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1.
Epigenomics ; 12(22): 1969-1981, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33242255

RESUMO

Aim: To elucidate the transcriptional characteristics of COVID-19. Materials & methods: We utilized an integrative approach to comprehensively analyze the transcriptional features of both COVID-19 patients and SARS-CoV-2 infected cells. Results: Widespread infiltration of immune cells was observed. We identified 233 genes that were codifferentially expressed in both bronchoalveolar lavage fluid and lung samples of COVID-19 patients. Functional analysis suggested upregulated genes were related to immune response such as neutrophil activation and antivirus response, while downregulated genes were associated with cell adhesion. Finally, we identified LCN2, STAT1 and UBE2L6 as core genes during SARS-CoV-2 infection. Conclusion: The identification of core genes involved in COVID-19 can provide us with more insights into the molecular features of COVID-19.


Assuntos
/patologia , Lipocalina-2/genética , Fator de Transcrição STAT1/genética , Enzimas de Conjugação de Ubiquitina/genética , Células A549 , Líquido da Lavagem Broncoalveolar/citologia , Adesão Celular/genética , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Citocinas/sangue , Humanos , Pulmão/imunologia , Ativação de Neutrófilo/genética , Ativação de Neutrófilo/imunologia , Transcrição Genética/genética
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(5): 596-602, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33131513

RESUMO

Objective To investigate the effect of pirfenidone on cytokine/chemokine production by alveolar macrophages(AMs)in patients with idiopathic nonspecific interstitial pneumonia(iNSIP)or idiopathic pulmonary fibrosis(IPF).Methods We prospectively enrolled 10 iNSIP patients,11 IPF patients,and 8 non-interstitial lung disease(non-ILD)patients(control group)from our center from January 2015 to December 2018.AMs from bronchoalveolar lavage fluid(BALF)were cultured with or without lipopolysaccharide(LPS)stimulation.The production of Th1 cytokines [soluble tumor necrosis factor receptor(sTNFR)-1,sTNFR-2,and interleukin(IL)-1ß],Th2 cytokines [IL-10 and granulocyte-macrophage colony-stimulating factor(GM-CSF)],angiogenic chemokines [IL-18 and macrophage inflammatory protein(MIP)-1ß],and angiostatic chemokines [interferon-gama inducible monokines(MIG)and interferon-gama inducible protein(IP-10)] in the culture supernatants were measured by a bead-based assay,Luminex.The effect of pirfenidone on the cytokine/chemokine production was tested at various concentrations(0,0.03,0.10,0.30 mg/ml).Results The spontaneous and LPS-stimulated release of TNF-α,sTNFR-1,sTNFR-2,IL-1ß,IL-10,MIP-1ß,MIG,and IP-10 by AMs were significantly increased in iNSIP and IPF groups compared with control group(all P<0.05),but no difference in IL-18 was seen among three groups(all P>0.05).MIG and IP-10 were significantly higher in iNSIP group than in IPF group(both P<0.05).Pirfenidone suppressed the spontaneous and LPS-stimulated AMs release of all studied cytokine/chemokine in iNSIP and IPF in a dose-dependent manner at concentrations of 0.10 and 0.30 mg/ml,and no difference was observed between iNSIP and IPF groups(both P>0.05).Conclusion Pirfenidone can markedly suppress cytokine/chemokine expression in iNSIP and IPF patients,but the difference is not significant between these two groups of patients.


Assuntos
Quimiocinas , Macrófagos Alveolares , Piridonas , Anti-Inflamatórios não Esteroides/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Macrófagos Alveolares/efeitos dos fármacos , Piridonas/farmacologia
3.
PLoS One ; 15(11): e0241719, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137121

RESUMO

INTRODUCTION: Interstitial lung disease (ILD) is a heterogeneous group of diseases characterized by varying degrees of lung inflammation and/or fibrosis. We investigated biomarkers to infer whether patients with collagen vascular diseases associated ILD (CVD-ILD) and interstitial pneumonia with autoimmune features (IPAF) benefit from immunosuppressive therapy. MATERIALS AND METHODS: We retrospectively investigated patients with CVD-ILD, IPAF, and idiopathic pulmonary fibrosis (IPF) between June 2013 and May 2017 at our department. First, we assessed differences in serum and bronchoalveolar lavage fluid (BALF) levels of cytokines between groups. Second, we assessed the associations of patient's clinical variables with serum and BALF levels of those cytokines that were different between groups. Finally, we assessed the associations of diagnosis and response to immunosuppressive therapy with serum levels of those cytokines that were different between groups. RESULTS: We included 102 patients (51 with IPF, 35 with IPAF, and 16 with CVD-ILD). Serum and BALF levels of CXCL9, CXCL10, and CXCL11 were significantly elevated in patients with IPAF or CVD-ILD compared with those in patients with IPF. BALF levels of CXCL9 and CXCL10 were correlated with the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9 and CXCL10 were correlated with BALF levels. Serum levels of CXCL9, CXCL10, and CXCL11 were correlated C-reactive protein, percent predicted forced vital capacity, alveolar-arterial oxygen difference, and the percentages of lymphocytes and macrophages in BALF. Serum levels of CXCL9, CXCL10, and CXCL11 showed moderate accuracy to distinguish patients with CVD-ILD from those with IPAF and IPF. Pre-treatment serum levels of CXCL9 and CXCL11 showed strong positive correlations with the annual forced vital capacity changes in patients with IPAF and CVD-ILD treated with immunosuppressive drugs. CONCLUSIONS: Serum CXCL9, CXCL10, and CXCL11 are potential biomarkers for autoimmune inflammation and predictors of the immunosuppressive therapy responses in ILD with background autoimmunity.


Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Vasculares/complicações , Idoso , Autoimunidade , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Proteína C-Reativa/análise , Quimiocina CXCL10/análise , Quimiocina CXCL11/análise , Quimiocina CXCL9/análise , Colágeno/metabolismo , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pulmonares Intersticiais/etiologia , Linfócitos/citologia , Linfócitos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças Vasculares/patologia , Capacidade Vital
4.
Sci Rep ; 10(1): 19983, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33204000

RESUMO

The bronchoscopy, though usually safe, is occasionally associated with complications, such as pneumonia. However, the use of prophylactic antibiotics is not recommended by the guidelines of the British Thoracic Society. Thus far there are few reports of the risk factors for post-bronchoscopy pneumonia; the purpose of this study was to evaluate these risk factors. We retrospectively collected data on patients in whom post-bronchoscopy pneumonia developed from the medical records of 2,265 patients who received 2666 diagnostic bronchoscopies at our institution between April 2006 and November 2011. Twice as many patients were enrolled in the control group as in the pneumonia group. The patients were matched for age and sex. In total, 37 patients (1.4%) had post-bronchoscopy pneumonia. Univariate analysis showed that a significantly larger proportion of patients in the pneumonia group had tracheobronchial stenosis (75.7% vs 18.9%, p < 0.01) and a final diagnosis of primary lung cancer (75.7% vs 43.2%, p < 0.01) than in the control group. The pneumonia group tended to have more patients with a history of smoking (83.8% vs 67.1%, p = 0.06) or bronchoalveolar lavage (BAL) (4.3% vs 14.9%, p = 0.14) than the control group. In multivariate analysis, we found that tracheobronchial stenosis remained an independent risk factor for post-bronchoscopy pneumonia (odds ratio: 7.8, 95%CI: 2.5-24.2). In conclusion, tracheobronchial stenosis was identified as an independent risk factor for post-bronchoscopy pneumonia by multivariate analysis in this age- and sex- matched case control study.


Assuntos
Broncoscopia/efeitos adversos , Pneumonia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Lavagem Broncoalveolar/métodos , Líquido da Lavagem Broncoalveolar/citologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
5.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198751

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Itália , Leucócitos Mononucleares/virologia , Lopinavir/uso terapêutico , Pulmão/citologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/terapia , Prognóstico , Estudos Prospectivos , Respiração Artificial/métodos , Ritonavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Taxa de Sobrevida , Vírion/metabolismo , Vírion/ultraestrutura
6.
Cells ; 9(11)2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138195

RESUMO

Cumulative data link cytokine storms with coronavirus disease 2019 (COVID-19) severity. The precise identification of immune cell subsets in bronchoalveolar lavage (BAL) and their correlation with COVID-19 disease severity are currently being unraveled. Herein, we employed iterative clustering and guide-gene selection 2 (ICGS2) as well as uniform manifold approximation and projection (UMAP) dimensionality reduction computational algorithms to decipher the complex immune and cellular composition of BAL, using publicly available datasets from a total of 68,873 single cells derived from two healthy subjects, three patients with mild COVID-19, and five patients with severe COVID-19. Our analysis revealed the presence of neutrophils and macrophage cluster-1 as a hallmark of severe COVID-19. Among the identified gene signatures, IFITM2, IFITM1, H3F3B, SAT1, and S100A8 gene signatures were highly associated with neutrophils, while CCL8, CCL3, CCL2, KLF6, and SPP1 were associated with macrophage cluster-1 in severe-COVID-19 patients. Interestingly, although macrophages were also present in healthy subjects and patients with mild COVID-19, they had different gene signatures, indicative of interstitial and cluster-0 macrophage (i.e., FABP4, APOC1, APOE, C1QB, and NURP1). Additionally, MALAT1, NEAT1, and SNGH25 were downregulated in patients with mild and severe COVID-19. Interferon signaling, FCγ receptor-mediated phagocytosis, IL17, and Tec kinase canonical pathways were enriched in patients with severe COVID-19, while PD-1 and PDL-1 pathways were suppressed. A number of upstream regulators (IFNG, PRL, TLR7, PRL, TGM2, TLR9, IL1B, TNF, NFkB, IL1A, STAT3, CCL5, and others) were also enriched in BAL cells from severe COVID-19-affected patients compared to those from patients with mild COVID-19. Further analyses revealed genes associated with the inflammatory response and chemotaxis of myeloid cells, phagocytes, and granulocytes, among the top activated functional categories in BAL from severe COVID-19-affected patients. Transcriptome data from another cohort of COVID-19-derived peripheral blood mononuclear cells (PBMCs) revealed the presence of several genes common to those found in BAL from patients with severe and mild COVID-19 (IFI27, IFITM3, IFI6, IFIT3, MX1, IFIT1, OASL, IFI30, OAS1) or to those seen only in BAL from severe-COVID-19 patients (S100A8, IFI44, IFI44L, CXCL8, CCR1, PLSCR1, EPSTI1, FPR1, OAS2, OAS3, IL1RN, TYMP, BCL2A1). Taken together, our data reveal the presence of neutrophils and macrophage cluster-1 as the main immune cell subsets associated with severe COVID-19 and identify their inflammatory and chemotactic gene signatures, also partially reflected systemically in the circulation, for possible diagnostic and therapeutic interventions.


Assuntos
/genética , Macrófagos/imunologia , Neutrófilos/imunologia , /imunologia , Adulto , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Humanos , Imunidade Inata , Interleucina-8/imunologia , Proteínas de Membrana/imunologia , Análise de Célula Única/métodos
7.
Toxicol Appl Pharmacol ; 408: 115280, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33065154

RESUMO

The pulmonary inflammatory response to inhalation exposure to a fracking sand dust (FSD 8) was investigated in a rat model. Adult male Sprague-Dawley rats were exposed by whole-body inhalation to air or an aerosol of a FSD, i.e., FSD 8, at concentrations of 10 or 30 mg/m3, 6 h/d for 4 d. The control and FSD 8-exposed rats were euthanized at post-exposure time intervals of 1, 7 or 27 d and pulmonary inflammatory, cytotoxic and oxidant responses were determined. Deposition of FSD 8 particles was detected in the lungs of all the FSD 8-exposed rats. Analysis of bronchoalveolar lavage parameters of toxicity, oxidant generation, and inflammation did not reveal any significant persistent pulmonary toxicity in the FSD 8-exposed rats. Similarly, the lung histology of the FSD 8-exposed rats showed only minimal changes in influx of macrophages following the exposure. Determination of global gene expression profiles detected statistically significant differential expressions of only six and five genes in the 10 mg/m3, 1-d post-exposure, and the 30 mg/m3, 7-d post-exposure FSD 8 groups, respectively. Taken together, data obtained from the present study demonstrated that FSD 8 inhalation exposure resulted in no statistically significant toxicity or gene expression changes in the lungs of the rats. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan, J.S., Toxicol Appl Pharmacol. 000, 000-000, 2020) has been designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems.


Assuntos
Poeira , Fraturamento Hidráulico , Areia , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Expressão Gênica , Inflamação/genética , Inflamação/imunologia , Contagem de Leucócitos , Pulmão/imunologia , Pneumopatias/genética , Pneumopatias/imunologia , Macrófagos/imunologia , Masculino , Ratos Sprague-Dawley
8.
Am J Trop Med Hyg ; 103(6): 2305-2314, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32975177

RESUMO

Toxocara canis, a common roundworm that mainly causes toxocariasis, is a zoonotic parasite found worldwide. Humans, an accidental host, can acquire T. canis infection through accidental ingestion of T. canis-embryonated egg-contaminated food, water, and soil, and by encapsulated larvae in a paratenic host's viscera or meat. Long-term residence of T. canis larvae in a paratenic host's lungs may induce pulmonary inflammation that contributes to lung injury, airway inflammatory hyperresponsiveness, and collagen deposition in mice and clinical patients. This study intended to investigate the relationship between T. canis infection and allergic asthma in BALB/c mice inoculated with high, moderate, and low doses of T. canis eggs for a 13-week investigation. The airway hyperresponsiveness (AHR) to methacholine, collagen deposition, cytokine levels, and pathological changes in lung tissues was assessed in infected mice at weeks 1, 5, and 13 postinfection. The cell composition in bronchoalveolar lavage fluid of infected mice was assessed at weeks 5 and 13 postinfection. Compared with uninfected control mice, all groups of T. canis-infected mice exhibited significant AHR, a dose-dependent increase in eosinophilic infiltration leading to multifocal interstitial and alveolar inflammation with abundant mucus secretion, and collagen deposition in which the lesion size increased with the infective dose. Infected mice groups also showed significant expressions of eotaxin and type 2 T-helper-dominant cytokines such as interleukin (IL)-4, IL-5, and IL-13. Overall, these results suggest that T. canis larval invasion of the lungs may potentially cause pulmonary inflammatory injury and could subsequently contribute to the development of allergic manifestations such as asthma.


Assuntos
Asma/imunologia , Pneumopatias Parasitárias/imunologia , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Toxocara canis , Toxocaríase/imunologia , Animais , Asma/etiologia , Asma/patologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Colágeno , Citocinas/imunologia , Modelos Animais de Doenças , Eosinofilia/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Interleucina-5/imunologia , Pulmão/parasitologia , Pulmão/patologia , Pulmão/fisiopatologia , Pneumopatias Parasitárias/complicações , Pneumopatias Parasitárias/patologia , Pneumopatias Parasitárias/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Muco , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologia , Células Th2/imunologia , Toxocaríase/complicações , Toxocaríase/patologia , Toxocaríase/fisiopatologia
9.
Am J Respir Cell Mol Biol ; 63(6): 780-793, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32915645

RESUMO

Lung myeloid cells are important in pulmonary immune homeostasis and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Multiparameter immunophenotypic characterization of these cells is challenging because of their autofluorescence and diversity. We evaluated the immunophenotypic landscape of airway myeloid cells in COPD using time of flight mass cytometry. Cells from BAL, which were obtained from never-smokers (n = 8) and smokers with (n = 20) and without (n = 4) spirometric COPD, were examined using a 44-parameter time of flight mass cytometry panel. Unsupervised cluster analysis was used to identify cellular subtypes that were confirmed by manual gating. We identified major populations of CD68+ and CD68- cells with 22 distinct phenotypic clusters, of which 18 were myeloid cells. We found a higher abundance of putative recruited myeloid cells (CD68+ classical monocytes) in BAL from patients with COPD. CD68+ classical monocyte population had distinct responses to smoking and COPD that were potentially related to their recruitment from the interstitium and vasculature. We demonstrate that BAL cells from smokers and subjects with COPD have lower AXL expression. Also, among subjects with COPD, we report significant differences in the abundance of PDL1high and PDL2high clusters and in the expression of PDL1 and PDL2 across several macrophage subtypes suggesting modulation of inflammatory responses. In addition, several phenotypic differences in BAL cells from subjects with history of COPD exacerbation were identified that could inform potential disease mechanisms. Overall, we report several changes to the immunophenotypic landscape that occur with smoking, COPD, and past exacerbations that are consistent with decreased regulation and increased activation of inflammatory pathways.


Assuntos
Antígeno B7-H1/metabolismo , Células Mieloides/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Humanos , Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fumar/imunologia
10.
Am J Physiol Lung Cell Mol Physiol ; 319(5): L825-L832, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32936024

RESUMO

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of Ccn1 is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring 1) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), 2) Ccn1 gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and 3) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI (n = 6) versus noninjured controls (n = 6). Ccn1 gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS (n = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS (n = 45) (P < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all P < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.


Assuntos
Proteína Rica em Cisteína 61/metabolismo , Respiração Artificial , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Inflamação/metabolismo , Pulmão/metabolismo , Camundongos , Respiração Artificial/métodos
11.
Nanotoxicology ; 14(8): 1096-1117, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909489

RESUMO

Gold nanoparticles (AuNP) are largely biocompatible; however, many studies have demonstrated their potential to modulate various immune cell functions. The potential allergenicity of AuNP remains unclear despite the recognition of gold as a common contact allergen. In these studies, AuNP (29 nm) dermal sensitization potential was assessed via Local Lymph Node Assay (LLNA). Soluble gold (III) chloride (AuCl3) caused lymph node (LN) expansion (SI 10.9), whereas bulk particles (Au, 942 nm) and AuNP did not. Next, the pulmonary immune effects of AuNP (10, 30, 90 µg) were assessed 1, 4, and 8 days post-aspiration. All markers of lung injury and inflammation remained unaltered, but a dose-responsive increase in LN size was observed. Finally, mice were dermally-sensitized to AuCl3 then aspirated once, twice, or three times with Au or AuNP in doses normalized for mass or surface area (SA) to assess the impact of existing contact sensitivity to gold on lung immune responses. Sensitized animals exhibited enhanced responsivity to the metal, wherein subsequent immune alterations were largely conserved with respect to dose SA. The greatest increase in bronchoalveolar lavage (BAL) lymphocyte number was observed in the high dose group - simultaneous to preferential expansion of BAL/LN CD8+ T-cells. Comparatively, the lower SA-based doses of Au/AuNP caused more modest elevations in BAL lymphocyte influx (predominantly CD4+ phenotype), exposure-dependent increases in serum IgE, and selective expansion/activation of LN CD4+ T-cells and B-cells. Overall, these findings suggest that AuNP are unlikely to cause sensitization; however, established contact sensitivity to gold may increase immune responsivity following pulmonary AuNP exposure.


Assuntos
Alérgenos/toxicidade , Compostos de Ouro/toxicidade , Ouro/toxicidade , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Pele/efeitos dos fármacos , Animais , Proteínas Sanguíneas/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Ensaio Local de Linfonodo , Pulmão/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pele/imunologia , Propriedades de Superfície
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 687-692, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958124

RESUMO

Objective To establish a mouse neutrophil-dominated asthma model using house dust mite (HDM). Methods With a random number table, a total of 16 specific pathogen-free (SPF) BALB/c mice were divided into control group and model group. The model group was sensitized and stimulated by HDM nasal drip, and the control group mice were given the same amount of saline. In 24 hours after the last stimulation, the enhanced pause (Penh) was measured by the BUXCO noninvasive lung function detector to determine the airway resistance; the bronchoalveolar lavage fluid (BALF) was collected to count cells and classify inflammatory cells. The infiltration degree of inflammatory cells in the lung tissue was observed by HE staining. The expression of IL-6, IL-17F and IL-1ß mRNA was detected by real-time quantitative PCR, and the levels of IL-4, IL-6, IL-17F and tumor necrosis factor α (TNF-α) in BALF were detected by cytometric bead array (CBA). Results Compared with the control group, the value of Penh in the model group was significantly higher; the tracheal and paravascular inflammation significantly aggravated; the levels of IL-6, IL-17F, IL-1ß mRNA, the cell count and neutrophil count in BALF, and the levels of neutrophil cytokines IL-6, IL-17F and TNF-α in the BALF increased significantly. Conclusion The mouse neutrophil-dominated house dust mite allergic asthma model has been successfully established.


Assuntos
Asma , Modelos Animais de Doenças , Hipersensibilidade , Neutrófilos , Pyroglyphidae , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Regulação da Expressão Gênica/imunologia , Hipersensibilidade/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Pyroglyphidae/imunologia , Distribuição Aleatória
13.
J Environ Pathol Toxicol Oncol ; 39(3): 213-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865913

RESUMO

Asthma is a chronic, serious allergic inflammatory disease in the airway. The inflammation in the airway is induced by the allergic T-helper 2 cells (Th2 cells), which leads to unfettered production of inflammatory cytokines. The accretion of inflammatory cells in the airway also speeds up the secretion of reactive oxygen species (ROS) and suppresses antioxidative processes. Hence, the present work aimed to study the antiasthmatic efficacy of betulin and its effect in suppressing the inflammatory markers of ovalbumin (OVA) challenged asthmatic mice. The observed results revealed that the levels of inflammatory cells including neutrophils, eosinophils, lymphocytes, and macrophages were effectively decreased by betulin treatment; furthermore, the inflammatory markers IL-4, IL-5, IL-13, and TNF-α levels were notably suppressed by betulin administration in OVA-challenged asthmatic mice. Similarly, the oral administration of betulin showed a reduction in IgE level and elevation in the IFN-γ level in bronchoalveolar lavage fluid (BALF). The elevated levels of antioxidant enzymes like catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) were observed in betulin treated mice. Furthermore, reduced levels of reactive oxygen species like NO2, NO3, and MDA were noted in the betulin treated group. Consistently, airway hyperreactivity (AHR) was depleted in the betulin administered group compared with the OVA-challenged asthmatic group. Betulin treatment was revealed to have noteworthy antiasthmatic effects mediated by the suppression of production of inflammatory cells and the expression of other inflammatory markers. Furthermore, the elevation in the level of antioxidant markers helped to disclose the original regulatory mode of betulin on asthma treatment.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Triterpenos/uso terapêutico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/imunologia , Asma/metabolismo , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinófilos/citologia , Feminino , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória , Triterpenos/administração & dosagem
14.
J Environ Pathol Toxicol Oncol ; 39(3): 225-234, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865914

RESUMO

Asthma is marked by chronic irritation in the airway lumen of the lungs due to the accretion of inflammatory cells that influence the regular inhalation process. An extended buildup of inflammation leads to oxidative pressure and the repression of antioxidant functions. In the current study, a potential compound, boldine, was tested for the containment of provocative markers along the path of antiasthmatic activity in an ovalbumin (OVA)-induced asthmatic mice model. As an effect, the boldine (10 and 20 mg/kg) treatment suppressed inflammatory cells such as eosinophil, macrophage, neutrophil, lymphocyte, and other inflammatory markers in the bronchoalveolar lavage fluid (BALF) of OVA-induced mice. Likewise, immunoglobulin E (IgE) levels were drastically condensed in the serum of boldine-treated animals. Levels of enzymatic and nonenzymatic antioxidants, such as superoxide dismutase (SOD) and glutathione (GSH), were upregulated in the boldine treatment group compared to the asthmatic control group, which displays the antioxidant effects of boldine on asthmatic animals. Interestingly, the reactive oxygen species (ROS) and malonaldehyde (MDA) levels were repressed in the BALF of boldine-treated mice groups. Therefore, the effects of boldine are significant for the management of asthma, reducing the accrual of inflammatory cells, along with other inflammatory markers, while improving antioxidant markers and containing ROS. Hence, boldine may be an option for clinical trials of chronic asthma management.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Aporfinas/uso terapêutico , Asma/tratamento farmacológico , Animais , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Aporfinas/administração & dosagem , Asma/imunologia , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Modelos Animais de Doenças , Eosinófilos/citologia , Imunoglobulina E/sangue , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Função Respiratória
15.
Toxicol Appl Pharmacol ; 405: 115201, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32828905

RESUMO

We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(-/-)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in the lungs of BLM-instilled mice. Bronchoalveolar lavage (BAL) fluid cell analysis indicated more severe inflammation in Slco2a1(-/-) on day 5 after BLM intratracheal instillation, and Slco2a1 deletion increased mRNA expression of pro-inflammatory cytokines (Tnf-α and Il-1ß) and chemokine (Ccl5) in BAL cells. Male Slco2a1(-/-) exhibited significantly higher amounts of released Il-1ß in BAL fluid, compared with female Slco2a1(-/-), male or female Slco2a1(+/+) group. The amount of PGE2 collected in BAL fluid tended to increase in Slco2a1(-/-) compared with Slco2a1(+/+) group, whereas the PGE2 concentrations in lung tissues were comparable between both groups. Besides, PGE2 accumulated more in BAL fluid of male than that of female mice. Therefore, Slco2a1-deficient male mice were found to be more susceptible to BLM-treatment. Moreover, CS extracts (CSE) significantly reduced initial PGE2 uptake by rat type1 alveolar epithelial cell-like (AT1-L) cells and human SLCO2A1-transfected cells. Exposure of AT1-L cells to CSE resulted in decreased mRNA expression of Slco2a1, suggesting that CS modulates SLCO2A1 function. These results indicate that exacerbated lung inflammation is attributed to an increase in Il-1ß peptide and PGE2 accumulation in the alveolar space, which exhibits a male predominance. SLCO2A1 inhibition by CSE is considered to be a new rationale for the lung toxicity of CS.


Assuntos
Bleomicina/toxicidade , Pulmão/efeitos dos fármacos , Transportadores de Ânions Orgânicos/genética , Fibrose Pulmonar/induzido quimicamente , Produtos do Tabaco/toxicidade , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Dinoprostona/metabolismo , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fumar/efeitos adversos
16.
Res Vet Sci ; 132: 338-341, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32738730

RESUMO

Exercise-induced pulmonary hemorrhage (EIPH) and asthma in barrel racing horses is a common disease across the United States. Limited information is available on non-infectious respiratory diseases in this population, the interaction between these two diseases, and the occurrence of both EIPH and asthma in the horse. The purpose of this study was to evaluate the bronchoalveolar lavage (BAL) fluid cytological results of barrel racing horses with EIPH, asthma, or both. A retrospective study was conducted using the medical records of horses that presented with cough and decreased athletic performance and BAL results that met the criteria for inclusion. Data from 95 horses were included from a private practice referral hospital in Texas. No statistical difference was found in the frequency of neutrophilia, eosinophilia, or mastocytosis between diagnoses of EIPH, asthma, or concurrent diagnoses of EIPH and asthma. Bronchoalveolar lavage of horses suspected of EIPH is warranted to fully characterize the noninfectious respiratory disease of barrel racing horses.


Assuntos
Asma/veterinária , Líquido da Lavagem Broncoalveolar/química , Hemorragia/veterinária , Doenças dos Cavalos/diagnóstico , Pneumopatias/veterinária , Animais , Asma/diagnóstico , Líquido da Lavagem Broncoalveolar/citologia , Hemorragia/diagnóstico , Cavalos , Pneumopatias/diagnóstico , Masculino , Condicionamento Físico Animal , Estudos Retrospectivos , Texas
17.
Nanotoxicology ; 14(8): 1058-1081, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32813574

RESUMO

Nickel nanoparticles (NiNPs) are increasingly used in nanotechnology applications, yet information on sex differences in NiNP-induced lung disease is lacking. The goal of this study was to explore mechanisms of susceptibility between male and female mice after acute or subchronic pulmonary exposure to NiNPs. For acute exposure, male and female mice received a single dose of NiNPs with or without LPS by oropharyngeal aspiration and were necropsied 24 h later. For subchronic exposure, mice received NiNPs with or without LPS six times over 3 weeks prior to necropsy. After acute exposure to NiNPs and LPS, male mice had elevated cytokines (CXCL1 and IL-6) and more neutrophils in bronchoalveolar lavage fluid (BALF), along with greater STAT3 phosphorylation in lung tissue. After subchronic exposure to NiNPs and LPS, male mice exhibited increased monocytes in BALF. Moreover, subchronic exposure of male mice to NiNP only induced higher CXCL1 and CCL2 in BALF along with increased alveolar infiltrates and CCL2 in lung tissue. STAT1 in lung tissue was induced by subchronic exposure to NiNPs in females but not males. Males had a greater induction of IL-6 mRNA in liver after acute exposure to NiNPs and LPS, and greater CCL2 mRNA in liver after subchronic NiNP exposure. These data indicate that susceptibility of males to acute lung inflammation involves enhanced neutrophilia with increased CXCL1 and IL-6/STAT3 signaling, whereas susceptibility to subchronic lung inflammation involves enhanced monocytic infiltration with increased CXCL1 and CCL2. STAT transcription factors appear to play a role in these sex differences. This study demonstrates sex differences in the lung inflammatory response of mice to NiNPs that has implications for human disease.


Assuntos
Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Níquel/toxicidade , Pneumonia/induzido quimicamente , Caracteres Sexuais , Animais , Líquido da Lavagem Broncoalveolar/citologia , Quimiocina CXCL1/metabolismo , Feminino , Humanos , Exposição por Inalação , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Pneumonia/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Testes de Toxicidade Aguda , Testes de Toxicidade Subcrônica
18.
Life Sci ; 259: 118191, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777302

RESUMO

Numerous population studies conducted worldwide indicate that the prevalence of asthma is higher in obese versus lean individuals. It has been reported that sensitized lean mice has a better recovery of lung inflammation in asthma. Extracellular matrix (ECM) plays an essential role in the structural support of the lungs regulating the airways diameter, thus preventing its collapse during expiration. ECM renewal by metalloproteinase (MMPs) enzymes is critical for pulmonary biology. There seems to be an imbalance of MMPs activity in asthma and obesity, which can impair the lung remodeling process. In this study, we characterized the pulmonary ECM of obese and lean mice, non-sensitized and sensitized with ovalbumin (OVA). Pharmacological intervention was performed by using anti-TNF-α, and MMP-8 and MMP-9 inhibitors in obese and lean sensitized mice. Activity of MMPs was assessed by gelatinase electrophorese, western blotting and zymogram in situ. Unbalance of MMP-2, MMP-8, MMP-9 and MMP-12 was detected in lung tissue of OVA-sensitized obese mice, which was accompanied by high degradation, corroborating an excessive deposition of types I and III collagen in pulmonary matrix of obese animals. Inhibitions of TNF-α and MMP-9 reduced this MMP imbalance, clearly suggesting a positive effect on pulmonary ECM. Obese and lean mice presented diverse phenotype of asthma regarding the ECM compounds and the inhibition of MMPs pathway could be a good alternative to regulate the activity in ECM lungs of asthmatic obese individuals.


Assuntos
Asma/etiologia , Asma/metabolismo , Metaloproteases/metabolismo , Obesidade/complicações , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Matriz Extracelular/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Inibidores de Proteases/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
19.
Sci Rep ; 10(1): 13045, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747644

RESUMO

Cyclophosphamide (CP) is a chemotherapeutic agent that induces oxidative stress causing multiple organ damage. Sacubitril/valsartan, is a combined formulation of neprilysin inhibitor (sacubitril) and angiotensin II receptor blocker (valsartan), that induces the protective effect of brain natriuretic peptide. The aim of the current study is to investigate the prophylactic impacts of sacubitril/valsartan versus valsartan against CP-induced lung toxicity in rats. Rats were assigned randomly into 6 groups; control; received corn oil (2 ml/kg/day; p.o. for 6 days), sacubitril/valsartan (30 mg/kg; p.o. for 6 days), valsartan (15 mg/kg; p.o. for 6 days), CP (200 mg/kg; i.p. on day 5), sacubitril/valsartan + CP (30 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively), valsartan + CP (15 mg/kg; p.o. for 6 days, 200 mg/kg; i.p. single dose on day 5, respectively). Both sacubitril/valsartan and valsartan produced a significant decrease in the inflammation and fibrosis markers in the BALF, in comparison with the CP group. Both sacubitril/valsartan and valsartan produced an apparent decrease in the relative genes expression of miR-150-3p and NF-κB, as well as a significant decrease in the relative expression of P38 and ERK1/2 MAPKs and an increase in the relative gene expression of Nrf-2, compared to CP group. Intriguingly, sacubitril/valsartan , showed subtle superiority in almost all investigated parameters, compared to valsartan. In conclusion, sacubitril/valsartan effectively abrogated the CP induced lung inflammation and fibrosis, providing a potential promising protection that could be linked to their ability to inhibit miR-150-3p via inhibition of NF-κB and MAPK signaling pathways.


Assuntos
Aminobutiratos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/genética , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , NF-kappa B/metabolismo , Substâncias Protetoras/uso terapêutico , Tetrazóis/uso terapêutico , Aminobutiratos/farmacologia , Animais , Antioxidantes/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Ciclofosfamida , Citocinas/metabolismo , Combinação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Mediadores da Inflamação/metabolismo , L-Lactato Desidrogenase/metabolismo , Contagem de Leucócitos , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Tetrazóis/farmacologia
20.
Toxicol Lett ; 333: 140-149, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32755622

RESUMO

Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.


Assuntos
Asbestos Serpentinas/toxicidade , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Poluentes Ambientais/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Asbestos Serpentinas/química , Líquido da Lavagem Broncoalveolar/citologia , China , Inibidor p16 de Quinase Dependente de Ciclina/genética , Citocinas/metabolismo , Poluentes Ambientais/química , Expressão Gênica/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibras Minerais/toxicidade , Proteínas Proto-Oncogênicas c-fos/genética , Ratos Wistar , Proteína Supressora de Tumor p53/genética
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