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1.
J Neuroinflammation ; 19(1): 303, 2022 Dec 16.
Article in English | MEDLINE | ID: mdl-36527099

ABSTRACT

BACKGROUND: Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. METHODS: Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-ß (Aß) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. RESULTS: Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aß peptide, and memory impairment in mice. CONCLUSION: The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.


Subject(s)
Pneumonia , Silicosis , Animals , Mice , Silicon Dioxide/toxicity , Mice, Inbred C57BL , Silicosis/pathology , Pneumonia/chemically induced , Pneumonia/pathology , Inflammation/chemically induced , Inflammation/pathology , Lung/pathology , Synapses/pathology , Amyloid beta-Peptides , Hippocampus/pathology , Memory Disorders/chemically induced , Memory Disorders/pathology , Cytokines
2.
Respir Physiol Neurobiol ; 259: 30-36, 2019 01.
Article in English | MEDLINE | ID: mdl-29997055

ABSTRACT

Acute lung injury (ALI) remains a major cause of mortality. In lipopolysaccharide (LPS)-stimulated macrophages, eugenol reduces cyclooxygenase-2 expression, NF-κB activation, and inflammatory mediators. We examined the anti-inflammatory and anti-oxidative action of eugenol in an in vivo model of LPS-induced lung injury. Lung mechanics and histology were analyzed in mice 24 h after LPS exposure, with and without eugenol treatment at different doses. Additional animals, submited to the same protocol, were treated with eugenol at 150 mg/kg to determine its effect on inflammatory cytokines (ELISA) and oxidative markers. LPS-induced lung functional and histological changes were significantly improved by eugenol, in a dose-dependent way. Furthermore, eugenol (150 mg/kg) was able to inhibit the release of inflammatory cytokines (TNF-α, IL-1ß and IL-6), NADPH oxidase activity, as well as antioxidant enzymes activity (superoxide dismutase, catalase and glutathione peroxidase). Finally, eugenol reduced LPS-induced protein oxidation. In conclusion, eugenol improved in vivo LPS-induced ALI through both anti-inflammatory and anti-oxidative effects, avoiding damage to lung structure.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Eugenol/therapeutic use , Inflammation/drug therapy , Inflammation/etiology , Lung Injury/complications , Oxidative Stress/drug effects , Animals , Antioxidants/metabolism , Cytokines/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Lipopolysaccharides/toxicity , Lung Injury/chemically induced , Male , Mice , Mice, Inbred BALB C , NADPH Oxidases/metabolism , Pulmonary Medicine/methods , Statistics, Nonparametric
3.
Front Physiol ; 9: 121, 2018.
Article in English | MEDLINE | ID: mdl-29515461

ABSTRACT

Murine papain-induced emphysema is a model that reproduces many of the features found in patients. Bone marrow-derived mononuclear cells (BMMC) have already been used to repair the alveolar epithelium in respiratory diseases, but not in the papain model. Thus, we hypothesized that BMMC could prevent the pathophysiological processes in papain-induced experimental emphysema. Female BALB/c mice received intratracheal instillation of 50 µL of saline (S groups) or papain (P groups, 10 IU/50 µl of saline) on days 1 and 7 of the experimental protocol. On the 14th day, 2 × 106 BMMC of male BALB/c mice (SC21 and PC21) or saline (SS21 and PS21) were injected by the jugular vein. Analyses were done on days 14 (S14 and P14) and 21 (SS21, PS21, SC21, and PC21) of the protocol. qPCR evaluated the presence of the Y chromosome in the lungs of BMMC recipient animals. Functional residual capacity (FRC), alveolar diameter, cellularity, elastic fiber content, concentrations of TNF-α, IL-1ß, IL-6, MIP-2, KC, IFN-γ, apoptosis, mRNA expression of the dual oxidase (DUOX1 and DUOX2), production of H2O2 and DUOX activity were evaluated in lung tissue. We did not detect the Y chromosome in recipients' lungs. FRC, alveolar diameter, polymorphonuclear cells (PMN) and levels of KC, MIP-2, and IFN-γ increased in P14 and PS21 groups; the changes in the latter were reverted by BMMC. TNF-α, IL-1ß e IL-6 were similar in all groups. The amount of elastic fibers was smaller in P14 and PS21 than in other groups, and BMMC did not increase it in PC21 mice. PS21 animals showed increased DUOX activity and mRNA expression for DUOX1 and 2. Cell therapy reverted the activity of DUOX and mRNA expression of DUOX1. BMMC reduced mRNA expression of DUOX2. Apoptosis index was elevated in PS21 mice, which was reduced by cell therapy in PC21. Static compliance, viscoelastic component of elastance and pressure to overcome viscoelasticity were increased in P14 and PS21 groups. These changes and the high resistive pressure found on day 21 were reverted by BMMC. In conclusion, BMMC showed potent anti-inflammatory, antiapoptotic, antioxidant, and restorative roles in papain-triggered pulmonary emphysema.

4.
PLoS One ; 9(10): e110185, 2014.
Article in English | MEDLINE | ID: mdl-25310682

ABSTRACT

Silicosis is an occupational lung disease, characterized by irreversible and progressive fibrosis. Silica exposure leads to intense lung inflammation, reactive oxygen production, and extracellular ATP (eATP) release by macrophages. The P2X7 purinergic receptor is thought to be an important immunomodulator that responds to eATP in sites of inflammation and tissue damage. The present study investigates the role of P2X7 receptor in a murine model of silicosis. To that end wild-type (C57BL/6) and P2X7 receptor knockout mice received intratracheal injection of saline or silica particles. After 14 days, changes in lung mechanics were determined by the end-inflation occlusion method. Bronchoalveolar lavage and flow cytometry analyzes were performed. Lungs were harvested for histological and immunochemistry analysis of fibers content, inflammatory infiltration, apoptosis, as well as cytokine and oxidative stress expression. Silica particle effects on lung alveolar macrophages and fibroblasts were also evaluated in cell line cultures. Phagocytosis assay was performed in peritoneal macrophages. Silica exposure increased lung mechanical parameters in wild-type but not in P2X7 knockout mice. Inflammatory cell infiltration and collagen deposition in lung parenchyma, apoptosis, TGF-ß and NF-κB activation, as well as nitric oxide, reactive oxygen species (ROS) and IL-1ß secretion were higher in wild-type than knockout silica-exposed mice. In vitro studies suggested that P2X7 receptor participates in silica particle phagocytosis, IL-1ß secretion, as well as reactive oxygen species and nitric oxide production. In conclusion, our data showed a significant role for P2X7 receptor in silica-induced lung changes, modulating lung inflammatory, fibrotic, and functional changes.


Subject(s)
Inflammation/metabolism , Inflammation/pathology , Lung/metabolism , Lung/physiopathology , Silicon Dioxide/toxicity , Animals , Apoptosis , Bronchoalveolar Lavage Fluid , Collagen/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Immunophenotyping , Interleukin-1beta/metabolism , Lung/pathology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , NIH 3T3 Cells , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/metabolism , Phagocytosis/drug effects , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/physiopathology , Purinergic P2X Receptor Antagonists/pharmacology , Reactive Oxygen Species/metabolism , Receptors, Purinergic P2X7/metabolism , Rosaniline Dyes/metabolism , Signal Transduction/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Transforming Growth Factor beta/metabolism
5.
Toxicon ; 58(2): 195-201, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21679722

ABSTRACT

Cyanobacterial blooms that generate microcystins (MCYSTs) are increasingly recognized as an important health problem in aquatic ecosystems. We have previously reported the impairment of pulmonary structure and function by microcystin-LR (MCYST-LR) exposure as well as the pulmonary improvement by intraperitoneally injected (i.p.) LASSBio 596. In the present study, we aimed to evaluate the usefulness of LASSBio 596 per os on the treatment of pulmonary and hepatic injuries induced by MCYST-LR. Swiss mice received an intraperitoneal injection of 40 µl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 µg/kg). After 6 h the animals received either saline (TOX and CTRL groups) or LASSBio 596 (50 mg/kg, LASS group) by gavage. Eight hours after the first instillation, lung impedance (static elastance, elastic component of viscoelasticity and resistive, viscoelastic and total pressures) was determined by the end-inflation occlusion method. Left lung and liver were prepared for histology. In lung and hepatic homogenates MCYST-LR, TNF-α, IL-1ß and IL-6 were determined by ELISA. LASSBio 596 per os (LASS mice) kept all lung mechanical parameters, polymorphonuclear (PMN) cells, pro-inflammatory mediators, and alveolar collapse similar to control mice (CTRL), whereas in TOX these findings were higher than CTRL. Likewise, liver structural deterioration (hepatocytes inflammation, necrosis and steatosis) and inflammatory process (high levels of pro-inflammatory mediators) were less evident in the LASS than TOX group. LASS and CTRL did not differ in any parameters studied. In conclusion, orally administered LASSBio 596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by MCYST-LR.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Bacterial Toxins/antagonists & inhibitors , Chemical and Drug Induced Liver Injury/prevention & control , Microcystins/antagonists & inhibitors , Phosphodiesterase Inhibitors/administration & dosage , Phthalimides/administration & dosage , Pneumonia/prevention & control , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bacterial Toxins/toxicity , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Inflammation Mediators/metabolism , Liver/drug effects , Liver/immunology , Liver/metabolism , Liver/pathology , Lung/drug effects , Lung/immunology , Lung/metabolism , Lung/pathology , Marine Toxins/antagonists & inhibitors , Marine Toxins/toxicity , Mice , Microcystins/toxicity , Neutrophil Infiltration/drug effects , Phosphodiesterase Inhibitors/therapeutic use , Phthalic Acids , Phthalimides/therapeutic use , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/pathology , Random Allocation , Sulfonamides
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