Hyperoxia induces endoplasmic reticulum stress‑associated apoptosis via the IRE1&amp;alpha; pathway in rats with bronchopulmonary dysplasia

Tong, Xin; Li, Mengyun; Liu, Na; Huang, Wanjie; Xue, Xindong; Fu, Jianhua

doi:10.3892/mmr.2020.11671

Cited by 4 publications

(4 citation statements)

References 42 publications

(59 reference statements)

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“…ER stress and OS are two interrelated states involved in many lung diseases [38]. It has recently been reported that increased ER stress is seen in the lungs of several established BPD animal models [11][12][13]39]. Using the lung explant model of GRP78 knockout fetal mice, Flodby et al demonstrated that the increased ER stress and impaired alveolar formation could be reversed by TUDCA, indicating a potential therapeutic strategy for preventing BPD development [40].…”

Section: Er Stress Is Increased In Bpdmentioning

confidence: 99%

“…Previously it was reported that HOX and interferon-gamma induce lung injury neutrophil arrival by increasing endoplasmic reticulum (ER) stress in the lungs of neonatal mice [11]. Tong has shown that chronic HOX induces ER stress in neonatal rat lungs [12] by a mechanism that we have shown can be inhibited by administering caffeine early on [13]. As the OS generated by the cycle of destruction [10] appears in conflict with caffeine-inhibitable ER stress, additional studies are required to understand how OS induces ER stress and the BPD phenotype as the disease progresses.…”

Section: Introductionmentioning

confidence: 99%

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Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia

et al. 2022

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Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are increased in the lungs of rat pups raised in hyperoxia, an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in hyperoxia rat pups. We treated Sprague-Dawley rat pups with tunicamycin or hyperoxia to determine this relationship. ER stress was detected using immunofluorescence, transcriptomic, proteomic, and electron microscopic analyses. Immunofluorescence observed increased ER stress in the lungs of hyperoxic rat BPD and human BPD. Proteomic and morphometric studies showed that tunicamycin directly increased ER stress of rat lungs and decreased lung complexity with a BPD phenotype. Previously, we showed that hyperoxia initiates a cycle of destruction that we hypothesized starts from increasing OS through MPO accumulation and then increases ER stress to cause BPD. To inhibit ER stress, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO, we used N-acetyl-lysyltyrosylcysteine amide (KYC). The fact that TUDCA improved lung complexity in tunicamycin- and hyperoxia-treated rat pups supports the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of tunicamycin- and hyperoxia-treated rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC’s inhibition of ER stress in the tunicamycin-treated rat pup’s lung provides additional support for the idea that MPO-induced ER stress plays a causal role in the BPD phenotype. ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impair growth and development. The encouraging effect of TUDCA indicates that this compound has the potential for treating BPD.

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Section: Er Stress Is Increased In Bpdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia

et al. 2022

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“…A recent study by Tong et al found that hyperoxia induces a non-canonical type of apoptotic cell death via ER stress (Tong et al 2021 ). ER stress induces the unfolded protein response (UPR).…”

Section: Hyperoxia Causes Cell Death Via Multiple Pathwaysmentioning

confidence: 99%

Oxygen toxicity: cellular mechanisms in normobaric hyperoxia

et al. 2022

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In clinical settings, oxygen therapy is administered to preterm neonates and to adults with acute and chronic conditions such as COVID-19, pulmonary fibrosis, sepsis, cardiac arrest, carbon monoxide poisoning, and acute heart failure. In non-clinical settings, divers and astronauts may also receive supplemental oxygen. In addition, under current standard cell culture practices, cells are maintained in atmospheric oxygen, which is several times higher than what most cells experience in vivo. In all the above scenarios, the elevated oxygen levels (hyperoxia) can lead to increased production of reactive oxygen species from mitochondria, NADPH oxidases, and other sources. This can cause cell dysfunction or death. Acute hyperoxia injury impairs various cellular functions, manifesting ultimately as physiological deficits. Chronic hyperoxia, particularly in the neonate, can disrupt development, leading to permanent deficiencies. In this review, we discuss the cellular activities and pathways affected by hyperoxia, as well as strategies that have been developed to ameliorate injury. Graphical abstract • Hyperoxia promotes overproduction of reactive oxygen species (ROS). • Hyperoxia dysregulates a variety of signaling pathways, such as the Nrf2, NF-κB and MAPK pathways. • Hyperoxia causes cell death by multiple pathways. • Antioxidants, particularly, mitochondria-targeted antioxidants, have shown promising results as therapeutic agents against oxygen toxicity in animal models.

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“…The high levels of ROS upon hyperoxia can overwhelm the antioxidant systems in pulmonary cell types, which then become targets of ROS-induced injury and death. Studies show that hyperoxia-induced lung injury is associated with the death of alveolar epithelial cells, showing features of both apoptosis and necrosis ( Das et al, 2004 ; Tong et al, 2021 ; Witkowski et al, 2016 ). Preterm human neonates who have received mechanical ventilation show higher levels of apoptosis, particularly, in epithelial cells ( Lukkarinen et al, 2003 ).…”

Section: Lung Development and Bpdmentioning

confidence: 99%

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies

Giusto

Wanczyk

Jensen

et al. 2021

Disease Models &Amp; Mechanisms

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Bronchopulmonary dysplasia (BPD) is a chronic lung disease caused by exposure to high levels of oxygen (hyperoxia) and is the most common complication that affects preterm newborns. At present, there is no cure for BPD. Infants can recover from BPD; however, they will suffer from significant morbidity into adulthood in the form of neurodevelopmental impairment, asthma and emphysematous changes of the lung. The development of hyperoxia-induced lung injury models in small and large animals to test potential treatments for BPD has shown some success, yet a lack of standardization in approaches and methods makes clinical translation difficult. In vitro models have also been developed to investigate the molecular pathways altered during BPD and to address the pitfalls associated with animal models. Preclinical studies have investigated the efficacy of stem cell-based therapies to improve lung morphology after damage. However, variability regarding the type of animal model and duration of hyperoxia to elicit damage exists in the literature. These models should be further developed and standardized, to cover the degree and duration of hyperoxia, type of animal model, and lung injury endpoint, to improve their translational relevance. The purpose of this Review is to highlight concerns associated with current animal models of hyperoxia-induced BPD and to show the potential of in vitro models to complement in vivo studies in the significant improvement to our understanding of BPD pathogenesis and treatment. The status of current stem cell therapies for treatment of BPD is also discussed. We offer suggestions to optimize models and therapeutic modalities for treatment of hyperoxia-induced lung damage in order to advance the standardization of procedures for clinical translation.

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Hyperoxia induces endoplasmic reticulum stress‑associated apoptosis via the IRE1α pathway in rats with bronchopulmonary dysplasia

Cited by 4 publications

References 42 publications

Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia

Role of endoplasmic reticulum stress in impaired neonatal lung growth and bronchopulmonary dysplasia

Oxygen toxicity: cellular mechanisms in normobaric hyperoxia

Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies

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