Search

Background Inflammatory stimuli rapidly activate mitogen-activated protein kinases (MAPKs) in neutrophils (PMNs). However, their role in cytotoxic function remains unknown. Elucidating the signals involved in release of cytotoxic agents from PMNs may provide new avenues for therapy in diseases of diminished or excessive PMN function. Hypothesis The p38 MAPK and extracellular signal-related kinase 1/2 (ERK1/2) modulate superoxide generation and elastase release in activated human PMNs. Study Design Isolated human PMNs were incubated with specific inhibitors of MAPK pathways, or vehicle control solution, before activation with the bacterial peptide f-Met-Leu-Phe. Main Outcome Measures The rate of superoxide release from activated PMNs was measured by the superoxide dismutase–inhibitable reduction of cytochrome-c. Elastase release from PMNs was determined by cleavage of the substrate Ala-Ala-Pro-Val-pNA. Results Superoxide release from activated PMNs was inhibited by blockade of p38 MAPK activation but unaffected by blockade of ERK1/2. Conversely, elastase release was unaffected by p38 MAPK inhibition and increased by ERK1/2 inhibition. Conclusions Activation of p38 MAPK promotes superoxide release from PMNs activated by f-Met-Leu-Phe. The ERK1/2 pathway may serve as a negative feedback mechanism for granule exocytosis.

Interleukin-6 (IL-6), interleukin-8 (IL-8), and adhesion molecules have been implicated as mediators in neutrophil (PMN) and endothelial cell (EC) interactions leading to postinjury multiple organ failure (MOF). Our hypothesis was that circulating levels of IL-6, IL-8, and soluble intercellular adhesion molecule-1 (sICAM-1) would discriminate patients at risk for postinjury MOF.Serial plasma levels of IL-6, IL-8, and sICAM-1 were measured in 27 high-risk trauma patients.The IL-6 and IL-8 levels were significantly elevated in MOF patients compared with non-MOF patients at 12 and 36 hours postinjury. The IL-6 level was also elevated at 84 and 132 hours, and IL-8 at 84 hours. The sICAM-1 level did not become elevated in MOF patients until 132 hours postinjury.Interleukin-6 and IL-8 are elevated early after trauma and discriminate patients who will develop MOF. Late elevation of sICAM-1 likely results from PMN cytotoxicity leading to EC injury or inflammation.

Despite numerous advances in critical care, the mortality of postinjury acute respiratory distress syndrome (ARDS) remains high. Recently, permissive hypercapnia (PHC) has been shown to be a viable alternative to traditional ventilator management in patients with ARDS. However, lowering tidal volume, as employed in PHC, below 5 cc/kg impinges upon anatomic dead space and precipitates a significant rise in PaCO2 The purpose of this study was to determine if continuous tracheal gas insufflation (cTGI) is a useful adjunct to PHC by lowering PaCO2, thus allowing adequate reduction in minute ventilation to achieve alveolar protection.Over a 5-year period, 68 trauma patients with ARDS were placed on permissive hypercapnia. Nine of these patients additionally received cTGI at 7 L/min. Arterial blood gas determinations and ventilatory parameters were examined immediately prior to the implementation of cTGI and after 6h.The cTGI produced significant improvement in pH (7.25 +/- 0.03 to 7.33 +/- 0.03), PaCO2 (72 +/- 5 to 59 +/- 5 torr), tidal volume (7.9 +/- 0.6 to 7.2 +/- 0.6 cc/kg), and minute ventilation (13 +/- 1 to 11 +/- 1 L/min; P0.05).Continuous TGI is a useful adjunct to permissive hypercapnia, allowing maintenance of an acceptable pH and PaCO2 while allowing further reduction in tidal volume and minute ventilation.

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.