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Postinjury neutrophil priming and activation: an early vulnerable window
Background:
Generation of extracellular, cytotoxic superoxide anion (O2-) by polymorphonuclear neutrophils (PMNs) contributes to an unbridled inflammatory response that can precipitate multiple organ failure (MOF). Release of O2- is markedly enhanced when activated PMNs have been previously "primed" by inflammatory mediators, such as those expressed after trauma. We therefore hypothesized that PMN priming occurs as an integral part of the early inflammatory response to trauma.
Methods:
PMNs were obtained from 17 high-risk patients with torso trauma at 3, 6, 12, 24, 48, and 72 hours after injury, as well as from 10 healthy donors, and the in vitro release of O2- was quantitated with a kinetic, superoxide dismutase (SOD)-inhibitable cytochrome c reduction assay. PMN O2- release was measured in the presence and absence of 1 mumol/L N-formyl-methionyl-leucyl-phenylalanine (fMLP) and after priming and activation with 20 nmol/L platelet-activating factor (PAF) and 1 mumol/L fMLP, respectively.
Results:
In vitro PMN O2- release was used to determine whether postinjury PMNs were (1) activated in vivo, (2) primed in vivo, or (3) primable in vitro. Unstimulated PMNs from trauma patients spontaneously expressed modest amounts of O2- in vitro from 6 to 48 hours after injury, suggesting endogenous activation. Also, fMLP-activated PMNs collected between 3 and 24 hours after injury expressed more O2- than controls (p < or = 0.02), indicating in vivo, trauma-related priming. Furthermore, postinjury PMNs were maximally primed in vivo (i.e., in vitro exposure to PAF before fMLP activation failed to significantly enhance O2- release) as compared to PMNs treated with fMLP.
Conclusions:
These data indicate that major torso trauma (first hit) primes and activates PMNs within 3 to 6 hours after injury. Consequently, we postulate that postinjury priming of PMNs may create an early vulnerable window during which a second hit (e.g., a secondary operation or delayed hemorrhage) activates exuberant PMN O2- release, rendering the injured patient at high risk for MOF.
Insights
Major torso trauma primes and activates neutrophils (PMNs) within hours, increasing superoxide anion release. This early inflammatory response elevates the risk of multiple organ failure (MOF) if a second injury occurs.
Area of Science:
- Immunology
- Trauma Research
- Critical Care Medicine
Background:
- Polymorphonuclear neutrophils (PMNs) generate superoxide anion (O2-), contributing to inflammation and potentially multiple organ failure (MOF).
- PMN activation and O2- release are significantly amplified by inflammatory mediators, particularly after trauma.
- This study investigates whether PMN priming is an inherent early response to trauma.
Purpose of the Study:
- To determine if trauma patients' PMNs are primed and activated in vivo.
- To assess the timing and extent of PMN priming following major torso trauma.
- To understand the implications of PMN priming for subsequent inflammatory responses and MOF risk.
Main Methods:
- Quantified in vitro O2- release from PMNs of 17 torso trauma patients and 10 healthy donors using a cytochrome c reduction assay.
- Collected PMNs at various time points post-injury (3-72 hours).
- Assessed PMN O2- release with and without stimulation (fMLP) and after priming (PAF) followed by activation (fMLP).
Main Results:
- Unstimulated PMNs from trauma patients showed spontaneous O2- release 6-48 hours post-injury, indicating in vivo activation.
- PMNs from patients 3-24 hours post-injury released more O2- upon fMLP stimulation, confirming in vivo priming.
- Post-injury PMNs exhibited maximal in vivo priming, as in vitro PAF priming did not further enhance fMLP-induced O2- release.
Conclusions:
- Major torso trauma rapidly primes and activates PMNs within 3-6 hours.
- This early PMN activation creates a window of vulnerability, where a 'second hit' can trigger excessive O2- release.
- Post-traumatic PMN priming is a significant factor contributing to the high risk of MOF in injured patients.