A Murine Model of Persistent Inflammation, Immune Suppression, and Catabolism Syndrome

Abstract

Critically ill patients that survive sepsis can develop a Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), which often leads to extended recovery periods and multiple complications. Here, we utilized a cecal ligation and puncture (CLP) method in mice with the goal of creating a model that concurrently displays all the characteristics of PICS. We observed that, after eight days, mice that survive the CLP develop persistent inflammation with significant myelopoiesis in the bone marrow and spleen. These mice also demonstrate ongoing immune suppression, as evidenced by the decreased total and naïve splenic CD4 and CD8 T cells with a concomitant increase in immature myeloid cells. The mice further display significant weight loss and decreased muscle mass, indicating a state of ongoing catabolism. When PICS mice are challenged with intranasal Pseudomonas aeruginosa, mortality is significantly elevated compared to sham mice. This mortality difference is associated with increased bacterial loads in the lung, as well as impaired neutrophil migration and neutrophil dysfunction in the PICS mice. Altogether, we have created a sepsis model that concurrently exhibits PICS characteristics. We postulate that this will help determine the mechanisms underlying PICS and identify potential therapeutic targets to improve outcomes for this patient population.

Innate Immunity in the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome and Its Implications for Therapy

“…Although these cytokines and protein biomarkers serve as signatures for PICS, the detailed mechanisms leading to this persistent inflammation, immune suppression, and catabolism have yet to be elucidated. The discovery of the underlying mechanisms will undoubtedly require further studies, including additional genomic and proteomic analyses, as well as the creation of murine models of PICS, which are currently underway ( 191 – 193 ). Future success in the treatment of CCI will likely require addressing the underlying pathophysiology of PICS, potentially through the use of immunomodulatory therapies.…”

Consumptive coagulopathy is associated with organ dysfunction during PICS

“…All animal protocols were approved by the Institutional Animal Care and Use Committee at the University of Cincinnati (Protocol 10-05-10-01). To induce acute polymicrobial sepsis, mice underwent 33% cecal ligation with a single, full-thickness, 25-gauge needle puncture under 2.5% isoflurane general anesthesia, as previously described (26,32). All surgeries were performed between 8 AM and 12 PM.…”

“…All surgeries were performed between 8 AM and 12 PM. After CLP, mice received 1 ml of subcutaneous normal saline resuscitation and recovered on a 37°C heating pad for 1 h. Cohort sizes were chosen based on previously published data to account for variability and mortality (26). The mortality rate of this moderate CLP injury is 25% to 33%, paralleling the 10% to 40% mortality rate observed in human sepsis (26).…”

“…Some sepsis survivors develop persistent inflammation, immunosuppression, and catabolism syndrome (PICS), marked by recurrent nosocomial infections, inadequate nutrition, poor wound healing, neurocognitive deficits, and the need for long-term skilled nursing. Physiologically, this syndrome is characterized by ongoing inflammation, suppressed host immunity, and loss of lean muscle mass (10,26). Many of these patients have prolonged recovery times, utilize immense hospital resources, and often progress to chronic critical illness (CCI) with less than 50% of patients surviving one year after hospital discharge (23,24).…”

Rethinking animal models of sepsis – working towards improved clinical translation whilst integrating the 3Rs

“…Criticism of sepsis models per se, have focussed on questionable experimental time courses, including the duration of the 'sepsis syndrome' , choice of endpoints or the length of follow up in survivors -which do not necessarily correspond to the clinical situation. It has been argued that the duration of follow-up is often too short and may not capture the more persistent changes in the inflammatory response that ensue in patients [26,27]. However, performing longer term sepsis studies in animals has the potential to increase the welfare burden and this requires careful consideration of harm vs. benefit.…”