Mitochondrial DNA-Induced Inflammatory Responses and Lung Injury in Thermal Injury Murine Model: Protective Effect of Cyclosporine-A

Liu, Ruiqi; Xu, Fanxing; Bi, Siwei; Zhao, Xueshan; Jia, Bangsheng; Cen, Ying

doi:10.1093/jbcr/irz029

Cited by 28 publications

(21 citation statements)

References 39 publications

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“…However, mitochondrial ROS also participate in other cellular processes including the activation of mitochondrial permeability transition pore (mPTP), dysregulation of mitophagy, imbalances in mitochondrial dynamics, and programmed cell death [48]. These processes represent potential routes for mtDNA displacement following ROS burst as evidenced by the finding of oxidized mtDNA fragments outside of mitochondria in the setting of several metabolic diseases [43,[49][50][51][52][53] (Figure 1). Under several stressors (e.g., mitochondrial dysfunction and consequent reactive oxygen species (ROS) production, viral and bacterial infections), several types of damage are inflicted to mitochondrial DNA (mtDNA) and a set of signaling pathways are activated to promote mitochondrial recovery or demise depending on the damage severity.…”

Section: Failing Mitochondrial Quality Control and Mtdna Releasementioning

confidence: 99%

Section: Mitochondrial Quality Control Mtdna Release and Inflammmentioning

confidence: 99%

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Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

et al. 2020

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Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

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Section: Failing Mitochondrial Quality Control and Mtdna Releasementioning

confidence: 99%

Section: Mitochondrial Quality Control Mtdna Release and Inflammmentioning

confidence: 99%

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

et al. 2020

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“…mtDNA is released after tissue injuries and plays a crucial role in the development of in ammation after injury. Studies have shown that mtDNA can induce in ammatory responses and cause lung injury in thermal injury murine models 13,14 . Furthermore, mitochondrion is among the most sensitive target organs when exposing to hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…Research has shown that burn injury results in a large number of mtDNA release, thereby activates systemic in ammatory pathways and causes acute lung injury. Inhibiting the release of mtDNA is an important potential target for the treatment of burn induced lung injury [12][13][14] Air evacuation of severely burned patients is a frequently seen scenario at both peacetime and wartime.…”

Section: Introductionmentioning

confidence: 99%

Simulated Aeromedical Evacuation Exacerbates Burn Induced Lung Injury: Targeting Mitochondrial DNA for Reversal

Xiao

Zou

et al. 2020

Preprint

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Abstract Background: Aeromedical evacuation of patients with burn trauma is an important transport method at both wartime and peacetime, which exposes patients to prolonged periods of hypobaric hypoxia. However, the effects of such exposure on burn injury, particularly on burn induced lung injury are largely unexplored. The objective of this study is to investigate the effect of hypobaric hypoxia on burn induced lung injury and to discuss the possible mechanism by using a rat burn model. Methods: Male wistar rats inflicted with 30% total body surface area burn were exposed to hypobaric hypoxia condition (simulated 2000m altitude) or normoxia control for 24 h. Deoxyribonuclease I was systemically administrated as treatment intervention. Systemic inflammatory mediators and mitochondrial deoxyribonucleic acid level were detected. The histopathological examination, and acute lung injury score were determined. Malonaldehyde content, myeloperoxidase activity, and the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome level in the lung tissue were measured. Data among groups were compared by using analysis of variance followed by the post hoc analysis of Tukey's test. Results: Burn resulted in remarkably higher level of systemic inflammatory cytokines and mitochondrial deoxyribonucleic acid release, which was further heightened by hypobaric hypoxia exposure. Moreover, hypobaric hypoxia exposure gave rise to increased NLRP3 inflammasome expression, elevated malonaldehyde content and myeloperoxidase activity in the lung. Burn induced lung injury was exacerbated as shown by histopathological examination and acute lung injury score. Administration of deoxyribonuclease I markedly reduced mitochondrial deoxyribonucleic acid release and systemic inflammatory cytokines production. Furthermore, NLRP3 inflammasome level in the lung tissue was decreased and burn induced lung injury was ameliorated. Conclusions: Our results suggested that simulated aeromedical evacuation further increased the burn induced mitochondrial deoxyribonucleic acid release and exacerbated burn induced inflammation and lung injury. Deoxyribonuclease I reduced the release of mitochondrial deoxyribonucleic acid and limited the mitochondrial deoxyribonucleic acid-induced systemic inflammation, ameliorated burn-induced acute lung injury. Intervening mitochondrial deoxyribonucleic acid level could be a potential target to protect from burn-induced lung injury during aeromedical conditions and provide with safer air evacuations for severely burned patients.

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“…Indeed, as recently reviewed (Moriyama et al 2020), the major contributing factor (besides human behavior) to respiratory virus outbreaks are the changes in environmental parameters. On the other hand, however, thermal stress/injury, either cold or heat, has been experimentally shown to be associated with emission of endogenous DAMPs (Cai et al 2019;Liu et al 2019).…”

Section: Superimposition Of Noninfectious Environmental and Infectioumentioning

confidence: 99%

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

Land

2020

Int J Environ Res

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Two prominent models emerged as a result of intense interdisciplinary discussions on the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept that links a molecular initiating event to the adverse outcome via key events. Here, evidence is discussed, suggesting that environmental stress/injury-induced damageassociated molecular patterns (DAMPs) may operate as an essential integrating element of both environmental health research paradigms. DAMP-promoted controlled/uncontrolled innate/adaptive immune responses reflect the key events of the AOP concept. The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. Clinical examples of such a scenario are briefly sketched, in particular, a model in relation to the emerging COVID-19 pandemic, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs. Article Highlights • This review is devoted to the first scientific attempt to integrate DAMP-controlled innate immune inflammatory and adaptive immune defense responses as well as DAMP-uncontrolled dysregulated pathological responses (acute and chronic human diseases) in the environmental health paradigm, called the "exposome" concept and the "adverse outcome pathway" (AOP) concept. • Evidence is discussed that DAMP-promoted controlled/uncontrolled innate immune/adaptive immune responses reflect the key events of the AOP concept. • The whole process starting from exposure to a distinct environmental stress/injury-associated with the presence/ emission of DAMPs-up to the manifestation of a disease may be regarded as an exposome. • Some exemplifying models of such a scenario are briefly sketched, including respiratory infections, autoimmune/ allergic diseases, organ fibrosis, and cancer. • In particular, a model in relation to the emerging COVID-19 pandemic is presented, where the interaction of noninfectious environmental factors (e.g., particulate matter) and infectious factors (SARS CoV-2) may promote SARS case fatality via superimposition of both exogenous and endogenous DAMPs.

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Mitochondrial DNA-Induced Inflammatory Responses and Lung Injury in Thermal Injury Murine Model: Protective Effect of Cyclosporine-A

Cited by 28 publications

References 39 publications

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Simulated Aeromedical Evacuation Exacerbates Burn Induced Lung Injury: Targeting Mitochondrial DNA for Reversal

Role of Damage-Associated Molecular Patterns in Light of Modern Environmental Research: A Tautological Approach

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