Endoplasmic Reticulum Stress in Bronchopulmonary Dysplasia: Contributor or Consequence?

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies.

Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth.

Role of Myeloperoxidase, Oxidative Stress, and Inflammation in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a lung complication of premature births. The leading causes of BPD are oxidative stress (OS) from oxygen treatment, infection or inflammation, and mechanical ventilation. OS activates alveolar myeloid cells with subsequent myeloperoxidase (MPO)-mediated OS.

Sterile inflammation induces vasculopathy and chronic lung injury in murine sickle cell disease.

Murine sickle cell disease (SCD) results in damage to multiple organs, likely mediated first by vasculopathy. While the mechanisms inducing vascular damage remain to be determined, nitric oxide bioavailability and sterile inflammation are both considered to play major roles in vasculopathy. Here, we investigate the effects of high mobility group box-1 (HMGB1), a pro-inflammatory damage-associated molecular pattern (DAMP) molecule on endothelial-dependent vasodilation and lung morphometrics, a structural index of damage in sickle (SS) mice.

Sleeve Gastrectomy Provides Cardioprotection from Oxidative Stress In Vitro Due to Reduction of Circulating Myeloperoxidase.

Bariatric surgery, including sleeve gastrectomy (SG), improves systolic and diastolic function, which is independent of weight loss in rodent models. The cause of weight loss-independent improvements in cardiac function are unknown but may originate from the gastrointestinal tract. In this study, we investigated whether a circulating blood factor is a mechanism for acute cardioprotection after SG by testing the utility of rodent SG plasma to reduce metabolic stress in vitro.

Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia.

Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth.

OLA1 Phosphorylation Governs the Mitochondrial Bioenergetic Function of Pulmonary Vascular Cells.

Mitochondrial function and metabolic homeostasis are integral to cardiovascular function and influence how vascular cells respond to stress. However, little is known regarding how mitochondrial redox control mechanisms and metabolic regulation interact in the developing lungs. Here we show that human OLA1 (Obg-like ATPase-1) couples redox signals to the metabolic response pathway by activating metabolic gene transcription in the nucleus.

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

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.

Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice.

Plaque psoriasis is a common inflammatory condition of the skin characterized by red, flaking lesions. Current therapies for plaque psoriasis target many facets of the autoimmune response, but there is an incomplete understanding of how oxidative damage produced by enzymes such as myeloperoxidase contributes to skin pathology. In this study, we used the Aldara (Imiquimod) cream model of plaque psoriasis in mice to assess myeloperoxidase inhibition for treating psoriatic skin lesions.

N-acetyl-lysyltyrosylcysteine amide, a novel systems pharmacology agent, reduces bronchopulmonary dysplasia in hyperoxic neonatal rat pups.

Bronchopulmonary dysplasia (BPD) is caused primarily by oxidative stress and inflammation. To induce BPD, neonatal rat pups were raised in hyperoxic (>90% O) environments from day one (P1) until day ten (P10) and treated with N-acetyl-lysyltyrosylcysteine amide (KYC). In vivo studies showed that KYC improved lung complexity, reduced myeloperoxidase (MPO) positive (+) myeloid cell counts, MPO protein, chlorotyrosine formation, increased endothelial cell CD31 expression, decreased 8-OH-dG and Cox-1/Cox-2, HMGB1, RAGE, TLR4, increased weight gain and improved survival in hyperoxic pups.

Neutrophil-Derived Myeloperoxidase Facilitates Both the Induction and Elicitation Phases of Contact Hypersensitivity.

Background: Allergic contact dermatitis (ACD) is a common skin disorder affecting an estimated 15-20% of the general population. The mouse model of ACD is contact hypersensitivity (CHS), which consists of two phases: induction and elicitation. Although neutrophils are required for both CHS disease phases their mechanisms of action are poorly understood.

Inhibition of myeloperoxidase increases revascularization and improves blood flow in a diabetic mouse model of hindlimb ischaemia.

Objective: Diabetes mellitus is a significant risk factor for peripheral artery disease. Diabetes mellitus induces chronic states of oxidative stress and vascular inflammation that increase neutrophil activation and release of myeloperoxidase. The goal of this study is to determine whether inhibiting myeloperoxidase reduces oxidative stress and neutrophil infiltration, increases vascularization, and improves blood flow in a diabetic murine model of hindlimb ischaemia.

Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn.

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown.

Redox Signaling in Sickle Cell Disease.

Sickle cell disease (SCD) is characterized by chronic hemolysis and repeated episodes of vascular occlusion leading to progressive organ injury. SCD is characterized by unbalanced, simultaneous pro-oxidant and anti-oxidant processes at the molecular, cellular and tissue levels, with the majority of reactions tipped in favor of pro-oxidant pathways. In this brief review we discuss new findings regarding how oxidized hemin, hemolysis, mitochondrial dysfunction and the innate immune system generate oxidative stress while hemopexin, haptoglobin, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) may provide protection in human and murine SCD.

Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance.

The import of superoxide dismutase-2 (SOD2) into mitochondria is vital for the survival of eukaryotic cells. SOD2 is encoded within the nuclear genome and translocated into mitochondria for activation after translation in the cytosol. The molecular chaperone Hsp70 modulates SOD2 activity by promoting import of SOD2 into mitochondria.

Myeloperoxidase: A new player in autoimmunity.

Myeloperoxidase (MPO) is the most toxic enzyme found in the azurophilic granules of neutrophils. MPO utilizes HO to generate hypochlorous acid (HClO) and other reactive moieties, which kill pathogens during infections. In contrast, in the setting of sterile inflammation, MPO and MPO-derived oxidants are thought to be pathogenic, promoting inflammation and causing tissue damage.

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice.

The interferon regulatory factor 5 (IRF5) is crucial for cells to determine if they respond in a pro-inflammatory or anti-inflammatory fashion. IRF5's ability to switch cells from one pathway to another is highly attractive as a therapeutic target. We designed a decoy peptide IRF5D with a molecular modeling software for designing small molecules and peptides.

Domain Mapping of Heat Shock Protein 70 Reveals That Glutamic Acid 446 and Arginine 447 Are Critical for Regulating Superoxide Dismutase 2 Function.

Stress-inducible heat shock protein 70 (hsp70) interacts with superoxide dismutase 2 (SOD2) in the cytosol after synthesis to transfer the enzyme to the mitochondria for subsequent activation. However, the structural basis for this interaction remains to be defined. To map the SOD2-binding site in hsp70, mutants of hsp70 were made and tested for their ability to bind SOD2.

Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke.

Background: Oxidative stress plays an important and causal role in the mechanisms by which ischemia/reperfusion (I/R) injury increases brain damage after stroke. Accordingly, reducing oxidative stress has been proposed as a therapeutic strategy for limiting damage in the brain after stroke. Myeloperoxidase (MPO) is a highly potent oxidative enzyme that is capable of inducing both oxidative and nitrosative stress in vivo.

An IRF5 Decoy Peptide Reduces Myocardial Inflammation and Fibrosis and Improves Endothelial Cell Function in Tight-Skin Mice.

Interferon regulatory factor 5 (IRF5) has been called a "master switch" for its ability to determine whether cells mount proinflammatory or anti-inflammatory responses. Accordingly, IRF5 should be an attractive target for therapeutic drug development. Here we report on the development of a novel decoy peptide inhibitor of IRF5 that decreases myocardial inflammation and improves vascular endothelial cell (EC) function in tight-skin (Tsk/+) mice.

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood-brain barrier integrity and ameliorates disease severity.

Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known.

Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic).

Background: Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury.

Interaction of endothelial nitric oxide synthase with mitochondria regulates oxidative stress and function in fetal pulmonary artery endothelial cells.

An increase in oxygen tension at birth is one of the key signals that initiate pulmonary vasodilation in the fetal lung. We investigated the hypothesis that targeting endothelial nitric oxide synthase (eNOS) to the mitochondrial outer membrane regulates reactive oxygen species (ROS) formation in the fetal pulmonary artery endothelial cells (PAEC) during this transition. We isolated PAEC and pulmonary arteries from 137-day gestation fetal lambs (term = 144 days).