Metformin attenuates ventilator-induced lung injury

Tsaknis, Georgios; Siempos, Ilias I.; Kopterides, Petros; Maniatis, Nikolaos A.; Kardara, Matina; Panoutsou, Stefania; Κοτανίδου, Αναστασία; Roussos, Charis; Armaganidis, Apostolos

doi:10.1186/cc11439

Cited by 40 publications

(35 citation statements)

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“…Similarly, exposure of cells to the AMPK activators metformin, AICAR or bereberine diminished TLR4 induced activation of neutrophils, macrophages, and endothelial cells (27, 33, 62). The severity of endotoxin-induced acute lung injury was decreased in mice treated with either metformin or AICAR (27, 45, 63). Of note, AICAR partially attenuates LPS-induced acute lung injury in humanized resistin mice.…”

Section: Discussionmentioning

confidence: 99%

Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury

Jiang

Park

Tadié

et al. 2014

The Journal of Immunology

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Although resistin was recently found to modulate insulin resistance in preclinical models of type II diabetes and obesity, recent studies have also suggested that resistin has proinflammatory properties. In these studies, we examined if the human specific variant of resistin affects neutrophil activation as well as the severity of LPS-induced acute lung injury (ALI). Because human and mouse resistin have distinct patterns of tissue distribution, experiments were performed using resistin humanized mice that exclusively express human resistin (hRTN+/−/−), but are deficient in mouse resistin. Enhanced production of TNF-α or MIP-2 was found in LPS-treated hRtn+/−/−, compared to control Rtn−/−/− neutrophils. Expression of human resistin inhibited the activation of AMP-activated protein kinase (AMPK), a major sensor and regulator of cellular bioenergetics that is also implicated in inhibiting inflammatory activity of neutrophils and macrophages. In addition to the ability of resistin to sensitize neutrophils to LPS stimulation, human resistin also enhanced neutrophil extracellular trap formation. In LPS-induced ALI, humanized resistin mice demonstrated enhanced production of pro-inflammatory cytokines, more severe pulmonary edema, increased NET formation, and elevated concentration of the alarmins HMGB1 and histone 3 in the lungs. Our results suggest that human resistin may play an important contributory role in enhancing TLR4 induced inflammatory responses, and may be a target for future therapies aimed at diminishing the severity of acute lung injury and other inflammatory situations where neutrophils play a major role.

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Section: Discussionmentioning

confidence: 99%

Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury

Jiang

Park

Tadié

et al. 2014

The Journal of Immunology

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“…Previous studies and results obtained from our laboratory have described antiinflammatory effects mediated by activated AMPK. Metformin, AICAR or berberine all were shown to diminish neutrophil and macrophage proinflammatory activation, as well as to decrease the severity of endotoxin-or ventilatorinduced acute lung injury (29,31,58). Exposure of macrophages to antiinflammatory mediators, such as IL-10 or TGF-β, resulted in activation of AMPK followed by transition of the cells from the M1 to M2 phenotype (33).…”

Section: Discussionmentioning

confidence: 99%

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

Park

Jiang

Tadié

et al. 2013

Mol Med

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An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis. Online address: https://doi.org/www.molmed.org

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“…Metformin, the first-line therapy for T2DM with undisputed efficacy and safety and additional antineoplastic, antiaging, anti-inflammatory, immunomodulatory, cardio-, neuro-, hepato-, and nephroprotective actions [275,276], has been proposed as a multi-action protection drug candidate for COVID-19 [277][278][279][280][281][282][283], particularly due to its strong systemic reparatory and modulatory mechanisms. While its effects on RAAS seem to be neutral, lung injury can be efficiently prevented and relieved by metformin, specially by the promotion of microvascular repairing actions [284][285][286][287][288][289], and has also exhibited antiviral activity, enhanced lymphocyte B function and enhanced innate immunity [290][291][292][293][294]. Conversely, metformin has formal contraindication for severe conditions due to the risk of lactic acidosis [295].…”

Section: Of Minor Relevancementioning

confidence: 99%

Repurposing existing drugs for COVID-19: an endocrinology perspective

Cadegiani

2020

BMC Endocr Disord

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Background Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. Main text While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. Conclusion While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.

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Metformin attenuates ventilator-induced lung injury

Cited by 40 publications

References 35 publications

Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury

Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

Repurposing existing drugs for COVID-19: an endocrinology perspective

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