Publication Date

2015

Journal Title

Mol Med

Abstract

Sepsis and septic shock are enormous public health problems with astronomical financial repercussions on health systems worldwide. The central nervous system (CNS) is closely intertwined in the septic process but the underlying mechanism is still obscure. AMP-activated protein kinase (AMPK) is a ubiquitous energy sensor enzyme and plays a key role in regulation of energy homeostasis and cell survival. In this study, we hypothesized that activation of AMPK in the brain would attenuate inflammatory responses in sepsis, particularly in the lungs. Adult C57BL/6 male mice were treated with 5-aminoimidazole-4-carboxamide riboneucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebro-ventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKalpha in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), compared to the vehicle. Similarly, the expressions of TNF-alpha, IL-1beta, keratinocyte-derived chemokine and macrophage inflammatory protein-2 as well as myeloperoxidase activity in the lungs of AICAR-treated mice were significantly reduced. Moreover, histological findings in the lungs showed improvement of morphologic features and reduction of apoptosis with AICAR treatment. We further found that the beneficial effects of AICAR on septic mice were diminished in AMPKalpha2 deficient mice, showing that AMPK mediates these effects. In conclusion, our findings reveal a new functional role of activating AMPK in the CNS to attenuate inflammatory responses and acute lung injury in sepsis.

Volume Number

21

Issue Number

1

Pages

637-44

Document Type

Article

EPub Date

2015/08/08

Status

Faculty, Northwell Researcher

Facility

School of Medicine; Northwell Health

Primary Department

Surgery

Additional Departments

Molecular Medicine

PMID

26252187

DOI

10.2119/molmed.2015.00179


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Surgery Commons

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