{
  "abstract": "Background Severe acute pancreatitis (SAP) is a life-threatening inflammatory disorder characterised by progressive multiorgan dysfunction. Direct investigation of human pancreatic tissue in SAP has been extremely limited, and effective targeted therapies are currently lacking.Objective We sought to define the cellular and molecular mechanisms of SAP progression to identify actionable therapeutic targets.Design Using rare pancreatic tissues from critically ill patients with SAP (n = 8), we constructed the first single-cell transcriptomic atlas of human SAP. Cellular compositional changes and intercellular communication were analysed to elucidate disease mechanisms. Findings were integrated with clinical data from a large patient cohort (n = 153) and validated through in vitro and in vivo studies in murine and porcine models.Results We identified pancreatic microcirculatory failure as a central pathological event in SAP, driven by CD8 + T cell-mediated endothelial injury. Mechanistically, tumour necrosis factor-alpha (TNF-α) upregulates UL16-binding proteins (ULBPs) on endothelial cells, activating the cytotoxic receptor NKG2D on infiltrating CD8+ T cells and creating a feed-forward loop that amplifies microvascular damage. The TNF-α/ULBP/NKG2D axis correlated with clinical disease severity and microcirculatory dysfunction in patients. In preclinical models, inhibition of TNF-α or CD8+ T cells preserved microvascular integrity, reduced tissue damage and improved survival.Conclusion This study provides the comprehensive cellular map of human SAP and uncovers a pathogenic immune-endothelial circuit—orchestrated by the TNF-α/ULBP/NKG2D axis—that drives microcirculatory dysfunction. These findings establish a mechanistic rationale for targeting TNF-α as a potential therapeutic strategy in SAP.",
  "authors": [
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Liang Shi"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Weiqi Li"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Duojiao Chen"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Boqiang Liu"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Zihao Huang"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Chenqi Jin"
    },
    {
      "affiliations": [
        "Department of Oncology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Lingfeng Ma"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Qiang Liu"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Bingzhi Dong"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Zhaoyuan Pan"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Lijun Du"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Lidan Hou"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Muxiong Chen"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China",
        "Department of Critical Care Medicine, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Jinyan Xie"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Rongpan Bai"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China",
        "Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Chinese Academy of Sciences Hefei Institutes of Physical Science, Hefei, Anhui, China"
      ],
      "name": "Hongcang Gu"
    },
    {
      "affiliations": [
        "Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Di Wang"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China",
        "Department of Anesthesiology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China"
      ],
      "name": "Xin Yu"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Bo Shen"
    },
    {
      "affiliations": [
        "Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China",
        "Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Junbin Qian"
    },
    {
      "affiliations": [
        "Department of General Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China",
        "Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China"
      ],
      "name": "Hong Yu"
    }
  ],
  "title": "TNF-α drives pancreatic microcirculatory dysfunction via CD8+ T cell-mediated endothelial injury in severe acute pancreatitis",
  "uid": "02b7e08c-9a93-5b55-9f40-2e66661042e5"
}