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Mecanismo da morte de células endoteliais pulmonares promovida pela acidemia láctica na sepse: papel da via CIRP-ZBP1-PANoptosis

  • role： Corresponding author, First author通信作者, 第一作者
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen 518110, Guangdong, China

  • Email：tinggong@pitt.edu
  • Introduction：* tinggong@pitt.edu
Ting Gong12*,  
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Qing-De Wang1,  
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Patricia A. Loughran1,  
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Yue-Hua Li1,  
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Melanie J. Scott1,  
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

Timothy R. Billiar13,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen 518110, Guangdong, China

  • Email：youtanliuhao@163.com
  • Introduction：youtanliuhao@163.com
You-Tan Liu2*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA

    Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

    Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA

  • Email：jif7@pitt.edu
  • Introduction：jif7@pitt.edu
Jie Fan1345*

Resumo

Background:Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive.Methods:C57BL/6 wild type (WT), Casp8–/–, Ripk3–/–, and Zbp1–/– mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways.Results:In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI.Conclusions:These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.

Palavras-chave

Extracellular cold-inducible RNA-binding protein (eCIRP);PANoptosis;Z-DNA binding protein 1 (ZBP1);Ubiquitination;Sepsis-induced acute lung injury (ALI)

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