The US Critical Illness and Injury Trials Group is funded to engage the relevant scientific communities and federal agencies to jointly advocate for clinical research. An inclusive, nationwide ...network of experts has been created to establish national priorities and pursue a strategic plan in conjunction with professional societies and existing research networks. Investigator-initiated clinical proposals will be presented and discussed at the inaugural National Institutes of Health meeting to promote collaboration and establish working groups to develop projects and core resources. Future US Critical Illness and Injury Trials Group meetings will convene triannually, providing a venue to gauge progress on strategic deliverables, foster development of the clinical projects, discuss education and training in clinical trial design, and address the ethical, legal, and social implications of research in the critically ill or injured patients.
Introduction: We hypothesized that the mouse plasma proteome during Gram-positive pneumonia would be similar to that of Gram-negative pneumonia when the infectious agents are used in doses that cause ...similar mortality rates.
Methods: Male C57/BL6 mice underwent intratracheal (i.t.). injections of either P. aeruginosa or S. pneumoniae at doses that resulted in 80–90% seven-day mortality; control mice received i.t. normal saline alone. Plasma was collected twenty-four hours after infection. Multiplex fluorescent 2-D gel electrophoresis was used to compare the plasma protein compositions in two replicates. Differentially expressed gel features were identified based on comparison to gel images of plasma from animals subjected to intra-abdominal sepsis (cecal ligation and puncture, CLP) or de novo by tandem mass spectrometry.
Results: Approximately 1200 gel features were detected in each replicate. The pattern of protein abundance clearly distinguishes P. aeruginosa, while more subtle variations separate S. pneumoniae from i.t. saline. As an example, the most prominent differences between the plasma samples are shown in the Table.
Table
Plasma Protein Abundance Fold Change, Relative to i.t. Saline Challenge (Control)
Apolipo- protein A-1
alpha-1 Acid Glyco- protein
Hapto- globin
alpha- fibrinogen
beta- fibrinogen
P. aeruginosa
−16
2.7 (ns)
−9.4
−5.3
−5.7
S. pneumoniae
−1.8 (ns)
3.8
−1.1 (ns)
−1.1 (ns)
−1.6 (ns)
All changes p < 0.05 unless noted as “ns”—not statistically significant.
Conclusions: Here we present the first proteomic analysis of the mouse plasma acute phase response to pneumonia and further compare Gram-positive to Gram-negative disease. These profiles are distinct, suggesting that the host response to pulmonary sepsis at the level of the plasma proteome may be diagnostic for these infectious agents.
Inflammation and the Host Response to Injury is a prospective, multicenter, federally funded collaborative study of the genomic and proteomic basis for injury response. This study has brought ...together clinical specialists in burn injury with experts in genomics, proteomics, and bioinformatics to answer questions related to immunoinflammatory responses to injury. The purpose of this report is to describe the structure, organization, goals, and current progress of this Glue Grant project.
Preconditioning by sublethal stress can protect a cell from subsequent injury and apoptosis through a mechanism that has been unclear. Many such stresses stimulate the formation of stress granules: ...transient cytoplasmic foci that contain heat shock protein as well as translationally stalled mRNA and various mRNA-binding proteins. Recent research suggests that sequestration in stress granules of TRAF2, an adaptor protein that is required for tumor necrosis factor receptor 1 signaling, may underlie preconditioning by sublethal stresses.
Background. Iron participates in diverse pathologic processes by way of the Fenton reaction, which catalyzes the formation of reactive oxygen species (ROS). To test the hypothesis that this reaction ...accelerates apoptosis, we used human umbilical vein endothelial cells (HUVECs) as surrogates for the microvasculature in vivo.
Methods. HUVECs were loaded with Fe III(ferric chloride and ferric ammonium citrate) with 8-hydroxyquinoline as carrier and were then challenged with two stimuli of the heat shock response, authentic heat or sodium arsenite. Iron dependence was tested with two chelators, membrane-impermeable deferoxamine and membrane-permeable o-phenanthroline. The role of ROS was assessed with superoxide dismutase, catalase, and the reporter compound dichlorofluorescein diacetate. The mechanism of cell death was assessed with three complementary techniques, Annexin V/propidium iodide labeling, the TUNEL stain, and electron microscopy.
Results. Iron-loaded HUVECs executed apoptosis after a heat shock stimulus. Iron-catalyzed formation of ROS appeared to be a critical mechanism, because both chelation of iron and enzymatic detoxification of ROS attenuated this apoptosis.
Conclusions. Inorganic iron, in concert with chemical and physical inducers of the heat shock response, may trigger apoptosis. The accumulation of iron in injured tissue may thereby predispose to accelerated apoptosis and account, in part, for poor wound healing and organ failure.
Four homosexual male patients with giant anal carcinomas, ranging from 10 to 17 cm in diameter, are presented. These patients were not candidates for abdominoperineal resection because of fixation to ...adjacent structures. Common symptoms included pain, sepsis, anemia, incontinence, and weight loss. Diverting colostomy was performed in all patients. Two of the four patients were treated by wide local excision of the tumors for palliation. Two patients were treated with chemotherapy and radiation therapy. Three of the four patients died within 12 months. The authors conclude that diverting colostomy and wide local excision of giant anal cancers offer effective palliation of local wound problems in selected cases.
Injury will equal or surpass communicable disease in the year 2020 as the number one cause of lost disability-adjusted life-years worldwide. The major cause of "late death" after trauma is organ ...dysfunction, commonly as a complication of shock or sepsis. The pathophysiology of injury-induced organ dysfunction is poorly characterized but has been linked to systemic inflammation as a result of infection (either obvious or occult) or massive tissue injury (systemic inflammatory response syndrome, SIRS). Subsequent complications of organ dysfunction, including death, may also stem from immunosuppression characteristic of what has been called the counter-regulatory anti-inflammatory response syndrome (CARS). At the cellular level, injurious stimuli trigger adaptive stress responses that include changes in gene expression. Multiple organ dysfunction syndrome (MODS) is the summation of these stress responses to severe systemic injury, integrated at the cellular, organ, and host levels. We hypothesize that a complete understanding at the molecular level of the stress responses induced by injury will aid in the development of therapeutic strategies for treating MODS in the critically ill surgical patient. This paper reviews recent data from our Cellular Injury and Adaptation Laboratory relevant to our understanding of MODS pathophysiology, particularly as it relates to stress-induced cell death by apoptosis. Our data suggest that inhibition of stress-induced apoptosis may improve survival after severe injury.
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