Mitogen-activated protein kinases in the intensive care unit: prognostic potential.

Multiple organ dysfunction syndrome (MODS) is the predominant cause of late death in patients requiring intensive care. Most consider it the pathologic sequela of an excessive host inflammatory response. The failure of current therapeutic interventions focused on the host’s immunoinflammatory response to affect the outcome of MODS stems, in part, from an incomplete understanding of the complex underlying pathophysiology and an inability to identify early the patients at greatest risk for development of MODS. 1 In the severely injured patient, our ability to predict many important outcomes is limited. Current scoring systems, such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, use population-based analyses and require the acquisition of many variables to compute a mathematical model to derive a numerical score indicative of outcome. 2–10 These scores define the net physiologic state of a heterogeneous population and, while valuable in estimating overall population mortality, correlate poorly with other important morbidity endpoints. Moreover, even a score associated with a high incidence of death frequently fails to identify the patient early enough so that potentially effective interventions may be implemented before the onset of an irreversible pathologic sequence. Regardless of the initiating sequence, an aberrant immunoinflammatory response is thought to underlie the pathophysiology of ischemia/reperfusion states, the systemic inflammatory response syndrome (SIRS), septic shock, and MODS. Identification of various components of these inflammatory states has generated a series of investigations to establish a potential association between the plasma concentrations of inflammatory products and patient outcome, specifically mortality. While the results are variable, several trials have demonstrated an association between the concentrations of certain inflammatory mediators and mortality. 1 Consequently, numerous clinical trials have been conducted employing selective anticytokine or antimediator compounds. While many of these agents have been proven effective in controlled animal models, they have failed to alter outcome when applied in the clinical arena. 1,11–18 Many of the implicated inflammatory mediators are regulated by intracellular signaling cascades involving the mitogen-activated protein kinases (MAPK). 19–24 One prominent member, p38, mediates the signal transduction induced by many environmental stresses, such as endotoxin and osmotic stress. While its activation is required for the production of such potent cytokines as tumor necrosis factor-alpha (TNF-α) and interleukin 8, p38 also participates in the reprogramming of inflammatory cells, including platelet-activating factor-induced “priming” of peripheral blood mononuclear cells. 19,24,25 Thus, the activation status of critical early signal transduction pathways, such as p38, might permit characterization of the host stress state, thereby enabling early identification of patients at risk for developing an aberrant host inflammatory response and subsequent MODS. Such a diagnostic tool would give clinicians the opportunity to institute and test potential therapeutic interventions. In this study we investigate the activation status of p38 in cells obtained by bronchoalveolar lavage from critically ill trauma patients in an attempt to identify the patients at greatest risk for progression of MODS.