title: Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis.
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 ribonucleotide (AICAR, 20 ng), an AMPK activator, or vehicle (normal saline) by intracerebroventricular (ICV) injection, followed by cecal ligation and puncture (CLP) at 30 min post-ICV. The septic mice treated with AICAR exhibited elevated phosphorylation of AMPKα in the brain along with reduced serum levels of aspartate aminotransferase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), compared with the vehicle. Similarly, the expressions of TNF-α, IL-1β, 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 AMPKα2 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.
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Mulchandani
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.|Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Weng-Lang
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Mohammad Moshahid
authors.initials: MM
authors.lastname: Khan
authors.affiliation: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Fangming
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nicastro
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.
authors.forename: Gene F
authors.initials: GF
authors.lastname: Coppa
authors.affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, New York, United States of America.|Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics; D055371:Acute Lung Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D012265:Ribonucleotides / Q000008:administration & dosage; D018805:Sepsis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide