Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases

Caldeira, Dayene de Assis Fernandes; Weiss, Daniel J.; Rocco, Patrícia Rieken Macêdo; Silva, Pedro L.; Cruz, Fernanda Ferreira

doi:10.3389/fimmu.2021.782074

Cited by 34 publications

(24 citation statements)

References 184 publications

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“…mtDNA damage is a DNA damage-associated molecular pattern that causes inflammation, immunological responses, and cell death, and is significantly linked to immune-related lung disorders. 11 , 12 …”

Section: Introductionmentioning

confidence: 99%

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence

Abo-Zaid

Moawed

Hassan

et al. 2022

Int J Immunopathol Pharmacol

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Background Bisphenol (BPA) and ionizing radiation exposure (IR) are potent oxidants that cause free radical induction, leading to signaling pathway activation that alters cell growth. Due to the insufficient knowledge of the impact of BPA and IR on the lungs, the current study determined the impact of BPA and IR on the lung tissue of adult female Wistar rats. Methods Forty Wister female rats were used in this study and were randomly divided into four groups. The rats received BPA (150 mg/kg body weight/day for 6 weeks) and were exposed to IR at 2 Gy/week up to 12 Gy for 6 weeks. Results It was found that BPA and IR possess a harmful effect on the lungs via induction of oxidative stress, confirmed by increasing levels of malondialdehyde (MDA), nitric oxide, myeloperoxidase (MPO), and lactate dehydrogenase (LDH). Exposure to BPA and IR activates inflammatory cytokines TNF-α, IL-6, IL-1β, growth factors such as TGF-β, and gastrin-releasing peptides. BPA/IR exposures induced phosphorylated expression p-ERK1/2 and p-MEK1/2 associated with triggering of the GPER/EGFR/KRAS signaling factors, resulting in matrix metalloproteinase-2 and 9 overexpression and the development of lung tumors. Our findings support the causal role of two deleterious environmental pollutants BPA and IR, via the cytotoxicity in the respiratory system in the form of severe lung damage resulting in cancerous cells.

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Section: Introductionmentioning

confidence: 99%

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence

Abo-Zaid

Moawed

Hassan

et al. 2022

Int J Immunopathol Pharmacol

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“…Moreover, knockdown of TFAM or RHOT1 in human lung epithelial cells or fibroblasts impairs their cellular properties, including PDGF secretion and myofibroblast migration. We speculate that changes in cellular properties due to disturbed mitochondrial activity and distribution contribute to the pathogenesis of COPD/emphysema ( Ryter et al, 2018 ; Caldeira et al, 2021 ; Hara et al, 2018 ; Cloonan and Choi, 2016 ). Disturbance of mitochondrial function and cellular properties could be related to inflammatory responses in COPD/emphysema.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria

Zhang

Yao

Chen

et al. 2022

eLife

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Alveolar formation requires coordinated movement and interaction between alveolar epithelial cells, mesenchymal myofibroblasts and endothelial cells/pericytes to produce secondary septa. These processes rely on the acquisition of distinct cellular properties to enable ligand secretion for cell-cell signaling and initiate morphogenesis through cellular contraction, cell migration and cell shape change. In this study, we showed that mitochondrial activity and distribution play a key role in bestowing cellular functions on both alveolar epithelial cells and mesenchymal myofibroblasts for generating secondary septa to form alveoli in mice. These results suggest that mitochondrial function is tightly regulated to empower cellular machineries in a spatially-specific manner. Indeed, such regulation via mitochondria is required for secretion of ligands, such as platelet-derived growth factor, from alveolar epithelial cells to influence myofibroblast proliferation and contraction/migration. Moreover, mitochondrial function enables myofibroblast contraction/migration during alveolar formation. Together, these findings yield novel mechanistic insights into how mitochondria regulate pivotal steps of alveologenesis. They highlight selective utilization of energy in cells and diverse energy demands in different cellular processes during development. Our work serves as a paradigm for studying how mitochondria control tissue patterning.

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“…Mitochondrial dysfunction was recently recognized to play a significant role in the pathogenesis of various diseases [29,151,152]. Its role in neonatal BPD is beginning to emerge, and the involvement of sphingolipids in propagating mitochondrial damage is yet to be elucidated in detail.…”

Section: Oxidative Stress and Mitochondrial Injurymentioning

confidence: 99%

The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

Thomas

Sudhadevi

Basa

et al. 2022

IJMS

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Premature infants are born with developing lungs burdened by surfactant deficiency and a dearth of antioxidant defense systems. Survival rate of such infants has significantly improved due to advances in care involving mechanical ventilation and oxygen supplementation. However, a significant subset of such survivors develops the chronic lung disease, Bronchopulmonary dysplasia (BPD), characterized by enlarged, simplified alveoli and deformed airways. Among a host of factors contributing to the pathogenesis is oxidative damage induced by exposure of the developing lungs to hyperoxia. Recent data indicate that hyperoxia induces aberrant sphingolipid signaling, leading to mitochondrial dysfunction and abnormal reactive oxygen species (ROS) formation (ROS). The role of sphingolipids such as ceramides and sphingosine 1-phosphate (S1P), in the development of BPD emerged in the last decade. Both ceramide and S1P are elevated in tracheal aspirates of premature infants of <32 weeks gestational age developing BPD. This was faithfully reflected in the murine models of hyperoxia and BPD, where there is an increased expression of sphingolipid metabolites both in lung tissue and bronchoalveolar lavage. Treatment of neonatal pups with a sphingosine kinase1 specific inhibitor, PF543, resulted in protection against BPD as neonates, accompanied by improved lung function and reduced airway remodeling as adults. This was accompanied by reduced mitochondrial ROS formation. S1P receptor1 induced by hyperoxia also aggravates BPD, revealing another potential druggable target in this pathway for BPD. In this review we aim to provide a detailed description on the role played by sphingolipid signaling in hyperoxia induced lung injury and BPD.

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Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases

Cited by 34 publications

References 184 publications

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence

Bisphenol-A/Radiation mediated inflammatory response activates EGFR/KRAS/ERK1/2 signaling pathway leads to lung carcinogenesis incidence

Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria

The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

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