2. Academic Validation
  3. Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice

Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice

  • Respir Res. 2023 Nov 17;24(1):288. doi: 10.1186/s12931-023-02594-0.
Jiang Yu # 1,  Boying Zhao # 2 3,  Qiangzhong Pi 4,  Guoxiang Zhou 1,  Zhe Cheng 5,  Can Qu 6,  Xiaowen Wang 7,  Lingwen Kong 2 3,  Suxin Luo 1,  Dingyuan Du 8 9,  Yongzheng Guo 10
Affiliations

Affiliations

  • 1 Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China.
  • 3 Chongqing Key Laboratory of Emergency Medicine, Chongqing, 400010, China.
  • 4 Department of Respiratory Medicine, Southwest Hospital, Army Military Medical University, Chongqing, P.R. China.
  • 5 Department of Cardiology, Chongqing University three Gorges Hospital, Chongqing, 404199, China.
  • 6 Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 7 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 8 Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing University, Chongqing, 400010, China. [email protected].
  • 9 Chongqing Key Laboratory of Emergency Medicine, Chongqing, 400010, China. [email protected].
  • 10 Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China. [email protected].
  • # Contributed equally.
PMID: 37978525 DOI: 10.1186/s12931-023-02594-0
Abstract

Background: We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis.

Methods: Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic.

Results: S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and Apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs.

Conclusion: The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.

Keywords

Acute lung injury; Pulmonary inflammation; S100A8/A9; Vascular leakage; sepsis.

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