Faculty Collaboration Database

Surviving lethal septic shock without fluid resuscitation in a rodent model. Surgery 2010 Aug;148(2):246-54

Date

06/22/2010

Pubmed ID

20561658

Pubmed Central ID

PMC4894305

DOI

10.1016/j.surg.2010.05.003

Scopus ID

2-s2.0-77955287968 (requires institutional sign-in at Scopus site)   56 Citations

Abstract

BACKGROUND: We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model.

METHODS: C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay.

RESULTS: All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations.

CONCLUSION: We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.

Author List

Li Y, Liu B, Fukudome EY, Kochanek AR, Finkelstein RA, Chong W, Jin G, Lu J, deMoya MA, Velmahos GC, Alam HB

Author

Marc Anthony De Moya MD Chief, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Cell Line
DNA Primers
Disease Models, Animal
Fluid Therapy
Gene Expression
Histone Deacetylase Inhibitors
Hydroxamic Acids
Inflammation Mediators
Interleukin-6
Lipopolysaccharides
Lung
Macrophages
Male
Mice
Mice, Inbred C57BL
Models, Biological
Myeloid Differentiation Factor 88
Resuscitation
Shock, Septic
Tumor Necrosis Factor-alpha