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Effect of glucocorticoid receptor (GR) blockade on endotoxemia in rats
1Department of Pathophysiology, Second Military Medical University, Shanghai, People's Republic of China.
Abstract:
To study the clinical significance of the decrease of glucocorticoid receptor (GR) in stress and shock, GR was blocked about 80% by mifepristone (RU38486), and the effects of the blockade on the pathological changes of endotoxemia were studied in rats. The results revealed that GR blockade may exacerbate the pathological and pathophysiological changes of endotoxemia: (1) the more rapid drop in arterial blood pressure, (2) the more severe pathological changes involving multiple organs, especially the lung and small intestine, (3) the increase of leukocyte adherence in venules and more pronounced rheological changes in the mesenteric microcirculation, and (4) the striking elevation of serum acid phosphatase (ACP), phospholipase A2 (PLA2) activity, and lipoperoxide (LPO). The changes of serum ACP, PLA2, and LPO in the rats with 80% GR blockade were more marked than in those with 50% GR blockade. Based on these findings, we propose that the decrease in GR during stress and shock might be a contributing factor in the pathogenesis of shock and multiple organ failure (MOF). The possible mechanisms of the above noted findings are discussed.
Insights
Glucocorticoid receptor (GR) blockade worsens endotoxemia in rats, leading to severe organ damage and circulatory issues. Reduced GR function may contribute to shock and multiple organ failure.
Area of Science:
- Endocrinology
- Pathophysiology
- Pharmacology
Background:
- Glucocorticoid receptors (GR) play a crucial role in the body's response to stress.
- Understanding GR's function in shock is vital for clinical management.
Purpose of the Study:
- To investigate the clinical significance of decreased glucocorticoid receptor (GR) function during stress and shock.
- To determine the effects of GR blockade on endotoxemia-induced pathological changes in rats.
Main Methods:
- Rats were treated with mifepristone to block GR function (50% and 80% blockade).
- The study assessed hemodynamic, pathological, microcirculatory, and biochemical changes following endotoxemia induction.
- Key markers included arterial blood pressure, organ pathology, leukocyte adherence, rheological changes, serum acid phosphatase (ACP), phospholipase A2 (PLA2), and lipoperoxide (LPO).
Main Results:
- GR blockade exacerbated endotoxemia, causing a faster drop in blood pressure and more severe multi-organ damage, particularly in the lungs and intestines.
- Increased leukocyte adherence and impaired mesenteric microcirculation were observed with GR blockade.
- Significant elevations in serum ACP, PLA2 activity, and LPO were noted, with greater severity at 80% GR blockade compared to 50%.
Conclusions:
- A decrease in GR function during stress and shock may contribute to the pathogenesis of shock and multiple organ failure (MOF).
- These findings highlight the critical role of GR in mitigating endotoxemic injury.