PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury

Shi, Jia; Yu, Jianbo; Zhang, Yuan; Wu, Lili; Dong, Shuying; Wu, Lina; Wu, Lingzhi; Du, Shihan; Zhang, Yanfang; Ma, Ding

doi:10.1038/s41374-019-0286-x

Cited by 105 publications

(65 citation statements)

References 50 publications

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“…The chronic inflammatory response in cell lines and skeletal muscle caused by OPA1 deficiency is well-documented in patients and animal models (55)(56)(57). In addition, the adequate response to sepsis caused by pulmonary infection, whichoften complicates other chronic conditions, also requires rapid upregulation of OPA1 (58). In post-mortem analyses of lung tissue obtained from areas with mild and severe emphysema, impaired fusion characterized by a low quantity of OPA1 protein is correlated with disease severity (59).…”

Section: Discussionmentioning

confidence: 99%

A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1

2021

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Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the OPA1 gene. It has variable onset, sometimes juvenile, but in other patients, the disease does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered healthy before the onset of clinical symptoms. Our research, nonetheless, indicates that on the cellular level pathology is evident from birth and mutant cells are different from controls. We argue that the adaptation and early recruitment of cytoprotective responses allows normal development and functioning but leads to an exhaustion of cellular reserves, leading to premature cellular aging, especially in neurons and skeletal muscle cells. The appearance of clinical symptoms, thus, indicates the overwhelming of natural cellular defenses and break-down of native protective mechanisms.

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Section: Discussionmentioning

confidence: 99%

A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1

2021

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“…It has been con rmed that α7nAChRs are core receptors mediating CAP. When α7nAChRs are activated, cholinergic anti-in ammatory signals can play anti-in ammatory roles in cells through NF-κB, Janus activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and PI3K/Akt pathways [10,14]. As a speci c α7nChRA agonist, PHA568487 stimulates CAP activity through speci c binding to α7nAChRs [16].…”

Section: Discussionmentioning

confidence: 99%

“…The target genes regulated by Nrf2 include stress genes and antioxidant genes, mainly including catalase (CAT), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1). Among them, HO-1 is considered to promote adaptive cytoprotective responses against oxidative stress and in ammatory stimulation [10]. It can alleviate endotoxic shockinduced lung injury through resisting in ammation and oxidative stress and inhibiting cytokine release.…”

Section: Introductionmentioning

confidence: 99%

α7nAChR Agonist Activates the Nrf2/HO-1 Signaling Pathway to Reduce Acute Lung Injury Induced by Endotoxic Shock

Zhang

Lun

Wang

et al. 2020

Preprint

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Objective: Alpha 7 nicotinic acetylcholine receptors (α7nAChRs) can inhibit the activation of macrophages and the production of pro-inflammatory cytokines and exert inhibitory effects on systemic and local inflammatory responses. The objective of this study was to observe the protective effect of α7nAChR agonist against acute lung injury (ALI) caused by endotoxic shock, and to explore the regulatory mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Methods: A total of 40 Sprague-Dawley rats were randomly divided into sham operation group (Sham group, n=10), endotoxic shock-induced ALI model group (ALI group, n=10), ALI + α7nAChR agonist (PHA568487, 3134, Tocris Bioscience, USA) group (PHA group, n=10) and ALI + α7nAChR agonist + Nrf2 inhibitor (ML385, HY-100523, MCE, USA) group (ML group, n=10). The rats received a tail vein injection of LPS to initiate ALI. Six hrs after injection, arterial blood was analyzed for blood gases and lung wet weight/dry weight (W/D) was determined. Lung histopathology was determined by H&E staining and apoptosis quantified by TUNEL. Levels of intercellular adhesion molecule-1 (ICAM-1), TNF-α, IL-1β, malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), choline acetyltransferase (ChAT) and acetylcholine esterase (AchE) in bronchoalveolar lavage fluid were measured via ELISA. Western blotting revealed levels of nuclear factor kappa-B (NF-κB), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (Akt), phosphorylated Akt (p-Akt), HO-1, Nrf2, thioredoxin reductase 1 (Trx-1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Results: It was found that α7nAChR agonist increased the partial pressure of oxygen (PaO2) and pH, reduced the partial pressure of carbon dioxide (PaCO2) and W/D ratio, alleviated pulmonary edema and oxidative stress injury, and suppressed inflammatory responses. At the same time, it activated PI3K to phosphorylate Akt, inhibited cell apoptosis, and protected the lung tissues of ALI rats. Moreover, α7nAChR agonist facilitated nuclear translocation of Nrf-2 and up-regulated HO-1 and Trx-1 expression. Nrf-2 activity was required for the protective effect of α7nAChR . Conclusion: α7nAChR agonist can improve endotoxic shock-induced ALI by activating the cholinergic anti-inflammatory pathway and the Nrf2/HO-1 signaling pathway.

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“…Previously, Shi et al [2019] demonstrated that LPS induced mitochondrial abnormalities and dysfunction both in vivo and in vitro. Therefore, we processed our lung tissues for transmission electron microscopy to explore the protective effects of CoQ10 and/or AES at subcellular levels.…”

Section: Electron Microscope Examinationmentioning

confidence: 99%

Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury

Ali

Ahmed

Eltrawy

et al. 2021

Cells Tissues Organs

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Sepsis-associated acute lung injury (ALI) is a critical condition characterized by severe inflammatory response and mitochondrial dysfunction. Coenzyme Q10 (CoQ10) and aescin (AES) are well-known for their anti-inflammatory activities. However, their effects on lipopolysaccharide (LPS)-induced lung injury have not been explored yet. Here, we asked whether combined pretreatment with CoQ10 and AES synergistically prevents LPS-induced lung injury. Fifty male rats were randomized into 5 groups: (1) control; (2) LPS-treated, rats received a single i.p. injection of LPS (8 mg/kg); (3) CoQ10-pretreated, (4) AES-pretreated, or (5) combined-pretreated; animals received CoQ10 (100 mg/kg), AES (5 mg/kg), or both orally for 7 days before LPS injection. Combined CoQ10 and AES pretreatment significantly reduced lung injury markers; 52.42% reduction in serum C-reactive protein (CRP), 53.69% in alkaline phosphatase (ALKP) and 60.26% in lactate dehydrogenase (LDH) activities versus 44.58, 37.38, and 48.6% in CoQ10 and 33.81, 34.43, and 39.29% in AES-pretreated groups, respectively. Meanwhile, combination therapy significantly reduced interleukin (IL)-1β and tumor necrosis factor (TNF)-α expressions compared to monotherapy (p < 0.05). Additionally, combination therapy prevented LPS-induced histological and mitochondrial abnormalities greater than separate drugs. Western blotting indicated that combination therapy significantly suppressed nucleotide-binding oligomerization domain (NOD)-like receptors-3 (NLRP-3) inflammasome compared to separate drugs (p < 0.05). Further, combination therapy significantly decreased the expression of signaling cascades, p38 mitogen-activated protein kinases (p38 MAPK), nuclear factor kappa B (NF-κB)-p65, and extracellular-regulated kinases 1/2 (ERK1/2) versus monotherapy (p < 0.05). Interestingly, combined pretreatment significantly downregulated high mobility group box-1 (HMGB1) by 72.93%, and toll-like receptor 4 (TLR4) by −0.93-fold versus 61.92%, −0.83-fold in CoQ10 and 38.67%, −0.70-fold in AES pretreatment, respectively. Our results showed for the first time that the enhanced anti-inflammatory effect of combined CoQ10 and AES pretreatment prevented LPS-induced ALI via suppression of NLRP-3 inflammasome through regulation of HMGB1/TLR4 signaling pathway and mitochondrial stabilization.

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PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury

Cited by 105 publications

References 50 publications

A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1

A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1

α7nAChR Agonist Activates the Nrf2/HO-1 Signaling Pathway to Reduce Acute Lung Injury Induced by Endotoxic Shock

Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury

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