Critical illness is a leading cause of death in the United States. Critical illness results in persistent and pervasive immune dysfunction, predisposing patients to infection. We hypothesize that the alterations in the function of the hematopoietic stem and progenitor cells contributes to critical-illness induced immunosuppression. For over 25 years it has been recognized that critical illness can alter the function of hematopoietic stem and progenitor cells (HSPC) in the bone marrow. Other studies have demonstrated that hematopoietic stem cells (HSC) regulate the immuno-inflammatory response, altering the production and function of leukocytes derived from these progenitors. We hypothesize that injury results in damage to the HSPC that results in changes in the function of progeny leukocytes, contributing to injury-induced immune dysfunction. We present preliminary data demonstrating that injury causes dramatic expansion of immature progenitors in the bone marrow through IL-1 mediated production of G-CSF and that myeloid cells derived from the bone-marrow of injured mice have a defective response to microbial products. Here we propose a line of investigation to define the role of HSPC in injury-induced immune dysfunction and to extend these results from the bench to the bedside. Key tasks of this proposal are 1. To directly link changes in the hematopoietic stem cells with changes in innate immunity in murine models of critical illness and in critically ill patients. 2. Define the mechanisms by which injury alters the function of the HSPC. 3. Determine how injury-induced changes in the HSPC are propagated to the effector leukocytes.
Critical illness is a leading cause of death in the US; immune dysfunction is a leading cause of death for these patients. We propose that injury alters the function of the leukocyte progenitors in the bone-marrow as a novel mechanisms for critical illness-induced immune dysfunction. We propose experiments to define this new mechanism and establish potential pathways for therapeutic modulation.
