Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
-
Burn wound healing complications, such as graft failure or infection, are a major source of morbidity and mortality in burn patients. The mechanisms by which local burn injury alters epidermal barrier function in autologous donor skin and surrounding burn margin are largely undefined. We hypothesized that defects in the epidermal cholinergic system may impair epidermal barrier function and innate immune responses. ⋯ As downstream proteins of inflammatory and cell death targets of nAChR activation, we found significant elevations in epidermal High Mobility Group Box Protein 1 and caspase 3 in donor and burn margin skin. Lastly, we employed a novel in vitro keratinocyte burn model to establish that burn injury influences the gene expression of these cholinergic mediators and their downstream targets. These results indicate that defects in cholinergic mediators and inflammatory/apoptotic molecules in donor and burn margin skin may directly contribute to graft failure or infection in burn patients.
-
Distinction between inflammation secondary to surgery, especially coronary artery bypass graft with cardiopulmonary bypass (CPB), and inflammation due to infection is difficult in surgical intensive care unit (ICU) patients. Development of biomarkers of infection could help clinicians in the early identification and thus treatment of sepsis in these patients. We compared the time course of the neutrophil CD64 index, a high affinity immunoglobulin FC γ receptor I whose expression is increased in bacterial infection, in 39 patients undergoing cardiac surgery with CPB and 11 patients admitted to the ICU with severe sepsis or septic shock. ⋯ Nevertheless, combination of low CD64 index with low CRP concentrations on day 1 ruled out sepsis except in three patients. There were no correlations between the CD64 index and cytokine levels (tumor necrosis factor [TNF]-α, interferon [IFN]γ, interleukin [IL]-6, IL-10, IL-8, IL-12) measured in subpopulations. In conclusion, CD64 index only in combination with CRP concentrations could be used to discriminate inflammation due to surgery from that due to infection in this particular population.
-
We previously identified a truncated human glucocorticoid receptor (hGR) isoform of 118 amino acids, hGR-S1(-349A), that despite lacking the major functional domains, was more hyperactive after glucocorticoid treatment than the full-length receptor. Furthermore, its 3' untranslated region (UTR) was required. To dissect the underlying mechanisms for hyperactivity, a series of hGR isoforms with consecutive deletions in the 3' UTR were created to test their transactivation potential using reporter assays. ⋯ Analysis of the 20 bp region neighboring the 1293 bp site showed a pattern: 3'UTR termination at every third base pair in this region resulted in a loss of transactivation potential while the other sites retained hyperactivity with or without glucocorticoid stimulation. Variations in the activity of an hGR isoform, due to changes in the 3' UTR sequence configuration, may provide an important link in explaining inconsistent responses to glucocorticoid treatment in individuals and ultimately enable tailored, patient-specific care. Furthermore, understanding the mechanisms underlying the cyclic hyperactivity/loss of activity phenomenon may be a step toward identifying a novel mechanism of gene regulation.
-
Patients with cardiogenic shock (CS) are at a high risk of developing infectious complications; however, their early detection is difficult, mainly due to a frequently occurring noninfectious inflammatory response, which accompanies an extensive myocardial infarction (MI) or a postcardiac arrest syndrome. The goal of our prospective study was to describe infectious complications in CS and the immune/inflammatory response based on a serial measurement of several blood-based inflammatory biomarkers. ⋯ The prevalence of infection in patients with CS was 46.3%, and respiratory tract infections were the most common type. Infections did not prolong statistically significantly the duration of mechanical ventilation and did not increase the prevalence of hospital mortality in this high-risk CS population. CS due to acute myocardial infarction was accompanied by a strong and highly variable inflammatory response, but it did not reach the intensity of the inflammatory response observed in patients with septic shock. An extensive immune/inflammatory response in patients with CS is linked to a poor prognosis.
-
Pulmonary Fas activation is essential in the pathogenesis of the acute respiratory distress syndrome. It remains unclear whether Fas-induced lung injury is dependent on neutrophils or mainly triggered by epithelial cell apoptosis. The contribution of lung epithelial cells (LEC) and alveolar macrophages (AM) remains elusive. ⋯ Inhibition of p38MAPK significantly increased, while inhibition of ERK1/2 reduced AM and LEC apoptosis. In conclusion, neutrophils are a necessary component of Fas-induced lung damage, while not affecting lung apoptosis directly per se. LEC display higher resistance to Fas-triggered inflammation and apoptosis than AM.