Corticosteroids in Endotoxic Shock

Mills, Lewis C.

doi:10.3181/00379727-138-35928

Cited by 15 publications

(8 citation statements)

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“…Pretreatment of animals with glucocorticoids prevents LPS-induced shock in animals (32). Previous studies demonstrated that the glucocorticoid dexamethasone inhibits TNF-␣ translation (4,19).…”

Section: Discussionmentioning

confidence: 95%

Jun N-Terminal Kinase/Stress-Activated Protein Kinase (JNK/SAPK) Is Required for Lipopolysaccharide Stimulation of Tumor Necrosis Factor Alpha (TNF-α) Translation: Glucocorticoids Inhibit TNF-α Translation by Blocking JNK/SAPK

Swantek

Cobb

Geppert

1997

Molecular and Cellular Biology

473

319

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The adverse effects of lipopolysaccharide (LPS) are mediated primarily by tumor necrosis factor alpha (TNF-␣). TNF-␣ production by LPS-stimulated macrophages is regulated at the levels of both transcription and translation. It has previously been shown that several mitogen-activated protein kinases (MAPKs) are activated in response to LPS. We set out to determine which MAPK signaling pathways are activated in our system and which MAPK pathways are required for TNF-␣ gene transcription or TNF-␣ mRNA translation. We confirm activation of the MAPK family members extracellular-signal-regulated kinases 1 and 2 (ERK1 and ERK2), p38, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), as well as activation of the immediate upstream MAPK activators MAPK/ERK kinases 1 and 4 (MEK1 and MEK4). We demonstrate that LPS also activates MEK2, MEK3, and MEK6. Furthermore, we demonstrate that dexamethasone, which inhibits the production of cytokines, including TNF-␣, significantly inhibits LPS induction of JNK/SAPK activity but not that of p38, ERK1 and ERK2, or MEK3, MEK4, or MEK6. Dexamethasone also blocks the sorbitol but not anisomycin stimulation of JNK/SAPK activity. A kinase-defective mutant of SAPK␤, SAPK␤ K-A, blocked translation of TNF-␣, as determined by using a TNF-␣ translational reporting system. Finally, overexpression of wild-type SAPK␤ was able to overcome the dexamethasone-induced block of TNF-␣ translation. These data confirm that three MAPK family members and their upstream activators are stimulated by LPS and demonstrate that JNK/SAPK is required for LPS-induced translation of TNF-␣ mRNA. A novel mechanism by which dexamethasone inhibits translation of TNF-␣ is also revealed.

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Section: Discussionmentioning

confidence: 95%

Jun N-Terminal Kinase/Stress-Activated Protein Kinase (JNK/SAPK) Is Required for Lipopolysaccharide Stimulation of Tumor Necrosis Factor Alpha (TNF-α) Translation: Glucocorticoids Inhibit TNF-α Translation by Blocking JNK/SAPK

Swantek

Cobb

Geppert

1997

Molecular and Cellular Biology

473

319

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“…As emphasized previously (lo), it is crucial to demonstrate that the challenge inoculum of gram-negative bacteria does not contain a lethal quantity of preformed endotoxin. Adrenal corticosteroids, if given early and in pharmacologic doses, protect against endotoxemic mortality (13)(14)(15)(16)(17)(18). Therefore, if gram-negative bacteria are inoculated in numbers sufficient to cause death from both preformed endotoxin as well as from infection, then adrenal corticosteroids alone or antibiotics alone, even if given promptly, could not be expected to prevent mortality whereas their combination, each protective against the respective lethal factors, would be protective.…”

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confidence: 99%

Experimental Gram-Negative Bacterial Sepsis: Optimal Methylprednisolone Requirements for Prevention of Mortality Not Preventable by Antibiotics Alone

Greisman

1982

Experimental Biology and Medicine

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Outbed ICR mice were inoculated ip with one LD,-,, Escherichia coli 0:18, Proteus mirabilis, or Klebsiella pneumoniae. After carefully timed intervals, aminoglycoside antibiotics were begun at dosages and intervals predetermined to constitute optimal therapy. With progressive delay of antibiotic therapy, mortality rates increased progressively from 0 to 90-1W0. Standardized models of infection were obtained by selecting delay periods before initiating antibiotic therapy such that 50 to 70% mortality rates resulted.In these models, 30 mg/kg methylprednisolone (MP) given prior to or concomitantly with the delayed antibiotic therapy and repeated 4 hr later was previously shown capable of preventing gram-negative septic mortality not preventable by the optimal antibiotic therapy alone.The present studies quantitate the optimal quantities of MP required for such protection. It was found that (1) in the absence of aminoglycoside antibiotics, MP consistently failed to reduce mortality; (2) in the antibiotic-treated animals, a single im injection of 30 mg/kg MP provided definite protection. A second and a third injection of 30 mdkg of MP at 4-hr intervals provided additional, but decremental, increments of protection; (3) decreasing the dose of MP to 10 mg/kg or less consistently reduced its protective activity; (4) increasing the dose of MP to 60 mg/kg or greater consistently reduced its protective activity; (5) short additional increments in delay in initiating antibiotic and MP therapy annulled the protective activity of MP. The findings indicate that the ability of MP to reduce murine mortality from gram-negative bacterial sepsis is not only critically restricted by the requirements for its early administration in conjunction with appropriate antibiotics, but also by its relatively narrow optimal dose-response range and the decremental increments in its effectiveness upon repetitive administration. 436

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“…In endotoxemia in rats, the rate of gluconeogenesis is reduced and the activity of 6‐glucose phosphate dehydrogenase is depressed (25). Mills (26) also observed the protective effect of corticosteroids in endotoxic shock. The adrenal steroids and their synthetic analogs provide marked protection against endotoxins, an effect which may arise partially from their glucocorticoid activity (27).…”

Section: Effects Of Corticosteroidsmentioning

confidence: 94%

Glucocorticoid Therapy in Sepsis/Shock Caused by Gram‐Negative Microorganisms†

Seneca

Grant

1975

J American Geriatrics Society

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A review of the literature reveals that glucocorticoids have: 1) a protective effect both in vitro and in vivo against bacterial endotoxins and exotoxins, and 2) a protective or therapeutic effect in sepsis/shock caused by Gram-negative microorganisms. At the Columbia Presbyterian Medical Center, the 1968-1973 mortality rate for general sepsis/shock due to Gram-negative organisms was 16.6 percent and for urologic sepsis/shock 15.3 percent. This low rate was the result of early diagnosis and early use of massive dosages of glucocorticoids (hydrocortisone, methylprednisolone, dexamethasone), beta-adrenergic isoproterenol, and bactericidal antibiotics (gentamicin, kanamycin, carbenicillin, cephalothin-cefazolin, ampicillin).

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Corticosteroids in Endotoxic Shock

Cited by 15 publications

References 0 publications

Jun N-Terminal Kinase/Stress-Activated Protein Kinase (JNK/SAPK) Is Required for Lipopolysaccharide Stimulation of Tumor Necrosis Factor Alpha (TNF-α) Translation: Glucocorticoids Inhibit TNF-α Translation by Blocking JNK/SAPK

Jun N-Terminal Kinase/Stress-Activated Protein Kinase (JNK/SAPK) Is Required for Lipopolysaccharide Stimulation of Tumor Necrosis Factor Alpha (TNF-α) Translation: Glucocorticoids Inhibit TNF-α Translation by Blocking JNK/SAPK

Experimental Gram-Negative Bacterial Sepsis: Optimal Methylprednisolone Requirements for Prevention of Mortality Not Preventable by Antibiotics Alone

Glucocorticoid Therapy in Sepsis/Shock Caused by Gram‐Negative Microorganisms†

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