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Neutrophil priming and activation in the pathogenesis of postinjury multiple organ failure
D A Partrick1, F A Moore, E E Moore
1Department of Surgery, Denver General Hospital, University of Colorado Health Sciences Center, USA.
Abstract:
The continuing study of multiple organ failure (MOF) has led to the development of inflammatory models of tissue injury in contrast to earlier infectious models. This change of focus is in response to more recent clinical observations suggesting that postinjury MOF frequently occurs in the absence of infection. In the alternative "two-hit" inflammatory model that has been proposed, the initial traumatic insult "primes" the inflammatory response such that a delayed, otherwise innocuous, inflammatory insult triggers an exaggerated response. The neutrophil (PMN), being uniquely equipped to cause oxidative tissue injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, has been implicated as an early pivotal player in this model of postinjury MOF. Similar to the "two-hit" inflammatory model, circulating PMNs respond to proinflammatory mediators by becoming primed for enhanced superoxide anion (O2.) production and by increasing adherence to endothelium of organs that are susceptible to PMN-mediated injury. Subsequent proinflammatory insults promote further neutrophil sequestration and activate them for enhanced release of O2.-. The resulting tissue injury can be perpetuated and lead to eventual end-organ damage and failure. In terms of the NADPH oxidase system, PMN priming and activation by various agonists have been well documented in vitro and lead to increased endothelial damage. PMN priming and activation are also operable in an in vivo model of gut ischemia/reperfusion, a surrogate of shock and trauma resuscitation, leading to distant organ damage. Finally, in clinical studies of severely injured trauma patients, PMN priming and activation sequences identify patients at risk for developing MOF with its associated high mortality. Further characterization of the mechanisms that regulate PMN priming and activation in the trauma patient is necessary for the development of new therapeutic interventions designed to block deleterious PMN responses which lead to MOF while not compromising beneficial PMN functions of host defense and tissue repair.
Insights
Multiple organ failure (MOF) is increasingly viewed as an inflammatory process. Neutrophils (PMN) play a key role in MOF by causing oxidative tissue injury, and their priming and activation can predict patient outcomes.
Area of Science:
- Immunology
- Pathophysiology
- Trauma Research
Background:
- Multiple organ failure (MOF) research has shifted from infectious to inflammatory models, reflecting clinical observations of MOF in non-infectious post-injury states.
- The "two-hit" inflammatory model suggests an initial insult primes the body for an exaggerated response to a subsequent, otherwise harmless, insult.
- Neutrophils (PMN) are implicated in MOF pathogenesis due to their capacity for oxidative tissue injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system.
Purpose of the Study:
- To investigate the role of neutrophil (PMN) priming and activation in the "two-hit" inflammatory model of post-traumatic multiple organ failure (MOF).
- To explore the mechanisms of PMN-mediated oxidative tissue injury and its contribution to end-organ damage.
- To identify PMN priming and activation patterns in trauma patients as potential predictors of MOF development and mortality.
Main Methods:
- Review of inflammatory models of tissue injury and the "two-hit" hypothesis.
- Examination of the neutrophil's (PMN) role, focusing on the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system.
- Analysis of in vitro and in vivo studies on PMN priming and activation, including gut ischemia/reperfusion models.
- Evaluation of clinical studies in severely injured trauma patients to correlate PMN activation with MOF risk.
Main Results:
- Circulating PMNs become primed for enhanced superoxide anion (O2.) production and increased adherence following an initial inflammatory insult.
- Subsequent insults lead to PMN sequestration and activation, exacerbating O2. release and perpetuating tissue injury.
- PMN priming and activation are observed in vitro and in vivo models (e.g., gut ischemia/reperfusion), leading to distant organ damage.
- In trauma patients, PMN priming and activation sequences identify individuals at high risk for developing MOF.
Conclusions:
- Neutrophil (PMN) priming and activation are critical early events in the inflammatory cascade leading to post-traumatic multiple organ failure (MOF).
- The NADPH oxidase system in PMNs is a key mediator of oxidative tissue injury contributing to MOF.
- Understanding the regulation of PMN priming and activation in trauma patients is essential for developing targeted therapies to prevent MOF while preserving host defense functions.