Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis

Tsubouchi, Kazuya; Araya, Jun; Yoshida, Masahiro; Sakamoto, Taro; Koumura, Tomoko; Minagawa, Shunsuke; Hara, Hiromichi; Hosaka, Yusuke; Ichikawa, Akihiro; Saito, Nayuta; Kadota, Tsukasa; Kurita, Yusuke; Kobayashi, Kenji; Ito, Saburo; Fujita, Yu; Utsumi, Hirofumi; Hashimoto, Mitsuo; Wakui, Hiroshi; Numata, Takanori; Kaneko, Yoshiaki; Mori, Shiro; Asano, Hiroaki; Matsudaira, Hideki; Ohtsuka, Takashi; Nakayama, Katsutoshi; Nakanishi, Yoichi; Imai, Hideki; Kuwano, Kazuyoshi

doi:10.4049/jimmunol.1801232

Cited by 47 publications

(37 citation statements)

References 56 publications

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“…In addition, 8-isoprostane is elevated fivefold 28 and oxidized proteins twofold 29 in bronchoalveolar lavage fluid (BALF) of patients with IPF. HNE in lung 30 and 8-isoprostane in blood 31 are also significantly elevated in IPF. The glutathione (GSH) level in epithelial lining fluid and sputum of patients with IPF is fourfold lower than in healthy controls 32 , indicating a deficiency of this important component of antioxidant defence in IPF.…”

Section: Roles Of Oxidative Stress In Diseasementioning

confidence: 93%

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Forman

Zhang

2021

Nat Rev Drug Discov

1,465

818

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Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mechanisms through which antioxidants act and where and when they are effective may provide a rational approach that leads to greater pharmacological success. Here, we review the relationships between oxidative stress, redox signalling and disease, the mechanisms through which oxidative stress can contribute to pathology, how antioxidant defences work, what limits their effectiveness and how antioxidant defences can be increased through physiological signalling, dietary components and potential pharmaceutical intervention.

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Section: Roles Of Oxidative Stress In Diseasementioning

confidence: 93%

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Forman

Zhang

2021

Nat Rev Drug Discov

1,465

818

View full text Add to dashboard Cite

show abstract

“…GPx4 is also an essential mitochondrial antioxidant peroxidase that catalyzes the reduction of hydroperoxides [51]. Increased lipid peroxidation is related to low levels of GPx4, presenting its activation as a mechanism to attenuate oxidative stress and lipid peroxidation [51,52]. Peptides are reported to regress oxidative stress by activating antioxidant enzymes like GPx and SOD.…”

Section: Discussionmentioning

confidence: 99%

Spent Hen Muscle Protein-Derived RAS Regulating Peptides Show Antioxidant Activity in Vascular Cells

Fan

Bhullar

2021

Antioxidants

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Spent hens are egg-laying hens reaching the end of their egg-laying cycles, being a major byproduct of the egg industry. Recent studies have been focusing on finding new value-added uses for spent hens. We have previously identified four bioactive peptides from spent hen muscle proteins, including three angiotensin-converting enzyme (ACE) inhibitory (ACEi) peptides (VRP, LKY, and VRY), and one ACE2 upregulating (ACE2u) peptide (VVHPKESF (V-F)). In the current study, we further assessed their antioxidant and cytoprotective activities in two vascular cell lines—vascular smooth muscle A7r5 cells (VSMCs) and endothelial EA.hy926 cells (ECs)—upon stimulation by tumor necrosis factor alpha (TNFα) and angiotensin (Ang) II, respectively. The results from our study revealed that all four peptides attenuated oxidative stress in both cells. None of the investigated peptides altered the expression of TNFα receptors in ECs; however, VRY and V-F downregulated Ang II type 1 receptor (AT1R), while V-F upregulated the Mas receptor (MasR) in VSMCs. Further, we found that the antioxidant effects of VRP, LKY, and VRY were likely through acting as direct radical scavengers, while that of V-F was at least partially ascribed to increased endogenous antioxidant enzymes (GPx4 and SOD2) in both cells. Besides, as an ACE2u peptide, V-F exerted antioxidant effect in a MasR-dependent manner, indicating a possible involvement of the upregulated ACE2-MasR axis underlying its antioxidant action. The antioxidant activities of VRP, LKY, VRY, and V-F in vascular cells indicated their multifunctional properties, in addition to their ACEi or ACE2u activity, which supports their potential use as functional food ingredients against hypertension.

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“…Glutathione peroxidase (GPx) is an important antioxidant enzyme that reduces phospholipid hydroperoxides and modulation of GPx expression or activity would tilt the redox balance towards oxidation. Reduced expression of GPx4 and increased 4-hydroxynonenal immunostaining was seen in IPF lungs, and genetic deletion of GPx4 (Gpx4 +/− ) mice showed enhanced bleomycin-induced lung fibrosis and TGF-β-mediated myofibroblast differentiation in vitro [316]. Thus, changes in the redox status due to tress could play a critical role in the pathophysiology of IPF.…”

Section: Lipid Peroxidation and Oxidized Phospholipids In Pulmonary Fmentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

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Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis

Cited by 47 publications

References 56 publications

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Targeting oxidative stress in disease: promise and limitations of antioxidant therapy

Spent Hen Muscle Protein-Derived RAS Regulating Peptides Show Antioxidant Activity in Vascular Cells

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

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