Characterization of a Preclinical Model of Hyperferritinemic Sepsis-Induced MODS

Sunday, January 22, 2023

11:15 AM – 12:15 PM PT

Location: Exhibit Hall - RST 04

First Author(s)

E. Scott Halstead, MD, PhD

Associate Professor
Penn State College of Medicine Hershey Children's Hospital
Hershey, United States

Disclosure information not submitted.

Co-Author(s)

TU

Todd Umstead, N/A

Laboratory Manager
Penn State University, United States

Disclosure information not submitted.
DM

Daniel McKeone, MD

Assistant Professor
Pennsylvania State Milton S Hershey Medical Center, United States

Disclosure information not submitted.
AB

Anthony S. Bonavia, MD

Associate Professor
Pennsylvania State Milton S Hershey Medical Center, United States

Disclosure information not submitted.

INTRODUCTION: Elevated serum ferritin levels are associated with increased severity and worse outcomes during pediatric sepsis. While this “hyperferritinemic sepsis” (HFS) subtype is increasingly being recognized as a distinct entity, the recent Sepsis-3 consensus definitions make no mention of ferritin. A knowledge gap exists regarding the diagnosis, incidence, and pathobiology of HFS. Below we describe a new preclinical model of HFS-induced MODS (HFS-MODS) via priming of the host with a viral stimulus followed by bacterial stimulus, Furthermore, we investigated the role of TNF in the disease process.

METHODS : Wild-type C57BL/6 mice were administered a viral RNA agonist, high-molecular weight poly(I:C) (5mg/kg), or vehicle control via intraperitoneal (i.p.) injection. Twenty-four hours (24h) later mice were administered lipopolysaccharide (LPS, 2.5 mg/kg) or vehicle control via i.p. injection. Serum was collected at defined time points. Cytokines were measured by bead-based multiplex array (Luminex Magpix). TNF was blocked in vivo using an anti-mouse TNF monoclonal antibody.

RESULTS: The sequential administration of poly(I:C) followed 24h later by LPS led to significant mortality as compared to LPS alone. Mice administered poly(I;C) and LPS demonstrated elevated ferritin levels, and demonstrated thrombocytopenia, elevated creatinine, elevated bilirubin and transaminases. Cytokine analysis was able to discriminate the various treatment groups, though some LPS-only mice clustered with the poly(I:C)/LPS group. TNF was consistently elevated in poly(I:C)/LPS administered mice. In vivo blockade of TNF during poly(I:C)-priming protected mice from LPS-induced mortality.

CONCLUSIONS: Our laboratory has developed a preclinical model of HFS-induced MODS (HFS-MODS) via priming of the host with a viral stimulus followed by bacterial stimulus. The HFS-MODS disease process leads to hyper-inflammatory monocyte/macrophage activation and multiple organ failure, and the disease process is dependent upon TNF signaling. Future work will delineate the mechanism of TNF-induced mortality.