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Antioxidants (Basel, Switzerland) Dec 2022High oxygen concentrations are often required to treat newborn infants with respiratory distress but have adverse effects, such as increased oxidative stress and...
High oxygen concentrations are often required to treat newborn infants with respiratory distress but have adverse effects, such as increased oxidative stress and ferroptosis and impaired alveolarization. Cathelicidins are a family of antimicrobial peptides that exhibit antioxidant activity, and they can reduce hyperoxia-induced oxidative stress. This study evaluated the effects of cathelicidin treatment on lung ferroptosis and alveolarization in hyperoxia-exposed newborn rats. Sprague Dawley rat pups were either reared in room air (RA) or hyperoxia (85% O) and then randomly given cathelicidin (8 mg/kg) in 0.05 mL of normal saline (NS), or NS was administered intraperitoneally on postnatal days from 1-6. The four groups obtained were as follows: RA + NS, RA + cathelicidin, O + NS, and O + cathelicidin. On postnatal day 7, lungs were harvested for histological, biochemical, and Western blot analyses. The rats nurtured in hyperoxia and treated with NS exhibited significantly lower body weight and cathelicidin expression, higher Fe, malondialdehyde, iron deposition, mitochondrial damage (TOMM20), and interleukin-1β (IL-1β), and significantly lower glutathione, glutathione peroxidase 4, and radial alveolar count (RAC) compared to the rats kept in RA and treated with NS or cathelicidin. Cathelicidin treatment mitigated hyperoxia-induced lung injury, as demonstrated by higher RAC and lower TOMM20 and IL-1β levels. The attenuation of lung injury was accompanied by decreased ferroptosis. These findings indicated that cathelicidin mitigated hyperoxia-induced lung injury in the rats, most likely by inhibiting ferroptosis.
PubMed: 36552613
DOI: 10.3390/antiox11122405 -
American Journal of Physiology. Lung... Oct 2011The concept of genetic susceptibility factors predisposing cigarette smokers to develop emphysema stems from the clinical observation that only a fraction of smokers...
The concept of genetic susceptibility factors predisposing cigarette smokers to develop emphysema stems from the clinical observation that only a fraction of smokers develop clinically significant chronic obstructive pulmonary disease. We investigated whether Smad3 knockout mice, which develop spontaneous air space enlargement after birth because of a defect in transforming growth factor-β (TGF-β) signaling, develop enhanced alveolar cell apoptosis and air space enlargement following cigarette smoke exposure. We investigated Smad3(-/-) and Smad3(+/+) mice at different adult ages and determined air space enlargement, alveolar cell proliferation, and apoptosis. Furthermore, laser-capture microdissection and real-time PCR were used to measure compartment-specific gene expression. We then compared the effects of cigarette smoke exposure on Smad3(-/-) and littermate controls. Smad3 knockout resulted in the development of air space enlargement in the adult mouse and was associated with decreased alveolar VEGF levels and activity and increased alveolar cell apoptosis. Cigarette smoke exposure aggravated air space enlargement and alveolar cell apoptosis. We also found increased Smad2 protein expression and phosphorylation, which was enhanced following cigarette smoke exposure, in Smad3-knockout animals. Double immunofluorescence analysis revealed that endothelial apoptosis started before epithelial apoptosis. Our data indicate that balanced TGF-β signaling is not only important for regulation of extracellular matrix turnover, but also for alveolar cell homeostasis. Impaired signaling via the Smad3 pathway results in alveolar cell apoptosis and alveolar destruction, likely via increased Smad2 and reduced VEGF expression and might represent a predisposition for accelerated development of emphysema due to cigarette smoke exposure.
Topics: Alveolar Epithelial Cells; Animals; Apoptosis; Cell Proliferation; Down-Regulation; Female; Immunohistochemistry; In Situ Nick-End Labeling; Lasers; Mice; Mice, Knockout; Microdissection; Polymerase Chain Reaction; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Risk Factors; Signal Transduction; Smad2 Protein; Smad3 Protein; Smoking; Nicotiana; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factor A
PubMed: 21743024
DOI: 10.1152/ajplung.00369.2010 -
Biology of Sex Differences Aug 2023Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented...
BACKGROUND
Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.
METHODS
Wild-type and miR-30a neonatal mice were exposed to hyperoxia [95% FiO, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a male and female lung transcriptome data.
RESULTS
Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.
CONCLUSIONS
miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.
Topics: Animals; Female; Male; Mice; Animals, Newborn; Bronchopulmonary Dysplasia; Hyperoxia; Lung; Lung Injury; MicroRNAs; Sex Factors
PubMed: 37553579
DOI: 10.1186/s13293-023-00535-6 -
Respiratory Medicine Case Reports 2014Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral...
Air in the epidural space is called pneumorachis. The usual mechanism of pneumorachis is air diffusion from the mediastinal tissue layers through the inter-vertebral foramen. Alternatively, air can diffuse directly after spine traumas (e.g., blunt deceleration with vertebral dislocation) or medical procedures. Several mechanisms could explain pneumomediastinum and pneumorachis after cocaine sniffing. Passive apnea and/or cough that occur after sniffing can cause intra alveolar hyper-pressure, which is responsible for alveolar rupture and air diffusion. Another mechanism is alveolar wall fragility and rupture induced by repeated cocaine sniffing, in turn causing air diffusion to the mediastinum, sub-cutaneous tissues and the epidural space. The diagnosis is usually made on Chest tomography scan. Management consists in close monitoring in the intensive care unit to detect aggravation of pneumomediastinum and pneumorachis, which would require surgical management. Supplemental nasal oxygen can be given to accelerate nitrogen washout. We present a case of a 28 years old male who presented to the emergency department for chest pain directly after sniffing cocaine. A computed tomography scan of the chest showed pneumomediastinum, pneumorachis and sub-cutaneous emphysema. The patient was admitted for 24 h: after that delay, surveillance chest tomodensitometry showed stability, and he could be discharged without further treatment.
PubMed: 26029527
DOI: 10.1016/j.rmcr.2013.12.011 -
Brazilian Journal of Medical and... Dec 2017Alveolar epithelia play an essential role in maintaining the integrity and homeostasis of lungs, in which alveolar epithelial type II cells (AECII) are a cell type with...
Alveolar epithelia play an essential role in maintaining the integrity and homeostasis of lungs, in which alveolar epithelial type II cells (AECII) are a cell type with stem cell potential for epithelial injury repair and regeneration. However, mechanisms behind the physiological and pathological roles of alveolar epithelia in human lungs remain largely unknown, partially owing to the difficulty of isolation and culture of primary human AECII cells. In the present study, we aimed to characterize alveolar epithelia generated from A549 lung adenocarcinoma cells that were cultured in an air-liquid interface (ALI) state. Morphological analysis demonstrated that A549 cells could reconstitute epithelial layers in ALI cultures as evaluated by histochemistry staining and electronic microscopy. Immunofluorescent staining further revealed an expression of alveolar epithelial type I cell (AECI) markers aquaporin-5 protein (AQP-5), and AECII cell marker surfactant protein C (SPC) in subpopulations of ALI cultured cells. Importantly, molecular analysis further revealed the expression of AQP-5, SPC, thyroid transcription factor-1, zonula occludens-1 and Mucin 5B in A549 ALI cultures as determined by both immunoblotting and quantitative RT-PCR assay. These results suggest that the ALI culture of A549 cells can partially mimic the property of alveolar epithelia, which may be a feasible and alternative model for investigating roles and mechanisms of alveolar epithelia in vitro.
Topics: A549 Cells; Alveolar Epithelial Cells; Analysis of Variance; Aquaporin 5; Cell Count; Cell Culture Techniques; Culture Media, Conditioned; Humans; Immunoblotting; Microscopy, Electron, Scanning; Mucin-5B; Pulmonary Surfactant-Associated Protein C; Real-Time Polymerase Chain Reaction; Reference Values; Reproducibility of Results; Thyroid Nuclear Factor 1; Time Factors; Zonula Occludens-1 Protein
PubMed: 29267508
DOI: 10.1590/1414-431X20176950 -
Journal of Thoracic Disease Nov 2017Persistent air leak (PAL) is a cause of significant morbidity in patients who have undergone lung surgery and those with significant parenchymal lung disease suffering... (Review)
Review
Persistent air leak (PAL) is a cause of significant morbidity in patients who have undergone lung surgery and those with significant parenchymal lung disease suffering from a pneumothorax. Its management can be complex and challenging. Although conservative treatment with chest drain and observation is usually effective, other invasive techniques are needed when conservative treatment fails. Surgical management and medical pleurodesis have long been the usual treatments for PAL. More recently numerous bronchoscopic procedures have been introduced to treat PAL in those patients who are poor candidates for surgery or who decline surgery. These techniques include bronchoscopic use of sealants, sclerosants, and various types of implanted devices. Recently, removable one-way valves have been developed that are able to be placed bronchoscopically in the affected airways, ameliorating air-leaks in patients who are not candidates for surgery. Future comparative trials are needed to refine our understanding of the indications, effectiveness, and complications of bronchoscopic techniques for treating PAL. The following article will review the basic principles of management of PAL particularly focusing on bronchoscopic techniques.
PubMed: 29268535
DOI: 10.21037/jtd.2017.10.122 -
Molecules (Basel, Switzerland) May 2021Paratuberculosis is an important disease of ruminants caused by ssp. (MAP). Early detection is crucial for successful infection control, but available diagnostic tests...
Paratuberculosis is an important disease of ruminants caused by ssp. (MAP). Early detection is crucial for successful infection control, but available diagnostic tests are still dissatisfying. Methods allowing a rapid, economic, and reliable identification of animals or herds affected by MAP are urgently required. This explorative study evaluated the potential of volatile organic compounds (VOCs) to discriminate between cattle with and without MAP infections. Headspaces above fecal samples and alveolar fractions of exhaled breath of 77 cows from eight farms with defined MAP status were analyzed in addition to stable air samples. VOCs were identified by GC-MS and quantified against reference substances. To discriminate MAP-positive from MAP-negative samples, VOC feature selection and random forest classification were performed. Classification models, generated for each biological specimen, were evaluated using repeated cross-validation. The robustness of the results was tested by predicting samples of two different sampling days. For MAP classification, the different biological matrices emitted diagnostically relevant VOCs of a unique but partly overlapping pattern (fecal headspace: 19, alveolar gas: 11, stable air: 4-5). Chemically, relevant compounds belonged to hydrocarbons, ketones, alcohols, furans, and aldehydes. Comparing the different biological specimens, VOC analysis in fecal headspace proved to be most reproducible, discriminatory, and highly predictive.
Topics: Air; Animals; Cattle; Feces; Gases; Mycobacterium avium subsp. paratuberculosis; Odorants; Paratuberculosis; Pulmonary Alveoli; ROC Curve; Reproducibility of Results; Volatile Organic Compounds
PubMed: 34064882
DOI: 10.3390/molecules26102854 -
Iranian Journal of Allergy, Asthma, and... Dec 2020The presence of ambient particulate matter (PM) poses more dangers to human health than that of other common air pollutants such as Carbon dioxide (Co2) and ozone. ...
The presence of ambient particulate matter (PM) poses more dangers to human health than that of other common air pollutants such as Carbon dioxide (Co2) and ozone. Epidemiologic studies show a direct correlation between PM and the risk of respiratory and cardiovascular diseases. The immune system seems to play a critical role in the process of these diseases. The main goal of this study was to investigate the effect of Tehran particulate matter in two aerodynamic diameters (PM2.5 and PM10) on alveolar macrophages (AM) from C57/BL6 mice. To evaluate the inflammatory effects of PMs, cultured alveolar, and peritoneal macrophages were treated with PM2.5 and PM10 (concentrations of 5 µg/mL and 10 µg/mL). Tumor necrosis factor-alpha (TNF-α) and IL-10 (representatives of inflammatory and anti-inflammatory cytokines, respectively) were assessed in the culture supernatant by ELISA. Expression of arginase and inducible nitric oxide synthase (iNOS) genes was carried out by quantitative real-time PCR. Different functional types of cultured alveolar macrophages (M1, M2) were also determined in this study. Our results suggest that PM2.5 induces M1 inflammatory phenotype in comparison with PM10. We found Also, an increase in TNF-α and M1-related gene expression (iNOS), as well as a decrease in both IL-10 and M2 phenotype genes (Arginase). Moreover, a reduction in phagocytic capacity and increased apoptosis function of macrophage cells were detected. PM2.5 as a major component in hydrocarbons has a considerable effect on polarizing the alveolar macrophages to an inflammatory phenotype and eliciting lung inflammation in mice.
Topics: Air Pollutants; Animals; Apoptosis; Arginase; Cytokines; Gene Expression; Inflammation; Interleukin-10; Macrophages, Alveolar; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Particulate Matter; Phagocytes; Phenotype; Tumor Necrosis Factor-alpha
PubMed: 33463134
DOI: 10.18502/ijaai.v19i6.4934 -
European Journal of Applied Physiology Jan 2023This review recalls the principles developed over a century to describe trans-capillary fluid exchanges concerning in particular the lung during exercise, a specific... (Review)
Review
PURPOSE
This review recalls the principles developed over a century to describe trans-capillary fluid exchanges concerning in particular the lung during exercise, a specific condition where dyspnea is a leading symptom, the question being whether this symptom simply relates to fatigue or also implies some degree of lung edema.
METHOD
Data from experimental models of lung edema are recalled aiming to: (1) describe how extravascular lung water is strictly controlled by "safety factors" in physiological conditions, (2) consider how waning of "safety factors" inevitably leads to development of lung edema, (3) correlate data from experimental models with data from exercising humans.
RESULTS
Exercise is a strong edemagenic condition as the increase in cardiac output leads to lung capillary recruitment, increase in capillary surface for fluid exchange and potential increase in capillary pressure. The physiological low microvascular permeability may be impaired by conditions causing damage to the interstitial matrix macromolecular assembly leading to alveolar edema and haemorrhage. These conditions include hypoxia, cyclic alveolar unfolding/folding during hyperventilation putting a tensile stress on septa, intensity and duration of exercise as well as inter-individual proneness to develop lung edema.
CONCLUSION
Data from exercising humans showed inter-individual differences in the dispersion of the lung ventilation/perfusion ratio and increase in oxygen alveolar-capillary gradient. More recent data in humans support the hypothesis that greater vasoconstriction, pulmonary hypertension and slower kinetics of alveolar-capillary O2 equilibration relate with greater proneness to develop lung edema due higher inborn microvascular permeability possibly reflecting the morpho-functional features of the air-blood barrier.
Topics: Humans; Lung; Pulmonary Edema; Blood-Air Barrier; Extravascular Lung Water; Hypoxia
PubMed: 36264327
DOI: 10.1007/s00421-022-05066-3 -
Biomedicine & Pharmacotherapy =... Jan 2021The main pathophysiological mechanism of acute respiratory distress syndrome (ARDS) invovles the increase in alveolar barrier permeability that is primarily caused by...
The main pathophysiological mechanism of acute respiratory distress syndrome (ARDS) invovles the increase in alveolar barrier permeability that is primarily caused by epithelial glycocalyx and tight junction (TJ) protein destruction. This study was performed to explore the effects of the alveolar epithelial glycocalyx on the epithelial barrier, specifically on TJ proteins, in ARDS. We used C57BL/6 mice and human lung epithelial cell models of lipopolysaccharide (LPS)-induced ARDS. Changes in alveolar permeability were evaluated via pulmonary histopathology analysis and by measuring the wet/dry weight ratio of the lungs. Degradation of heparan sulfate (HS), an important component of the epithelial glycocalyx, and alterations in levels of the epithelial TJ proteins (occludin, zonula occludens 1, and claudin 4) were assessed via ELISA, immunofluorescence analysis, and western blotting analysis. Real-time quantitative polymerase chain reaction was used to detect the mRNA of the TJ protein. Changes in glycocalyx and TJ ultrastructures in alveolar epithelial cells were evaluated through electron microscopy. In vivo and in vitro, LPS increased the alveolar permeability and led to HS degradation and TJ damage. After LPS stimulation, the expression of the HS-degrading enzyme heparanase (HPA) in the alveolar epithelial cells was increased. The HPA inhibitor N-desulfated/re-N-acetylated heparin alleviated LPS-induced HS degradation and reduced TJ damage. In vitro, recombinant HPA reduced the expression of the TJ protein zonula occludens-1 (ZO-1) and inhibited its mRNA expression in the alveolar epithelial cells. Taken together, our results demonstrate that shedding of the alveolar epithelial glycocalyx aggravates the epithelial barrier and damages epithelial TJ proteins in ARDS, with the underlying mechanism involving the effect of HPA on ZO-1.
Topics: A549 Cells; Alveolar Epithelial Cells; Animals; Blood-Air Barrier; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Glycocalyx; Heparitin Sulfate; Humans; Male; Mice, Inbred C57BL; Permeability; Respiratory Distress Syndrome; Tight Junctions; Zonula Occludens-1 Protein; Mice
PubMed: 33378942
DOI: 10.1016/j.biopha.2020.111026