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Toxicological Sciences : An Official... May 2017Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health...
Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.
Topics: Animals; Cell Communication; Cell Line; Connexin 43; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells; Gap Junctions; Inflammation; Lung; Mice; Mitogen-Activated Protein Kinases; Mitogens; Polycyclic Aromatic Hydrocarbons; Signal Transduction; Tobacco Smoke Pollution; Transcriptome
PubMed: 28329830
DOI: 10.1093/toxsci/kfx027 -
International Journal of... 2014Involvement of imbalance between pro- and anti-inflammatory events has been reported in the developed pathogenesis after scorpion envenomation. The immunosuppressive and...
Involvement of imbalance between pro- and anti-inflammatory events has been reported in the developed pathogenesis after scorpion envenomation. The immunosuppressive and anti-inflammatory properties of tacrolimus (FK-506) have been investigated: i) to better understand evolution of signaling pathways which are involved in the immune system ii) to reduce observed clinical signs while keeping a balance between pro- and anti-inflammatory cytokines. Naval Medical Research Institute (NMRI) mice received tacrolimus (1 mg/kg every 12 hours per os) for 21 days before envenomation with a sublethal dose (10 microg/20 g body weight) of Androctonus australis hector venom (Aah). Cell migration, pulmonary edema, exudation, Myeloperoxydase (MPO), Eosinophil peroxydase (EPO), C-reactive protein (CRP), C3, Creatine phosphokinase (CPK), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and hyperglycemia were analyzed 30 min, 3 and 24 hours after injection of Aah venom. Histological analysis of lung parenchyma was undertaken 24 hours after envenomation. Aah lethality was evaluated on mice with or without pretreatment with tacrolimus. (Fab)2 fragments (40 mg/kg) were also used as specific treatment in all protocols. Tacrolimus significantly inhibited cell migration, pulmonary edema, exudation, CRP and hyperglycemia. It also decreased MPO and EPO activities and prevented tissue damage in lung tissue, balancing seric parameter levels (CPK, ASAT and ALAT). The pretreated animals seemed to be protected by this macrolide against the venom lethality. These findings suggest that the overactivation of the immune system is one of the causes involved in the aggravation of the pathophysiological effects induced after envenomation. The obtained results showed that the use of F(ab)2 fragments as specific treatment cannot reduce the induced inflammatory response.
Topics: Animals; Anti-Inflammatory Agents; Immunosuppressive Agents; Lung; Male; Mice; Mice, Inbred Strains; Pulmonary Edema; Scorpion Stings; Tacrolimus; Treatment Outcome
PubMed: 24674680
DOI: 10.1177/039463201402700109 -
The Journal of Clinical Investigation Jul 1977We have investigated the morphological differences responsible for the variability in two tests of pulmonary function, maximal expiratory flow rates (MEF) and the...
We have investigated the morphological differences responsible for the variability in two tests of pulmonary function, maximal expiratory flow rates (MEF) and the frequency dependence of dynamic compliance (CDYN ratio). Functional measurements were obtained from 53 normal and minimally diseased postmortem human lungs. Morphological measurements performed on these same lungs included airway diameter at three levels in the bronchial tree, the amount of bronchial gland mass, and the alveolar surface to volume ratio. Multiple regression analysis suggests that the diameter of the peripheral conduction airways (membranous bronchioles) is the major morphological determinant for both MEF and the CDYN ratio in lungs at any particular age. Age-dependent changes in both functional tests were associated primarily with differences in the alveolar surface to volume ratio. Minimal emphysema and a lesion associated with cigarette smoking, respiratory bronchiolitis, have no demonstrable effect on either MEF or the CDYN ratio. These studies provide further evidence that the peripheral conducting airways are a major determinant of ventilatory function in the normal human lung.
Topics: Adolescent; Adult; Age Factors; Aged; Autopsy; Bronchi; Bronchography; Humans; Lung; Lung Compliance; Lung Volume Measurements; Male; Middle Aged; Pulmonary Alveoli; Pulmonary Ventilation; Respiratory Function Tests
PubMed: 874079
DOI: 10.1172/JCI108750 -
European Review For Medical and... Dec 2021COVID-19 is associated with an increased incidence of pulmonary embolism (PE). Elevated D-dimer levels are linked to an increased risk of PE and poor clinical outcome.... (Review)
Review
OBJECTIVE
COVID-19 is associated with an increased incidence of pulmonary embolism (PE). Elevated D-dimer levels are linked to an increased risk of PE and poor clinical outcome. We reported a case of PE in a COVID-19 patient with normal D-dimer levels and conducted a review of the literature on the subject.
CASE REPORT
A 38-year-old man with no prior comorbidities returned to the COVID-19 outpatient clinic 36 hours after being discharged from the hospital, where he had been treated for COVID-19 pneumonia. He reported a sudden feeling of dyspnea and chest pain. The physical examination was unremarkable. No new changes were detected on the chest X-ray. D-dimer and cardiac-specific markers values were within the referent range. The patient underwent an urgent computerized tomography pulmonary angiography which revealed signs of bilateral arterial thrombosis. He was treated with a therapeutic dose of low molecular weight heparin and discharged after 15 days, with a recommendation to use a direct oral anticoagulant.
CONCLUSIONS
Healthcare professionals should be aware that PE can occur as a late complication of COVID-19. Clinical suspicion of PE should lead physicians to use additional diagnostic methods to confirm or rule out PE, even if D-dimer levels are within the referent range.
Topics: Adult; COVID-19; Chest Pain; Computed Tomography Angiography; Fibrin Fibrinogen Degradation Products; Heparin, Low-Molecular-Weight; Humans; Incidence; Lung; Male; Pulmonary Embolism; Reference Values; SARS-CoV-2; Treatment Outcome
PubMed: 34982460
DOI: 10.26355/eurrev_202112_27647 -
Journal of Lipid Research Oct 2018Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells,... (Comparative Study)
Comparative Study
Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [UC]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.
Topics: Animals; Biological Products; Lung; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Phosphatidylcholines; Phospholipids; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein C; Pulmonary Surfactants
PubMed: 30108154
DOI: 10.1194/jlr.M085431 -
Journal of Virology Oct 1984Monoclonal antibodies to varicella-zoster virus were used to study viral glycoproteins by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel...
Monoclonal antibodies to varicella-zoster virus were used to study viral glycoproteins by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Based on the viral glycoproteins immunoprecipitated, the five monoclonal antibodies fell into three groups. Two antibodies, 4B7 and 8G9 (group 1), immunoprecipitated a single glycoprotein of molecular weight (MW) 118,000 (118K glycoprotein) and had high neutralizing activity in the absence of complement. One antibody, 3C7 (group 2), which lacked neutralizing activity, immunoprecipitated two glycoproteins of MWs 120,000 and 118,000 and a glycoprotein giving a diffuse band in the region of 64,000 to 65,000. Pulse-chase experiments and experiments with monensin as an inhibitor of glycosylation suggested that the 120K polypeptide was derived by glycosylation of the 118K polypeptide and that a 43K antigen was processed into the 64 to 65K glycoprotein. Two antibodies, 3G8 and 4E6 (group 3), both had neutralizing activity only in the presence of complement, and both immunoprecipitated at least five polypeptides, with MWs ranging from 50,000 to 90,000. Antibody 3G8 was isotype immunoglobulin G2b (IgG2b), and its immunoprecipitating activity was stronger than that of 4E6, which was isotype IgG1. Pulse-chase experiments with antibody 3G8 showed that lower-MW glycopeptides chased into three polypeptides of MWs 90,000, 80,000, and 60,000 by 24 h. Immunoprecipitation experiments with antibody 3G8 on infected cells treated with glycosylation inhibitors 2-deoxyglucose, monensin, and tunicamycin, suggested that a prominent, early-appearing 70K polypeptide may have been processed into the glycoproteins of higher MWs and that the 60K polypeptide may have been derived by glycosylation of polypeptides of lower MWs.
Topics: Antibodies, Monoclonal; Cell Line; Electrophoresis, Polyacrylamide Gel; Glycoproteins; Herpesvirus 3, Human; Humans; Kinetics; Lung; Molecular Weight; Viral Proteins
PubMed: 6090710
DOI: 10.1128/JVI.52.1.55-62.1984 -
American Journal of Physiology. Lung... Feb 2010Hyaluronan (HA) degradation fragments have been linked to inflammation in a wide range of lung diseases. In idiopathic pulmonary arterial hypertension, HA accumulation...
Hyaluronan (HA) degradation fragments have been linked to inflammation in a wide range of lung diseases. In idiopathic pulmonary arterial hypertension, HA accumulation has been associated with advanced disease. In this study, we investigated the potential role of HA degradation in the early stages of disease by examining HA distribution, molecular mass, synthesis, and enzymatic degradation at different stages of disease progression in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). At 28 days post-MCT, severe PH was associated with increased total lung HA (P = 0.04). In contrast, a significant decrease in total lung HA was observed on day 10, before the onset of PH (P = 0.02). Molecular mass analysis revealed a loss of high molecular mass (HMM) HA at 10 and 24 days post-MCT, followed by an increase in HMM HA at 28 days. Expression of HA synthase 2 (HAS2) was elevated in MCT-challenged animals at 24 and 28 days, consistent with increased synthesis of HMM HA. Analysis by Morgan Elson assay and zymography demonstrated increased hyaluronidase-1 activity in the lungs of MCT-challenged rats, indicating that the observed increases in HAS2 expression and HA synthesis were counterbalanced, in part, by enhanced degradation. The present data demonstrate that, in the MCT model, early-stage PH is associated with enhanced hyaluronidase-1 activity, while both degradation and synthesis are increased at later stages. Thus an early increase in the generation of proinflammatory HA fragments may play a role in the onset and progression of pulmonary arterial hypertension.
Topics: Animals; Disease Progression; Glucuronosyltransferase; Hyaluronan Synthases; Hyaluronic Acid; Hyaluronoglucosaminidase; Hypertension, Pulmonary; Lung; Male; Molecular Weight; Monocrotaline; Rats; Rats, Inbred F344
PubMed: 19915162
DOI: 10.1152/ajplung.00097.2009 -
The Journal of Histochemistry and... Jun 2019Secretoglobins (SCGBs) are cytokine-like small molecular weight secreted proteins with largely unknown biological functions. Three SCGB proteins, SCGB1A1, SCGB3A1, and...
Secretoglobins (SCGBs) are cytokine-like small molecular weight secreted proteins with largely unknown biological functions. Three SCGB proteins, SCGB1A1, SCGB3A1, and SCGB3A2, are predominantly expressed in lung airways. To gain insight into the possible functional relationships among the SCGBs, their protein and mRNA expression patterns were examined in lungs during gestation and in adult mice, using Scgb3a1-null and Scgb3a2-null mice as negative controls, by immunohistochemistry and by qRT-PCR analysis, respectively. The three SCGBs exhibited unique spatiotemporal expression patterns during embryogenesis. The lack of Scgb3a1 or Scgb3a2 did not affect expression of the other Scgb genes as determined by mRNA measurements. Moreover, the lack of Scgb3a1 or Scgb3a2 did not affect development of the pulmonary neuroepithelial bodies during embryogenesis, while the lack of Scgb3a2 may have resulted in slightly fewer ciliated cells than in the wild-type. These results suggest that SCGB1A1, SCGB3A1, and SCGB3A2 each may possess its own unique biological function.
Topics: Animals; Cell Differentiation; Epithelium; Gene Expression Regulation; Lung; Mice; Proteins; Secretoglobins; Spatio-Temporal Analysis; Uteroglobin
PubMed: 30768367
DOI: 10.1369/0022155419829050 -
BMC Pulmonary Medicine Jul 2015Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to...
BACKGROUND
Secretoglobin (SCGB) 3A2, a cytokine-like secretory protein of small molecular weight, is predominantly expressed in airway epithelial cells. While SCGB3A2 is known to have anti-inflammatory, growth factor, and anti-fibrotic activities, whether SCGB3A2 has any other roles, particularly in lung homeostasis and disease has not been demonstrated in vivo. The aim of this study was to address these questions in mice.
METHODS
A transgenic mouse line that expresses SCGB3A2 in the lung using the human surfactant protein-C promoter was established. Detailed histological, immunohistochemical, physiological, and molecular characterization of the Scgb3a2-transgenic mouse lungs were carried out. Scgb3a2-transgenic and wild-type mice were subjected to bleomycin-induced pulmonary fibrosis model, and their lungs and bronchoalveolar lavage fluids were collected at various time points during 9 weeks post-bleomycin treatment for further analysis.
RESULTS
Adult Scgb3a2-transgenic mouse lungs expressed approximately five-fold higher levels of SCGB3A2 protein in comparison to wild-type mice as determined by western blotting of lung tissues. Immunohistochemistry showed that expression was localized to alveolar type II cells in addition to airway epithelial cells, thus accurately reflecting the site of surfactant protein-C expression. Scgb3a2-transgenic mice showed normal lung development and histology, and no overt gross phenotypes. However, when subjected to a bleomycin-induced pulmonary fibrosis model, they initially exhibited exacerbated fibrosis at 3 weeks post-bleomycin administration that was more rapidly resolved by 6 weeks as compared with wild-type mice, as determined by lung histology, Masson Trichrome staining and hydroxyproline content, inflammatory cell numbers, expression of collagen genes, and proinflammatory cytokine levels. The decrease of fibrosis coincided with the increased expression of SCGB3A2 in Scgb3a2-transgenic lungs.
CONCLUSIONS
These results demonstrate that SCGB3A2 is an anti-fibrotic agent, and suggest a possible therapeutic use of recombinant SCGB3A2 in the treatment of pulmonary fibrosis.
Topics: Animals; Bleomycin; Blotting, Northern; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Developmental; Immunohistochemistry; Lung; Mice; Mice, Transgenic; Pulmonary Fibrosis; RNA; Reverse Transcriptase Polymerase Chain Reaction; Secretoglobins
PubMed: 26178733
DOI: 10.1186/s12890-015-0065-4 -
Open Biology Oct 2014Heat-shock protein (Hsp)10 is the co-chaperone for Hsp60 inside mitochondria, but it also resides outside the organelle. Variations in its levels and intracellular...
Heat-shock protein (Hsp)10 is the co-chaperone for Hsp60 inside mitochondria, but it also resides outside the organelle. Variations in its levels and intracellular distribution have been documented in pathological conditions, e.g. cancer and chronic obstructive pulmonary disease (COPD). Here, we show that Hsp10 in COPD undergoes changes at the molecular and subcellular levels in bronchial cells from human specimens and derived cell lines, intact or subjected to stress induced by cigarette smoke extract (CSE). Noteworthy findings are: (i) Hsp10 occurred in nuclei of epithelial and lamina propria cells of bronchial mucosa from non-smokers and smokers; (ii) human bronchial epithelial (16HBE) and lung fibroblast (HFL-1) cells, in vitro, showed Hsp10 in the nucleus, before and after CSE exposure; (iii) CSE stimulation did not increase the levels of Hsp10 but did elicit qualitative changes as indicated by molecular weight and isoelectric point shifts; and (iv) Hsp10 nuclear levels increased after CSE stimulation in HFL-1, indicating cytosol to nucleus migration, and although Hsp10 did not bind DNA, it bound a DNA-associated protein.
Topics: Aged; Bronchi; Cell Nucleus; Chaperonin 10; Chaperonin 60; Computer Simulation; Cytosol; DNA; Epithelial Cells; Female; Fibroblasts; Humans; Immunohistochemistry; Isoelectric Point; Lung; Male; Middle Aged; Mitochondrial Proteins; Molecular Weight; Nucleosomes; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Smoke; Smoking; Tobacco Products
PubMed: 25355063
DOI: 10.1098/rsob.140125