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Tjaakje Visser

Thursday 11 October 2012

Monitoring and Modulation of the neutrophil response

Promotor: Prof. dr. L.P.H. Leenen & Prof. dr. L. Koenderman
Defence: 26 November 2012

A disproportional innate immune response underlies the pathogenesis of organ failure and sepsis as seen in trauma patients. It is known that additional inflammatory stimuli, induced by e.g. surgical interventions, augment the risk for occurrence of these complications. Treatment strategies may be beneficially adjusted when we are able to identify patients at risk for these complications. Also, there is an unmet need for immunomodulating therapies to reduce the occurrence of inflammatory complications.
Review of the literature showed that inflammatory markers are up till now, insufficient to identify patients at risk for inflammatory complications (Chapter 2). In order to get better insight of the innate immune response we looked at the neutrophil reaction in patients with isolated thorax trauma. In Chapter 3 we showed that a moderate trauma results in a transient systemic neutrophil response (Chapter 3). This was objectified by a transient altered surface receptor phenotype of circulating neutrophils. The neutrophil response was characterized by an influx of young banded cells in the circulation and appearance of different neutrophil (sub)populations. Interestingly, a short-term innate response did not lead to organ failure in patients at risk.
In chapter 4 we showed that one of the populations that appears in the circulation after severe injury are neutrophil progenitor cells. These neutrophil progenitor cells had a diminished anti-microbial function. Neutrophil progenitors were able to mature outside the bone marrow in absence of stimulating factors.
In chapter 5 we compared the early neutrophil reaction induced by damage associated molecular patterns (DAMP) to the neutrophil reaction induced by pathogen associated molecular patterns (PAMP). For this purpose circulating neutrophils were obtained from trauma patients at 3 and 24 hrs after injury and from healthy volunteers at 3 and 24 hrs after intravenous injection of lipopolysaccharide (LPS). We showed that the early neutrophil reaction was comparable in the two conditions.
The human endotoxemia model, in which LPS is injected in healthy volunteers to induce an inflammatory reaction, may not only serve as model for infectious diseases but also for conditions in relation to trauma. The endotoxemia model may be used for further investigations towards the early neutrophil response and may also be used to test potential therapies.
Therapeutical interventions designated to modulate the immune response are up till now unable to reduce morbidity and mortality in severely injured patients (Chapter 6). We tested the effect of injection of the endogenous acute phase protein C-1 esterase inhibitor (C1INH) on the inflammatory response (Chapter 7). Administration of C1INH resulted in a reduced concentration of circulating pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and TNF-α. It also resulted in an increased concentration of the anti-inflammatory IL-10. Interestingly, C1INH did not attenuate the neutrophil response (Chapter 8). From this result we can conclude that the humeral response does not correlate with the cellular response. The potential beneficial effect of C1INH administration will be examined in a placebo controlled randomized study in patients with femoral fracture.