Septic shock is the commonest cause of death in intensive care units. Although sepsis usually produces a low systemic vascular resistance and elevated cardiac output, strong evidence (decreased ejection fraction and reduced response to fluid administration) suggests that the ventricular myocardium is depressed and the ventricle dilated. In survivors, these abnormalities are reversible. Failure to develop ventricular dilatation in nonsurvivors suggests that dilatation is a compensatory mechanism needed to maintain adequate cardiac output. With a canine model of septic shock that is very similar to human sepsis, myocardial depression was confirmed using load-independent measures of ventricular performance. Endotoxin administration to humans simulates the qualitative, cardiovascular abnormalities of sepsis. The pathogenesis of septic shock is extraordinarily complex. Diverse microorganisms can generate toxins, stimulating release of potent mediators that act on vasculature and myocardium. A circulating myocardial depressant substance has been closely associated with the myocardial depression of human septic shock. Therapy has emphasized early use of antibiotics, critical care monitoring, aggressive volume resuscitation, and, if shock continues, use of inotropic agents and vasopressors. Pharmacologic or immunologic antagonism of endotoxin or other mediators may prove to enhance survival in this highly lethal syndrome.

Septic Shock in Humans: Advances in the Understanding of Pathogenesis, Cardiovascular Dysfunction, and Therapy

Laboratory models of sepsis and septic shock

Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes.

Bacterial modulins: a novel class of virulence factors which cause host tissue pathology by inducing cytokine synthesis.

The aryl hydrocarbon receptor (AhR) is an evolutionarily old transcription factor belonging to the Per-ARNT-Sim-basic helix-loop-helix protein family. AhR translocates into the nucleus upon binding of various small molecules into the pocket of its single-ligand binding domain. AhR binding to both xenobiotic and endogenous ligands results in highly cell-specific transcriptome changes and in changes in cellular functions. We discuss here the role of AhR for immune cells of the barrier organs: skin, gut, and lung. Both adaptive and innate immune cells require AhR signaling at critical checkpoints. We also discuss the current two prevailing views-namely, 1) AhR as a promiscuous sensor for small chemicals and 2) a role for AhR as a balancing factor for cell differentiation and function, which is controlled by levels of endogenous high-affinity ligands. AhR signaling is considered a promising drug and preventive target, particularly for cancer, inflammatory, and autoimmune diseases. Therefore, understanding its biology is of great importance.

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

Lipid X, the major biosynthetic precursor of lipid A, has recently been described. Although lipid X is a mitogen and coagulates the Limulus amebocyte lysate, we found that it is not lethal for mice, even when given in large doses (2 X 10(6) micrograms/kg). Furthermore, lipid X was found to give partial protection against a 100% lethal dose of endotoxin, even if the lipid X was given as late as 6 h after endotoxin challenge.

Protection of mice against lethal endotoxemia by a lipid A precursor.

Susceptibility to oxygen toxicity was studied in three inbred and two hybrid strains of mice. Because in vitro studies have shown that the cytochrome P-450 enzymes can produce oxygen radicals and H2O2, we tested the hypothesis that inducibility of these enzymes might play a role in oxygen toxicity. Mice responsive to hepatic microsomal enzyme induction by aromatic hydrocarbons [C3H/HeJ, C3H/HeN, C3H/HeJ X DBA/2J (designated C3D2F1/J), C3H/HeN X DBA/2J (designated C3D2F1/N)] were more sensitive to the toxic effects of 100% oxygen exposure than were genetically unresponsive mice (DBA/2J). DBA/2J mice survived significantly longer exposure periods with less lung damage. Lung and liver cytochrome P-450 levels increased 2-to 3-fold in C3H and F1 mice during 100% oxygen exposure (maximum levels at 72-96 hr) and subsequently fell prior to death. No increases were seen in cytochrome P-450 levels in DBA/2J mice. Metabolic pathways involving cytochrome P-450 enzymes may initiate or modulate oxidative damage due to oxygen radicals. The difference in responsiveness of mice to microsomal enzyme induction may imply genetic differences in susceptibility to oxidative stress, may help to explain species differences in susceptibility, and may have long-term implications in therapeutics and patient care if similar inherited differences exist in humans.

Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.

An electrode array supports multiple electrodes and energizes them so that adjacent electrodes do not have the same polarity In one embodiment, the electrodes are held about a circumference outside and surrounding a tumor and opposed electrodes are energized in a round robin fashion to promote current flow through the center of the tumor from a variety of angles

Circumferential electrode array for tissue ablation

The chemical structure of the biologically active lipid A portion of Gram-negative endotoxin [lipopolysaccharide (LPS)] has recently been elucidated. This was greatly facilitated by the isolation of an Escherichia coli mutant that accumulates large quantities of lipid X, a novel monosaccharide precursor of lipid A (C. R. H. Raetz, Rev. Infect. Dis. 6: 463–471, 1984). We now report on the activity of lipid X in the lung-lymph model in sheep. We have measured the response to cumulative bolus injections of lipid X (2,3-diacylglucosamine 1-phosphate) in six chronically instrumented unanesthetized sheep. Lipid X at a total dose of 40 micrograms/kg produced a biphasic pattern of changes. The early phase was characterized by a rapid transient pulmonary arterial constrictive response that was dose dependent, accompanied by a delayed transient increase in lung-lymph flow (P less than 0.05), a significant (P less than 0.01) decrease in arterial blood O2 tension and an increase (P less than 0.05) in lung-lymph protein clearance. Protein permeability changes in the first phase are not usually seen following endotoxin injection. However, like endotoxin, lipid X also produced a late phase (3–6 h later) of increased lung vascular permeability to fluid and protein as reflected by significant (P less than 0.05) increases in both lung-lymph flow and lung-lymph protein clearance in the presence of stable pulmonary vascular pressures at or below base-line levels. We conclude that some of the pulmonary pressor activity of the endotoxin molecule can be attributed to the lipid X substructure. Furthermore, changes in vascular permeability may also be initiated by this substance.

Pulmonary pathophysiological changes in sheep caused by endotoxin precursor, lipid X.

A method of treating animals to protect them from the toxic effects of gram-negative endotoxin comprises administering to said animals a safe and effective amount of a compound having lipid X activity.

J. A. Will

Papers

Protection of mice against lethal endotoxemia by a lipid A precursor.

Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.

Circumferential electrode array for tissue ablation

Pulmonary pathophysiological changes in sheep caused by endotoxin precursor, lipid X.

Method of preventing diseases caused by gram-negative endotoxin in mammals