Abstract
Background and objectives: Catecholamine-dependent acute obstructive suppurative cholangitis (CD-AOSC) is a severe form of cholangitis characterized by refractory hypotension. This study aimed to investigate its underlying pathogenic mechanisms. Methods: We conducted a retrospective case-control study involving 345 patients with biliary infections treated at Tongji Hospital, Tongji University, between 2012 and 2022. Patients were divided into three groups: chronic cholecystitis (CC; negative control), acute obstructive suppurative cholangitis (AOSC; positive control), and CD-AOSC (case group). Clinical and laboratory data were analyzed. Endotoxin levels in subcutaneous adipose tissue were measured, and transcriptomic analysis was performed to explore potential mechanisms. A rat model of cholangitis was used to validate findings related to hypotension in CD-AOSC. Results: Patients with CD-AOSC exhibited slower endotoxin clearance from adipose tissue (1st week vs. 2nd week: 72.7 ± 4.0 EU/g vs. 23.3 ± 3.2 EU/g) and milder inflammation (Immune cell count: 665.4 ± 179.1, Immunodeconv analysis: 0.3 ± 0.1) compared to AOSC patients (1st week vs. 2nd week: 9.7 ± 2.6 EU/g vs. 2.6 ± 0.7 EU/g, Immune cell count: 1344.0 ± 599.3, Immunodeconv analysis: 0.6 ± 0.1). This slower clearance of endotoxin allowed adipose tissue to function as an endotoxin reservoir. Persistent endotoxin release resulted in prolonged activation of the interleukin-18 (IL-18)/IL-18 receptor accesary protein (IL-18RAP) pathway, thereby sustaining inflammation and contributing to extended hypotension. The rat model confirmed the role of the interleukin-1β (IL-1β) inhibitor in decelerating endotoxin release and maintaining activation of the IL-18/IL-18RAP/interferon-γ (IFN-γ) pathway. Conclusions: Persistent hypotension in CD-AOSC appears to result from sustained activation of the IL-18/IL-18RAP pathway, driven by prolonged endotoxin release from adipose tissue. These findings highlight the potential of "Hours Exchanged Against (severity) Loss (HEAL)" strategy, in which early modulation of endotoxin release from adipose tissue by IL-1β inhibition during the initial phase of sepsis in cholangitis may improve patient survival.