Immunological and histopathological features of secondary injury in a long-term mouse model of persistent inflammation, immunosuppression, and catabolism syndrome

Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is a major cause of prolonged morbidity and poor outcomes among critical illness survivors. We established long-term murine PIICS models using two peritonitis-induced sepsis methods-cecal ligation and puncture (CLP) and fecal suspension intraperitoneal injection (FSI)-and investigated their immunological and histopathological features over 2 months. Survivors were defined as PIICS model mice, with unoperated mice serving as controls. Following an intraperitoneal lipopolysaccharide (LPS; 10 mg/kg) challenge, 27 plasma cytokines and chemokines were quantified before and 20 h after administration, and survival was monitored for 14 days. Survivors of CLP and FSI exhibited sustained baseline elevations in inflammatory mediators (G-CSF, IL-7, CCL3/4) and reductions in anti-inflammatory cytokines (IL-13, TGF-β2) compared with those in controls. Following the LPS challenge, control mice showed robust cytokine induction, and 4 of 13 died, whereas both PIICS groups exhibited globally suppressed cytokine responses with no mortality (p = 0.011 vs. controls). Histopathological staining showed mild splenic macrophage infiltration at baseline in both PIICS groups. Upon LPS administration, pulmonary congestion, splenic macrophage infiltration, and neutrophil infiltration into the portal vein were observed. Intra-abdominal abscesses or granuloma-like masses occurred in 50% of CLP-PIICS mice. Collectively, these long-term PIICS models recapitulate key clinical features, including persistent dysregulated inflammation, impaired responsiveness to secondary stimuli, and chronic tissue pathology, providing a platform to investigate the transition from acute sepsis to PIICS and for preclinical testing of immune-restorative or metabolic interventions in survivors of sepsis.