Long-term survivors of murine sepsis are predisposed to enhanced LPS-induced lung injury and proinflammatory immune reprogramming

Abstract

Millions of people who survive sepsis each year are rehospitalized and die due to late pulmonary complications. In order to prevent and treat these complications, biomarkers and molecular mediators must be identified. Persistent immune reprogramming in the form of immunoparalysis and impaired host defense is proposed to mediate late pulmonary complications after sepsis, particularly new pulmonary infections. However, immune reprogramming may also involve enhanced/primed responses to secondary stimuli, although their contribution to long-term sepsis complications remains understudied. We hypothesize that enhanced/primed immune responses in the lungs of sepsis survivors are associated with late pulmonary complications. To this end, we developed a murine sepsis model using cecal ligation and puncture (CLP) followed 3 weeks later by administration of intranasal lipopolysaccharide to induce inflammatory lung injury. Mice surviving sepsis exhibit enhanced lung injury with increased alveolar permeability, neutrophil recruitment, and enhanced Ly6Chi monocyte Tnf expression. To determine the mediators of enhanced lung injury, we performed flow cytometry and RNA sequencing of lungs 3 weeks after CLP, prior to lipopolysaccharide. Sepsis survivor mice showed expanded Ly6Chi monocytes populations and increased expression of many inflammatory genes. Of these, S100A8/A9 was also elevated in the circulation of human sepsis survivors for months after sepsis, validating our model and identifying S100A8/A9 as a potential biomarker and therapeutic target for long-term pulmonary complications after sepsis. These data provide new insight into the importance of enhanced/primed immune responses in survivors of sepsis and establish a foundation for additional investigation into the mechanisms mediating this response.

Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization

“…Similarly, SOCS3 was found to dampen inflammation in macrophage cultures and in lipopolysaccharide (LPS)-induced inflammation ( Qin et al., 2012 ), and G-CSF signaling via STAT3 and induction of SOCS3 limit inflammation in bone remodeling ( Isojima et al., 2022 ). Therefore, we reason that failed G-CSF signaling and induction of SOCS3 expression in sepsis survivors may also contribute to the enhanced responses to LPS stimulation observed in sepsis survivors ( Denstaedt et al., 2021 ).…”

Metformin Mitigates Sepsis-Induced Acute Lung Injury and Inflammation in Young Mice by Suppressing the S100A8/A9-NLRP3-IL-1β Signaling Pathway

“… 56 A previous study indicated that S100A8/A9 in the plasma of patients following ALI brought about by sepsis or pneumonia significantly elevated as compared with healthy controls. 57 S100A8/A9 has been established to be one of the most distinctive DAMPs in sepsis, 58 , 59 which interacts with cell surface receptors on various immune cells, platelets, endothelial cells, and intracellular PRRs, exerting detrimental impacts on sepsis pathogenesis. 43 Specifically, activation of the S100A8/A9 complex through binding with TLR4 can induce pro-inflammatory cytokine production and promote not only recruitment but also activation of immune cells, ultimately leading to tissue damage and dysfunctions of organs in sepsis.…”

On race, human variation, and who gets and dies of sepsis

“…Around 15% develop one to two significant functional limitations, cognitive impairments, or mental health conditions (Prescott & Angus, 2018). Common symptoms of this “post‐sepsis syndrome” (PSS) include fatigue, lethargy, cognitive difficulty, executive function problems, muscle wasting and joint pain and associated difficulty moving or completing physical tasks (e.g., trouble dressing, bathing, walking), long‐term immunosuppression, kidney failure, lung fibrosis, and associated hypertension (Annane & Sharshar, 2015; Arens et al, 2016; Chao et al, 2014; Denstaedt et al, 2021; Fitzgerald et al, 2016; Iwashyna et al, 2010; Vanhorebeek et al, 2020) (Burnham et al, 2014). The effects of sepsis are long‐term, with 50% of survivors experiencing PSS symptoms 5 years after the sepsis event (reviewed in (Annane & Sharshar, 2015).…”