Mitogen-Activated Protein Kinases in the Intensive Care Unit: Prognostic Potential

Abstract

ObjectiveTo evaluate the prognostic significance of the activational status of p38, specifically progression to multiple organ dysfunction syndrome (MODS), in a group of severely injured trauma patients. Summary Background DataTo date, therapeutic manipulation of the host immunoinflammatory response has not affected the outcome of patients with MODS. A major concern is the inability to identify the patient most at risk so as to enable early intervention. MethodsNineteen trauma patients underwent bronchoalveolar lavage (BAL). Cells obtained were plated, stimulated with lipopolysaccharide (LPS), and then harvested at varying time points after stimulation. p38 was evaluated by Western blot. ResultsNineteen patients were categorized into two groups according to baseline and LPS-stimulated p38 activation in cells obtained by BAL. Group 1 demonstrated a 10-fold increase in p38 activation with LPS treatment over unstimulated controls. Group 2 had high baseline levels of p38 that were unresponsive to subsequent LPS stimulation. Both groups were similar with respect to age, gender, shock (systolic blood pressure Ͻ 90), Injury Severity Score, APACHE II, lactate levels, base deficit, blood transfusions, and the cell differential of BAL fluid. However, patients in group 2 had a greater incidence of progression to MODS as defined by the Marshall MOD score, a longer duration of mechanical ventilation, a longer stay in the intensive care unit, and a longer overall hospital stay than group 1. ConclusionsThese results demonstrate the prognostic significance of p38 activation in predicting outcome in critically ill trauma patients. Furthermore, these results demonstrate that trauma populations identical by current scoring systems contain a mixture of patients with markedly different outcomes as identified by p38 activation. Measurement of p38 may enable early identification of a subgroup of patients at increased risk for MODS to permit effective therapeutic intervention.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. Moreo...

Alterations in Cell Signaling in Sepsis

“…Of note, at the time the neutrophils were isolated, there were no differences in terms of demographics, severity of illness, or oxygenation abnormalities in the 2 groups of patients. Such results, as well as those described by Rosengart et al [61] among trauma patients, suggest that persons whose neutrophils have a proinflammatory phenotype, as defined by increased activation of kinases, are more likely to have severe clinical course associated with their critical illness. Because the cellular alterations precede many of the organ dysfunctions that contribute to mortality in this setting, these studies also suggest that identification and correction of alterations in cellular signaling pathways at early time points in a patient's clinical course may improve outcome.…”

“…In a study by Rosengart et al [61] of uninfected trauma patients, increased progression to multiple organ dysfunction was found in the group with high baseline levels of p38 activation among cells obtained by bronchoalveolar lavage. Of note, there were no differences in terms of demographic characteristics, hypotension, injury severity score, number of blood transfusions, or severity of illness scores at the time samples were collected among patients with low or high baseline p38 activation patterns.…”

Mitogen-activated protein kinase (MAPK)

“…Additionally, a recent in vitro investigation demonstrated that increased basal activity of p38 occurs following thermal injury and may be responsible for postburn immunosuppression (15). Consistent with these data are the findings in one clinical study demonstrating that the basal level of p38 activation within alveolar macrophages accurately identified patients at risk for ARDS and MODS (16). Whether this is due to an immunohyperactive or immunosuppressive state, however, is unknown.…”

Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study

“…We applied DAVID to functionally cluster the top 500 probesets ( Table S7 ), yielding five gene groups that strongly support the IPA results. Both analyses identified several genes that have been individually targeted in previous model system studies [27] , [28] . We discuss below two gene sets identified from the analyses, with analogous results being shown for three others.…”