Acute trauma and critical illness cause increases in G-CSF that correlate with post-injury outcomes and are associated with changes in bone marrow progenitor populations.

Background: Critical illness dramatically increases the demand for and consumption of leukocytes. This demand induces emergency hematopoiesis (EH) whereby the hematopoietic stem and progenitor cells in the bone marrow become activated and proliferate to increase leukocyte production. Recent studies in murine models of trauma demonstrate that trauma induces EH through IL-1-dependent production of G-CSF. We hypothesized that non-septic critical illness (NSCI) would similarly drive IL-1 and G-CSF- mediated EH in critically ill humans. Methods: Two independent prospective observational trials were conducted. Plasma cytokine levels were measured in a cohort of 55 critically injured trauma patients. G-CSF levels were measured on arrival and at 1, 6, 24, and 72 hours after arrival. Correlation between G-CSF levels and injury severity, length of stay, ICU length of stay and inflammatory cytokine levels were measured. Bone marrow was isolated from an independent cohort 6 non-septic critically ill organ donation candidates and 5 healthy donors. Hematopoietic stem and progenitor cells were measured by flow cytometry. Results: Critical injury induced a rapid and significant increase in plasma G-CSF levels, detectable within 1 hour of hospital arrival, with peak levels measured 6 hours after injury. G-CSF levels 1 hour after arrival correlated with injury severity, length of stay and ICU length of stay. 6 hour G-CSF levels correlated with ICU LOS. 6 hour G-CSF levels correlated strongly with 6-hour levels of IL-1β, IL-6 and IL-8. NSCI caused a significant increase in hematopoietic stem cells (HSC) and common myeloid progenitors and a significant decrease in multipotent progenitors and common lymphoid progenitors as compared to healthy controls. Conclusions: Trauma induces a rapid increase in plasma G-CSF levels that is strongly correlated with plasma IL-1β, suggesting that as in murine models, IL-1 may be driving G-CSF production. As in mice, NSCI induced EH, characterized by expansion of the HSC cohort and a shift toward myelopoiesis. In critically ill humans these data suggest that sterile injury induces IL-1 and G-CSF mediated EH, recapitulating the murine finding.