AMP-activated Protein Kinase Activation by 5-Aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside (AICAR) Reduces Lipoteichoic Acid-induced Lung Inflammation

Hoogendijk, Arie J.; Pinhanços, Sandra S.; Poll, Tom van der; Wieland, Catharina W.

doi:10.1074/jbc.m112.413138

Cited by 37 publications

(35 citation statements)

References 23 publications

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“…10,21 In addition, treatment with AICAR alleviated inflammatory lung injury insulted by lipoteichoic acid, LPS, toluene polyinosinic-polycytidylic acid [poly (I:C)] or diisocyanate, and protected against colitis induced by dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid. 16,17,[22][23][24][25] Apoptosis constitutes a hallmark in LPS/DGal-induced liver damage. 3 In the present study, LPS/ D-Gal-induced elevation in cleaved caspase-3, caspases activities and TUNEL-positive hepatocytes was significantly inhibited by AICAR, indicating that AICAR suppressed hepatocyte apoptosis in LPS/D-Gal-exposed mice.…”

Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-attenuates LPS/D-Gal-induced acute hepatitis in mice

Zhou

et al. 2015

Innate Immun

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The AMP-activated protein kinase (AMPK)-mediated energy-sensing signals play important roles in reprogramming the expression of inflammatory genes. In the present study, the potential effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) were investigated in a mouse model with LPS/D-Gal-induced acute hepatitis. Our experimental data indicated that treatment with AICAR suppressed the elevation of plasma aminotransferases and alleviated the histopathological abnormalities in mice exposed to LPS/D-Gal. Treatment with AICAR also inhibited the LPS/D-Gal-induced up-regulation of TNF-α, NO and myeloperoxidase. In addition, the LPS/D-Gal-induced expression of pro-apoptotic factor Bax, cleavage of caspase-3, elevation of hepatic caspase-3, caspase-8, caspase-9 activities and induction of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive cells were all suppressed by AICAR. These results suggested that the AMPK activator AICAR could attenuate LPS/D-Gal-induced acute hepatitis, which implies that AMPK might become a novel target for the treatment of inflammation-based liver disorders.

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Section: Discussionmentioning

confidence: 99%

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-attenuates LPS/D-Gal-induced acute hepatitis in mice

Zhou

et al. 2015

Innate Immun

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“…In vitro activation of AMPK reduces cytokine production in the alveolar macrophage cell line MH-S and LTA-induced neutrophil influx, as well as the protein leakage and cytokine/chemokine levels in the bronchoalveolar space [39]. Autoimmune encephalomyelitis was more severe in AMPKα1 −/− mice than in controls [29] and knockdown of the gene that encodes AMPK in macrophages (or expression of a dominant negative mutant) promoted a pro-inflammatory state [31].…”

Section: Discussionmentioning

confidence: 99%

Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice

et al. 2013

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A positive relationship between obesity and asthma has been well documented. The AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. The cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. In obese mice, greater levels of eotaxin, TNF-α and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. In addition, metformin nearly abrogated the binding of NF-κB subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. In separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.

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“…Nikhil Mulchandani, 1 Weng-Lang Yang, 1,2 Mohammad Moshahid Khan, 2 Fangming Zhang, 2 Philippe Marambaud, 3 Jeffrey Nicastro, 1 Gene F Coppa, 1 and Ping Wang AICAR has been shown to inhibit inflammation and to alleviate organ injury in rodents (13,(20)(21)(22). There is growing evidence that the central nervous system (CNS) plays an important and functionally relevant role in regulating the inflammatory response.…”

Section: Stimulation Of Brain Amp-activated Protein Kinase Attenuatesmentioning

confidence: 99%

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

Mulchandani

Yang

Khan

et al. 2015

Mol Med

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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.

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AMP-activated Protein Kinase Activation by 5-Aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside (AICAR) Reduces Lipoteichoic Acid-induced Lung Inflammation

Cited by 37 publications

References 23 publications

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-attenuates LPS/D-Gal-induced acute hepatitis in mice

5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside-attenuates LPS/D-Gal-induced acute hepatitis in mice

Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice

Stimulation of Brain AMP-Activated Protein Kinase Attenuates Inflammation and Acute Lung Injury in Sepsis

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