A genomic storm in critically injured humans

Abstract

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

Genomic responses in mouse models poorly mimic human inflammatory diseases

“…amounts of blood received (total transfusion in milliliters; M = 1,900, MQ = 1,050-3,000), and patient clinical outcomes as indicated by survival (96%), multiorgan failure (maximum Marshall score; M = 5, MQ = 3-7), time to recovery (days; M = 7, MQ = 4-15), nosocomial infections (54.5%), and hospital length of stay (days; M = 21, MQ = 12-32) (15,21). Similarly, in the burn patient population, significant variations existed in the extent of burn injuries, for example, in terms of total body surface area of burns (TBSA; M = 53%, MQ = 32-74%), percentages of flame burns (86%) and inhalation injury (52%), and survival (85%).…”

“…The Inflammation and Host Response to Injury, Large Scale Collaborative Research Program has completed multiple studies on the genomic responses to systemic inflammation in patients and human volunteers as well as murine models (14)(15)(16)(17)(18). These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16)(17)(18).…”

“…These datasets include genome-wide expression analysis on white blood cells obtained from serial blood draws in 167 patients up to 28 d after severe blunt trauma (15), 244 patients up to 1 y after burn injury, and 4 healthy humans for 24 h after administration of low-dose bacterial endotoxin (14) and expression analysis on analogous samples from well-established mouse models of trauma, burns, and endotoxemia (16 treated and 16 controls per model) (16)(17)(18). In humans, severe inflammatory stress produces a genomic storm affecting all major cellular functions and pathways (15) and therefore, provided sufficient perturbations to allow comparisons between the genes in the human conditions and their orthologs in the murine models.…”

The immune response of the human brain to abdominal surgery

“…The anti-inflammatory response is generally more protracted than the proinflammatory response, leading to a state of immune suppression in patients surviving the initial "cytokine storm." 16,43 Upon reaching the brain, the proinflammatory signals interact with the resident brain immune system (eg, microglia and astrocyte populations), 3,9,27 causing a neuroinflammatory reaction and consequent neuronal dysfunction; this was shown in preclinical surgical models to affect CNS plasticity in brain regions relevant for higher cognitive functions. [1][2][3][4] We used plasma tau and NFL as markers of acute neuronal injury 39,40 on postoperative days 3 to 4 and at 3 months.…”

Development of a Genomic Metric that can be Rapidly Used to Predict Clinical Outcome in Severely Injured Trauma Patients

“…To obtain a better global understanding of the complex immune response following severe injury in humans, we examined genome-wide expression patterns of blood leukocytes following severe injury, and observed what was termed a 'genomic storm', in which greater than 75% of the host leukocyte transciptome was altered following severe injury (13). More importantly, we demonstrated that genomic information collected in the first 12 hours of severe trauma contained information independent of anatomical and physiological prognosticators that was associated with different clinical outcomes (14).…”