Exploring the Association Between Immunothrombotic Dysregulation and Disease Severity in Sepsis - Can Mesenchymal Stromal Cells Modulate this Effect?
Creators: name: Doolan, Aoife
Publisher: name: Royal College of Surgeons in Ireland
Year: 2022
Subjects: subject: 110301 Anaesthesiology
subject: FOS: Clinical medicine
subject: 110303 Clinical Microbiology
subject: 110707 Innate Immunity
subject: 110310 Intensive Care
subject: 110799 Immunology not elsewhere classified
subject: 110203 Respiratory Diseases
subject: 110309 Infectious Diseases
subject: FOS: Health sciences

description: <strong>Introduction: </strong>Sepsis causes 6 million deaths annually. There is increasing evidence to suggest that the pathogenesis involves immune dysregulation, endothelial dysfunction and coagulation activation. Lipids also contribute significantly to the innate immune response and hypolipidemia is evident in sepsis. The time course of some aspects of immunothrombotic dysregulation and its association with disease severity remains to be defined. Antibiotic resistance is growing worldwide and no specific therapy targeting the mediators of sepsis has proven successful. Mesenchymal stromal cells (MSCs) show promise in several models of sepsis. However, the potential for MSCs to modulate coagulation activation in sepsis has not yet been examined with any great detail. Further questions about MSCs efficacy in sepsis involve issues with MSC heterogeneity, limited sources, and reducing effectiveness with proliferation. Heterogeneity and issues of MSC potency could be ameliorated using induced pluripotent stem cell (iPSC) -derived MSCs and/or relevant immune mediator pre-activation techniques. We aimed to explore the association between immunothrombotic dysregulation and diseases severity in COVID-19 induced sepsis and examine the role of interferon gamma (IFN-γ)-primed iPSC-derived MSCs in in vitro and in vivo models of sepsis. <strong>Methods: </strong>We first described the time course of various markers of immunothrombotic dysregulation in25 patients with severe COVID-19-induced sepsis in critical care in Tallaght university Hospital (TUH). We examined the profile based on the following outcomes: secondary infection, ventilator-free days (VFDs)≤ 14 days, venous thromboembolism (VTE) and mortality. We then sought to examine the effects of IFN-γ-primed MCA-MSCs on macrophage phagocytosis and reactive oxygen species (ROS) production in vitro. Finally, we examined the effects of IFN-γ-primed MCA-MSCs on immunothrombotic dysregulation and outcome in a rodent E. coli pneumonia-induced sepsis model. <strong>Results: </strong>The hyperinflammatory response was greatest on admission to critical care and decreased as the clinical picture improved. However, the coagulation pathway remained activated, as evidenced by a persistently high d-dimer level throughout admission. Although the study was not powered to detect statistically significant differences in these parameters, d-dimers remained persistently higher in patients who developed secondary infection and in patients who died, suggesting that d-dimers may not only be a marker of thrombosis but a marker of immunothrombotic dysregulation and disease severity in sepsis. The prevalence of secondary infection was higher than quoted previously. HDL remained &lt; 1 mmol/l throughout admission and may be useful as a marker of immunosuppression but this needs to be investigated in a larger study. This study failed to demonstrate that greater immunothrombotic dysregulation was associated with worse outcome in critical care but there was a trend to suggest the same. IFN-γ-primed MCA-MSCs enhanced macrophage phagocytosis and ROS production in in-vitro experiments. They also increased oxygenation in the animal study. There was a trend towards enhanced bacterial clearance and reduced inflammation in rodents treated with IFN-γ-primed MCA-MSCs but this was not statistically significant. MCA-MSCs did not modulate the pro-thrombotic response. <strong>Conclusion: </strong>This study provides evidence to suggest that patients with sepsis display evidence of a highly dysregulated immunothrombotic response. Even after elevations in pro-inflammatory cytokines have subsided, the coagulation cascade is still active. The results highlight that patient with COVID-19-induced sepsis are at significant risk of immunoparesis throughout their critical care stay. As clinicians, we must be vigilant in examining for secondary infection and VTE even after the initial insult has resolved. In both in vitro and in vivo models of sepsis, we have provided some evidence to suggest that IFN-γ-primed MCA-MSCs may modify the immune response and improve outcome. We did not demonstrate an effect of MCA-MSCs on the pro-thrombotic response during pneumonia-induced sepsis. Future work needs to focus on examining their effects on immunothrombotic dysregulation in more detail.