Carbon Monoxide Confers Protection in Sepsis by Enhancing Beclin 1-Dependent Autophagy and Phagocytosis

Lee, Seonmin; Lee, Seon-Jin; Coronata, Anna; Fredenburgh, Laura E.; Chung, Sung Min; Perrella, Mark A.; Nakahira, Kiichi; Ryter, Stefan W.; Choi, Augustine M.K.

doi:10.1089/ars.2013.5368

Cited by 102 publications

(106 citation statements)

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“…As the biallelic loss of BECN results in embryonic lethality, we used MSCs from BECN1 heterozygous knockout mice. These mice have previously been validated to have impaired autophagy (18,20). Both LC3B and BECN1 represent core autophagy proteins, even though they differ in their role in autophagy regulation.…”

Section: Original Researchmentioning

confidence: 99%

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Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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Oxidative stress resulting from inflammatory responses that occur during acute lung injury and sepsis can initiate changes in mitochondrial function. Autophagy regulates cellular processes in the setting of acute lung injury, sepsis, and oxidative stress by modulating the immune response and facilitating turnover of damaged cellular components. We have shown that mesenchymal stromal cells (MSCs) improve survival in murine models of sepsis by also regulating the immune response. However, the effect of autophagy on MSCs and MSC mitochondrial function during oxidative stress is unknown. This study investigated the effect of depletion of autophagic protein microtubule-associated protein 1 light chain 3B (LC3B) and beclin 1 (BECN1) on the response of MSCs to oxidative stress. MSCs were isolated from wild-type (WT) and LC3B 2/2 or Becn1 1/2 mice. MSCs from the LC3B 2/2 and Becn1 1/2 animals had increased susceptibility to oxidative stress-induced cell death as compared with WT MSCs. The MSCs depleted of autophagic proteins also had impaired mitochondrial function (decreased intracellular ATP, reduced mitochondrial membrane potential, and increased mitochondrial reactive oxygen species production) under oxidative stress as compared with WT MSCs. In WT MSCs, carbon monoxide (CO) preconditioning enhanced autophagy and mitophagy, and rescued the cells from oxidative stress-induced death. CO preconditioning was not able to rescue the decreased survival of MSCs from the LC3B 2/2 and Becn1 1/2 animals, further supporting the tenet that CO exerts its cytoprotective effects via the autophagy pathway.

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Section: Original Researchmentioning

confidence: 99%

“…Among the numerous autophagy-related genes that have been identified, beclin 1 (Becn1), plays a critical regulatory function in the initiation of the autophagic pathway (18). It is important for the nucleation of autophagosomes (19).…”

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confidence: 99%

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Ghanta

Tsoyi

Liu

et al. 2017

Am J Respir Cell Mol Biol

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“…Conversely, knocking out Becn1 renders the mice more susceptible to septic injury and unresponsive to carbon monoxide therapy. 10 A helminth product, ES-62, also downregulates TLR2-and TLR4-driven inflammatory responses by enhancing MYD88-dependent autophagosome formation. 21 The mechanisms of protective effect of autophagy activation in sepsis remain to be elucidated.…”

Section: Microbe-host Interactions and Autophagymentioning

confidence: 99%

“…8 Further ex vivo experiments revealed that the mRNA expression of IRGM is significantly lower in the TT genotype, rendering it defective in autophagy. 8 Accumulating evidence from in vitro and in vivo studies [9][10][11][12][13][14][15] suggest that autophagy plays a protective role in sepsis, although contradictory findings have been reported. 16,17 In support of this notion, newly tested therapeutic agents in animal models have targeted modulation of the same molecular pathway-autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy in sepsis: Degradation into exhaustion?

Wong

et al. 2016

Autophagy

127

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Autophagy is one of the innate immune defense mechanisms against microbial challenges. Previous in vitro and in vivo models of sepsis demonstrated that autophagy was activated initially in sepsis, followed by a subsequent phase of impairment. Autophagy modulation appears to be protective against multiple organ injuries in these murine sepsis models. This is achieved in part by preventing apoptosis, maintaining a balance between the productions of pro-and anti-inflammatory cytokines, and preserving mitochondrial functions. This article aims to discuss the role of autophagy in sepsis and the therapeutic potential of autophagy enhancers.

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Carbon Monoxide in Lung Injury and Disease

Ryter

2022

Carbon Monoxide in Drug Discovery

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Carbon Monoxide Confers Protection in Sepsis by Enhancing Beclin 1-Dependent Autophagy and Phagocytosis

Abstract: CO increases the survival of mice injured by CLP through systemic enhancement of autophagy and phagocytosis. Taken together, we suggest that CO gas may represent a novel therapy for patients with sepsis.

Cited by 102 publications

References 50 publications

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Mesenchymal Stromal Cells Deficient in Autophagy Proteins Are Susceptible to Oxidative Injury and Mitochondrial Dysfunction

Autophagy in sepsis: Degradation into exhaustion?

Carbon Monoxide in Lung Injury and Disease

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