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Tracking the wily speckle in darkest sepsis.

Critical Care Medicine www.ccmjournal.org 1577 Nearly everywhere, Escherichia coli happens. As indicated by the bacterial species name, the mammalian colon particularly cultivates the generally harmless organism (1, 2) (Fig. 1). Some varieties, however, excrete exotoxins, and all types exhibit a cell wall containing lipopolysaccharide (LPS). If any of that endotoxic material translocates into the bloodstream, the immune system reacts and can do so violently. In this issue of Critical Care Medicine, Hestenes et al (3) incur the wrath of anesthetized swine toward IV injected, heat-inactivated (nonviable) E. coli cells. The insult was cardiovascularly shocking. The 10 sleeping beasts waxed so wroth that three pigs abdicated before completing 4 hours of bacteremia. The bacterial dose was 1.5 billion cells over 4 hours. Therefore, a slow infusion of about 0.4 mg (dry weight) of cells was devastating to 53-kg animals. That mass of enterically harmless microbes contains perhaps 4 nanomoles of LPS endotoxin (4). This potency is staggering, as was the cardiovascular impact. In order to maintain an end-diastolic left ventricular pressure of 10 mm Hg and a stable hemoglobin concentration, each animal received about 20 L of crystalloid during less than 8 hours (3). Indeed, the anesthetized pigs were as sick as dogs. The article by Hestenes et al (3) focuses on echocardiography findings, but the heart is examined in the setting of the severe systemic microvascular leakage of sepsis (5). Septic leaking is well known, but the mechanism is not completely established (6). There are leaks not only in the vascular endothelium but also in the sarcoplasmic reticulum of the heart (7). Like the vascular endothelium, the cardiac reticulum constitutes a semipermeable barrier to the interstitial fluid. Beutler (8) garnered a portion of the 2011 Nobel Prize in Physiology or Medicine for demonstrating that toll-like receptor 4 is the critical receptor for LPS. The Germanically “amazing” toll gene had been originally found in amazingly shaped fruit flies, but a similar one is expressed in mammalian monocytes/macrophages, myeloid dendritic cells, mast cells, recovery using a vapor impermeable membrane which inhibits the expected up-regulation of AMP expression (10–12). Previous studies of host-defense peptide and protein (HDPs) expression in response to thermal injury have demonstrated complex alterations in HDP levels, whereas other studies have demonstrated localization of AMPs in burned and in unburned skin (7–9, 13). In the current study, Plichta et al (6) demonstrate compromised skin barrier function after thermal injury in a murine model. They demonstrate altered transepidermal water loss, elevation in pH, a global decrease in AMPs, and a shift in lipid synthesis in burned skin but also in normal skin (i.e., potential donor sites for skin graft harvest). In a patient with a large burn, these alterations contribute to wound colonization with pathogenic organisms and represent a susceptibility to burn wound infection or sepsis. In the era of rising antimicrobial resistance, these pathways also represent novel strategies for prevention and treatment of burn wound colonization and infection via the induction of endogenous HDPs.