New Rationale for Glucocorticoid Treatment in Septic Shock

Abstract

Two recent small randomized trials evaluating a 5- to 12-day course of low dose hydrocortisone in patients with septic shock have reported a significant clinical improvement and a reduction in mortality. Recent studies indicate that an overaggressive and unregulated systemic inflammatory response is a major determinant of outcome in sepsis. In septic shock, nonsurvivors as opposed to survivors have over time: (1) significantly higher NF-kB activity in peripheral mononuclear cells, (2) persistent elevation in circulating inflammatory cytokine levels, and (3) elevated ACTH and cortisol levels. Current research recognizes that cytokines can cause a concentration-dependent resistance to endogenous glucocorticoids (GC). It is postulated that an excess of cytokine-induced transcription factors, such as NF-kB, may form complexes with activated glucocorticoid receptors (GCR), preventing GCR interaction with DNA. When T cells are incubated with a combination of cytokines, GC resistance is induced in a cytokine concentration-dependent fashion and reversed by removal of cytokines. Prolonged treatment with physiological doses of exogenous GCs may be necessary to compensate adequately for the inability of target organs to respond to endogenous cortisol and for the inability of the host to produce appropriately elevated levels of GCs. This hypothesis is supported by the laboratory findings of a recent randomized study of patients with unresolving acute respiratory disease.

Application of Tissue Microarrays to Study the Influence of Dexamethasone on NF-κB Expression of Pancreas in Rat with Severe Acute Pancreatitis

“…After years of studies, most scholars now agree that glucocorticoid (represented by dexamethasone) treatment has effects on AP. Its mechanism includes inflammatory mediation, anti-endotoxin, improving microcirculation [21], elimination of OFR [22], inhibiting NO and NF-jB [23][24][25], etc. It is now believed that glucocorticoid can inhibit NF-jB in two ways in order to inhibit the expression of manifold inflammatory genes: (1) by combing the activated glucocorticoid receptors and their expression regulating transcripton (activated NF-jB subunit); (2) by upregulating the expression level of IjBtranscriptional in certain cells to stop the combination of nuclear transfer and DNA of NF-jB.…”

Macrophage Migration Inhibitory Factor is a Constitutively Expressed Cytokine in the Human Adrenal Gland

“…MIF is a glucocorticoidinduced regulator (2), which also has been speculated to have an important role in catecholamine metabolism by virtue of its enzymatic activity (5 -7). Interestingly, glucocorticoids and catecholamines share some common modulators and responses (25,26). Thus, there may be a basis for MIF to regulate the systemic effects of both glucocorticoids and catecholamines in stress circumstances and perhaps also to locally modulate their production.…”

Influence of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis

“…As a long-acting glucocorticoid, dexamethasone can be applied extensively in a clinical setting. It can regulate inflammatory mediators [36,37] , improve microcirculation [38] , eliminate OFR (oxygen free radical) [39] , and inhibit NF-kB [40,41] . There have now been several studies on the mechanism of dexamethasone in SAP, but there has still been no study on the effect of dexamethasone on mesenteric lymph nodes.…”