impaired lysosomal function was identified as the cause of autophagic flux blockade, linked to the PI3K-Akt-mTOR pathway.

Conclusions:

  • PICK1 deficiency disrupts autophagic flux and exacerbates sepsis-induced ALI.
  • Impaired lysosomal function mediates the autophagic flux blockade in PICK1-deficient sepsis.
  • PICK1 plays a critical role in regulating autophagy during sepsis.
  • Findings provide novel insights into autophagy's role in sepsis and suggest PICK1 as a potential therapeutic target.

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