scholarly journals Oxygen Toxicity to the Immature Lung—Part I: Pathomechanistic Understanding and Preclinical Perspectives

2021 ◽  
Vol 22 (20) ◽  
pp. 11006
Author(s):  
Yesi Choi ◽  
Lisa Rekers ◽  
Ying Dong ◽  
Lena Holzfurtner ◽  
Maurizio J. Goetz ◽  
...  
Keyword(s):  
Pulmonary Inflammation ◽  
Oxygen Toxicity ◽  
Clinical Situation ◽  
Experimental Models ◽  
Ros Production ◽  
Research Activities ◽  
Hypoxic Environment ◽  
Altered Gene ◽  
Key Events ◽  
Immature Lung

In utero, the fetus and its lungs develop in a hypoxic environment, where HIF-1α and VEGFA signaling constitute major determinants of further development. Disruption of this homeostasis after preterm delivery and extrauterine exposure to high fractions of oxygen are among the key events leading to bronchopulmonary dysplasia (BPD). Reactive oxygen species (ROS) production constitutes the initial driver of pulmonary inflammation and cell death, altered gene expression, and vasoconstriction, leading to the distortion of further lung development. From preclinical studies mainly performed on rodents over the past two decades, the deleterious effects of oxygen toxicity and the injurious insults and downstream cascades arising from ROS production are well recognized. This article provides a concise overview of disease drivers and different therapeutic approaches that have been successfully tested within experimental models. Despite current studies, clinical researchers are still faced with an unmet clinical need, and many of these strategies have not proven to be equally effective in clinical trials. In light of this challenge, adapting experimental models to the complexity of the clinical situation and pursuing new directions constitute appropriate actions to overcome this dilemma. Our review intends to stimulate research activities towards the understanding of an important issue of immature lung injury.

Lack of effect of cocaine on lysine and alanine uptake in human placental villi or transfer in perfused human placenta

1995 ◽  
Vol 7 (6) ◽  
pp. 1495 ◽  
Author(s):  
RB Krishna ◽  
M Levitz ◽  
J Dancis
Keyword(s):  
Amino Acid ◽  
Human Placenta ◽  
Clinical Situation ◽  
Experimental Models ◽  
Antipyrine Clearance ◽  
Placental Villi ◽  
Glucose Clearance ◽  
Index Ratio ◽  
Transfer Index

The effect of cocaine on lysine and alanine uptake in human placental villi and transfer across the dually perfused placenta was studied. Uptake (in terms of the intracellular to extracellular distribution ratio) of alanine and lysine was 2.81 +/- 0.30 (n = 5) and 1.45 +/- 0.24 (n = 5) respectively and was unaffected by cocaine (50-500 ng mL(-1) in the incubation medium. In the dually perfused placenta, the clearance index (ratio of amino acid to antipyrine clearance) was 0.35 +/- 0.03 and 0.30 +/- 0.05 and the transfer index (ratio of amino acid to L-glucose clearance) was 2.20 +/- 0.07 and 1.89 +/- 0.29 for lysine and alanine respectively. Cocaine at concentrations of 100 ng mL(-1) or 250 ng mL(-1) had no effect on the clearance of either amino acid. The results of this study indicate that concentrations of cocaine likely to be encountered in vivo do not affect uptake of lysine or alanine by placental villi or transfer across the perfused placental lobule, in contrast with the report that cocaine reduces uptake of alanine by placental vesicles. Experimental models must be critically evaluated before accepting the results as pertinent to a clinical situation.

scholarly journals Regulation of Vascular Calcification by Reactive Oxygen Species

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 963 ◽  
Author(s):  
Andrea Tóth ◽  
Enikő Balogh ◽  
Viktória Jeney
Keyword(s):  
Reactive Oxygen Species ◽  
Signal Transduction ◽  
Vascular Calcification ◽  
Reactive Oxygen ◽  
Experimental Models ◽  
Signal Transduction Pathways ◽  
Ros Production ◽  
Oxygen Species ◽  
Protective Mechanisms ◽  
Phenotype Switch

Vascular calcification is the deposition of hydroxyapatite crystals in the medial or intimal layers of arteries that is usually associated with other pathological conditions including but not limited to chronic kidney disease, atherosclerosis and diabetes. Calcification is an active, cell-regulated process involving the phenotype transition of vascular smooth muscle cells (VSMCs) from contractile to osteoblast/chondrocyte-like cells. Diverse triggers and signal transduction pathways have been identified behind vascular calcification. In this review, we focus on the role of reactive oxygen species (ROS) in the osteochondrogenic phenotype switch of VSMCs and subsequent calcification. Vascular calcification is associated with elevated ROS production. Excessive ROS contribute to the activation of certain osteochondrogenic signal transduction pathways, thereby accelerating osteochondrogenic transdifferentiation of VSMCs. Inhibition of ROS production and ROS scavengers and activation of endogenous protective mechanisms are promising therapeutic approaches in the prevention of osteochondrogenic transdifferentiation of VSMCs and subsequent vascular calcification. The present review discusses the formation and actions of excess ROS in different experimental models of calcification, and the potential of ROS-lowering strategies in the prevention of this deleterious condition.

scholarly journals Evidences of Herbal Medicine-Derived Natural Products Effects in Inflammatory Lung Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Fernanda Paula R. Santana ◽  
Nathalia M. Pinheiro ◽  
Márcia Isabel B. Mernak ◽  
Renato F. Righetti ◽  
Mílton A. Martins ◽  
...  
Keyword(s):  
Natural Products ◽  
Herbal Medicine ◽  
Biological Activities ◽  
Biological Effects ◽  
Pulmonary Inflammation ◽  
Experimental Models ◽  
Chronic Obstructive ◽  
Anti Inflammatory

Pulmonary inflammation is a hallmark of many respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory syndrome distress (ARDS). Most of these diseases are treated with anti-inflammatory therapy in order to prevent or to reduce the pulmonary inflammation. Herbal medicine-derived natural products have been used in folk medicine and scientific studies to evaluate the value of these compounds have grown in recent years. Many substances derived from plants have the biological effectsin vitroandin vivo, such as flavonoids, alkaloids, and terpenoids. Among the biological activities of natural products derived from plants can be pointed out the anti-inflammatory, antiviral, antiplatelet, antitumor anti-allergic activities, and antioxidant. Although many reports have evaluated the effects of these compounds in experimental models, studies evaluating clinical trials are scarce in the literature. This review aims to emphasize the effects of these different natural products in pulmonary diseases in experimental models and in humans and pointing out some possible mechanisms of action.

Recent advances in late lung development and the pathogenesis of bronchopulmonary dysplasia

2013 ◽  
Vol 305 (12) ◽  
pp. L893-L905 ◽  
Author(s):  
Alicia Madurga ◽  
Ivana Mižíková ◽  
Jordi Ruiz-Camp ◽  
Rory E. Morty
Keyword(s):  
Gas Exchange ◽  
Surface Area ◽  
Bronchopulmonary Dysplasia ◽  
Lung Development ◽  
Oxygen Toxicity ◽  
Structural Development ◽  
Vascular Structure ◽  
Recent Developments ◽  
Immature Lung ◽  
Prematurely Born Infants

In contrast to early lung development, a process exemplified by the branching of the developing airways, the later development of the immature lung remains very poorly understood. A key event in late lung development is secondary septation, in which secondary septa arise from primary septa, creating a greater number of alveoli of a smaller size, which dramatically expands the surface area over which gas exchange can take place. Secondary septation, together with architectural changes to the vascular structure of the lung that minimize the distance between the inspired air and the blood, are the objectives of late lung development. The process of late lung development is disturbed in bronchopulmonary dysplasia (BPD), a disease of prematurely born infants in which the structural development of the alveoli is blunted as a consequence of inflammation, volutrauma, and oxygen toxicity. This review aims to highlight notable recent developments in our understanding of late lung development and the pathogenesis of BPD.

scholarly journals COVID-19

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 294-299 ◽  
Author(s):  
Paolo Verdecchia ◽  
Claudio Cavallini ◽  
Antonio Spanevello ◽  
Fabio Angeli
Keyword(s):  
Angiotensin Ii ◽  
Severe Acute Respiratory Syndrome ◽  
Adverse Reactions ◽  
Angiotensin Receptor Blockers ◽  
Pulmonary Inflammation ◽  
Experimental Models ◽  
Therapeutic Approaches ◽  
Angiotensin Converting Enzyme 2 ◽  
Receptor Blockers ◽  
External Site

Diffuse pulmonary inflammation, endothelial inflammation, and enhanced thrombosis are cardinal features of coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2. These features are reminiscent of several adverse reactions triggered by angiotensin II and opposed by angiotensin 1-7 , in many experimental models. Severe acute respiratory syndrome coronavirus 2 binds to ACE2 (angiotensin-converting enzyme 2) receptors and entries into the cell through the fusion of its membrane with that of the cell. Hence, it downregulates these receptors. The loss of ACE2 receptor activity from the external site of the membrane will lead to less angiotensin II inactivation and less generation of antiotensin 1-7 . In various experimental models of lung injury, the imbalance between angiotensin II overactivity and of antiotensin 1-7 deficiency triggered inflammation, thrombosis, and other adverse reactions. In COVID-19, such imbalance could play an important role in influencing the clinical picture and outcome of the disease. According to this line of thinking, some therapeutic approaches including recombinant ACE2, exogenous angiotensin 1-7 , and angiotensin receptor blockers seem particularly promising and are being actively tested.

Abstract 262: Cytochrome P450 1B1 is Critical for the Development of Atherosclerosis and Hypertension in ApoE Knockout Mice

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Khuzema Ghafoor ◽  
Hafiz Usama Ghafoor ◽  
Brett L Jennings ◽  
Nayaab S Khan ◽  
Shyamala Thirunavukkarasu ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
T Lymphocytes ◽  
Lipid Analysis ◽  
Plasma Lipid ◽  
Atherogenic Diet ◽  
Experimental Models ◽  
Normal Diet ◽  
Ros Production ◽  
Collagen Deposition ◽  
Novel Target

We have reported that cytochrome P450 (CYP) 1B1 contributes to hypertension in various experimental models and promotes neointimal growth in injured carotid arteries. This study was conducted to determine the role of CYP1B1 in the development of atherosclerosis and its pathogenesis, including reactive oxygen species (ROS) production, inflammation, and hypertension caused by atherogenic diet (AD; TD02028). Eight weeks old male ApoE knockout ( ApoE -/- /Cyp1b1 +/+ ) and ApoE /CYP1B1 knockout ( ApoE -/- /Cyp1b1 -/- ) mice were fed a normal diet (ND) or AD for 12 weeks. A separate group of ApoE -/- /Cyp1b1 +/+ mice on AD, were injected twice weekly with the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS) (300 μg/kg), or its vehicle DMSO (i.p.). Systolic blood pressure (SBP) was measured weekly by tail cuff. After 12 weeks, animals were sacrificed; blood was collected for lipid analysis and aorta for measurement of lesions by Oil red O, collagen deposition by Masson’s trichrome and ROS production by dihydroethidium staining, and infiltration of macrophages (F4/80) and T-lymphocytes (CD3) by immunohistochemistry. Plasma lipid levels, area of lipids and collagen deposition, ROS production (Table), infiltration of macrophages, and T lymphocytes in the aorta and SBP were increased in ApoE -/- /Cyp1b1 +/+ mice on AD vs. ND; these were minimized in mice on AD given TMS but not its vehicle, and in ApoE -/- /Cyp1b1 -/- mice on AD. These data suggest that the development of hypercholesterolemia by AD and associated pathogenesis including increase in SBP in ApoE -/- /Cyp1b1 +/+ mice depend on CYP1B1 and that it could serve as a novel target for treatment of atherosclerosis.

Inflammatory signatures for eosinophilic vs. neutrophilic allergic pulmonary inflammation reveal critical regulatory checkpoints

2011 ◽  
Vol 300 (5) ◽  
pp. L679-L690 ◽  
Author(s):  
Pieter Bogaert ◽  
Thomas Naessens ◽  
Stefaan De Koker ◽  
Benoit Hennuy ◽  
Jonathan Hacha ◽  
...  
Keyword(s):  
T Cell ◽  
Alveolar Macrophage ◽  
Inflammatory Mediator ◽  
Pulmonary Inflammation ◽  
Allergen Challenge ◽  
Experimental Models ◽  
Arachidonic Acid Metabolism ◽  
Th 17 ◽  
Bronchial Inflammation ◽  
Th 1

Contrary to the T-helper (Th)-2 bias and eosinophil-dominated bronchial inflammation encountered in most asthmatic subjects, other patients may exhibit neutrophil-predominant asthma subphenotypes, along with Th-1 and Th-17 cells. However, the etiology of many neutrophil-dominated asthma subphenotypes remains ill-understood, in part due to a lack of appropriate experimental models. To better understand the distinct immune-pathological features of eosinophilic vs. neutrophilic asthma types, we developed an ovalbumin (OVA)-based mouse model of neutrophil-dominated allergic pulmonary inflammation. Consequently, we probed for particular inflammatory signatures and checkpoints underlying the immune pathology in this new model, as well as in a conventional, eosinophil-dominated asthma model. Briefly, mice were OVA sensitized using either aluminum hydroxide (alum) or complete Freund's adjuvants, followed by OVA aerosol challenge. T-cell, granulocyte, and inflammatory mediator profiles were determined, along with alveolar macrophage genomewide transcriptome profiling. In contrast to the Th-2-dominated phenotype provoked by alum, OVA/ complete Freund's adjuvants adjuvant-based sensitization, followed by allergen challenge, elicited a pulmonary inflammation that was poorly controlled by dexamethasone, and in which Th-1 and Th-17 cells additionally participated. Analysis of the overall pulmonary and alveolar macrophage inflammatory mediator profiles revealed remarkable similarities between both models. Nevertheless, we observed pronounced differences in the IL-12/IFN-γ axis and its control by IL-18 and IL-18 binding protein, but also in macrophage arachidonic acid metabolism and expression of T-cell instructive ligands. These differential signatures, superimposed onto a generic inflammatory signature, denote distinctive inflammatory checkpoints potentially involved in orchestrating neutrophil-dominated asthma.

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