Kinetics of the excessive cellular innate immune response after injury

Abstract

Organ failure is a severe complication frequently seen in injured patients, with mortality rates of up to 80%. Failure of function of one or more organs after trauma occurs during an early phase (0-3 days) and/or a late phase (>7 days). Neutrophils and monocytes (both leukocytes and important effector cells of the innate immune system) are essential in the pathophysiology of organ failure after trauma. It is thought that early phase organ failure is caused by the excessive activation of the above mentioned cells, while organ failure during the late phase is the consequence of severe infection resulting in sepsis. The exact mechanisms underlying early and late phase organ failure are currently unknown. Therefore, diagnosis and treatment remain difficult. The pathophysiology of organ failure after injury was studied by investigating the phenotype and function of neutrophils and monocytes in trauma patients. Severe injury is known to cause stimulation of these innate immune cells. Indeed, activated neutrophils were found in the lungs, however, neutrophils with decreased functionality were found in the circulation. Functionality of neutrophils was measured by the responsiveness of an active receptor complex (active Fc-gamma-RII) towards in vitro stimulation with a bacterial derived product (fMLP). With increasing injury severity, a decreasing responsiveness of neutrophils in the peripheral circulation was found. In addition, patients who developed early phase respiratory failure (ARDS) demonstrated a striking decreased neutrophil responsiveness. Similar changes in the monocyte population were found, measured by the expression of a receptor used for antigen recognition (e.g. HLA-DR). An increase in trauma severity was related to a marked redistribution of the HLA-DR monocyte population. Patients who developed ARDS demonstrated a distinctly lower percentage of HLA-DR positive monocytes after trauma. Trauma led to neutrophils in the circulation with a decreased functionality and a redistribution of the monocyte population. As a result in injured patients with an excessive inflammatory response, the innate immune system becomes exhausted after a week. Exhaustion of the immune system was demonstrated by 1) a further decline of neutrophil responsiveness, reaching its minimum prior to the development of sepsis and 2) an inadequate response of HLA-DR negative monocytes in the second week after trauma, predisposing the patient to severe infections. Besides a decreased neutrophil responsiveness, subpopulations of neutrophils appeared in the peripheral circulation of injured patients. After severe trauma, premature cells (i.e. metamyelocytes) and toxic neutrophils coexist besides normally mature neutrophils. All cells have distinct morphology, phenotype and function. In patients with septic shock, these toxic neutrophils were also found in the lymphatic system. It is hypothesized that under the extreme conditions of sepsis, fresh neutrophils are not produced in a sufficient number, which forces the release of premature cells from the bone marrow and recirculation of toxic neutrophils from the tissues. Above mentioned data provide important information on the normal homeostasis of human innate immune cells and their role after excessive stimulation by injury. With these new insights in the pathophysiology of organ failure after trauma, a foundation is made for the development of new immunomodulatory treatments.