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1.
PLoS Negl Trop Dis ; 14(3): e0007675, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32119672

RESUMO

Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1 and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (MΦ) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, MΦs, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.


Assuntos
Angiopoietina-2/metabolismo , Células Endoteliais/patologia , Orientia tsutsugamushi/crescimento & desenvolvimento , Pneumonia/patologia , Receptor TIE-2/metabolismo , Tifo por Ácaros/patologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Pneumonia/imunologia , Tifo por Ácaros/imunologia
2.
J Infect ; 80(5): e7-e13, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171865

RESUMO

BACKGROUND: The ongoing outbreak of COVID-19 pneumonia is globally concerning. We aimed to investigate the clinical and CT features in the pregnant women and children with this disease, which have not been well reported. METHODS: Clinical and CT data of 59 patients with COVID-19 from January 27 to February 14, 2020 were retrospectively reviewed, including 14 laboratory-confirmed non-pregnant adults, 16 laboratory-confirmed and 25 clinically-diagnosed pregnant women, and 4 laboratory-confirmed children. The clinical and CT features were analyzed and compared. FINDINGS: Compared with the non-pregnant adults group (n = 14), initial normal body temperature (9 [56%] and 16 [64%]), leukocytosis (8 [50%] and 9 [36%]) and elevated neutrophil ratio (14 [88%] and 20 [80%]), and lymphopenia (9 [56%] and 16 [64%]) were more common in the laboratory-confirmed (n = 16) and clinically-diagnosed (n = 25) pregnant groups. Totally 614 lesions were detected with predominantly peripheral and bilateral distributions in 54 (98%) and 37 (67%) patients, respectively. Pure ground-glass opacity (GGO) was the predominant presence in 94/131 (72%) lesions for the non-pregnant adults. Mixed consolidation and complete consolidation were more common in the laboratory-confirmed (70/161 [43%]) and clinically-diagnosed (153/322 [48%]) pregnant groups than 37/131 (28%) in the non-pregnant adults (P = 0·007, P < 0·001). GGO with reticulation was less common in 9/161 (6%) and 16/322 (5%) lesions for the two pregnant groups than 24/131 (18%) for the non-pregnant adults (P = 0·001, P < 0·001). The pulmonary involvement in children with COVID-19 was mild with a focal GGO or consolidation. Twenty-three patients underwent follow-up CT, revealing progression in 9/13 (69%) at 3 days whereas improvement in 8/10 (80%) at 6-9 days after initial CT scans. INTERPRETATION: Atypical clinical findings of pregnant women with COVID-19 could increase the difficulty in initial identification. Consolidation was more common in the pregnant groups. The clinically-diagnosed cases were vulnerable to more pulmonary involvement. CT was the modality of choice for early detection, severity assessment, and timely therapeutic effects evaluation for the cases with epidemic and clinical features of COVID-19 with or without laboratory confirmation. The exposure history and clinical symptoms were more helpful for screening in children versus chest CT.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia/diagnóstico por imagem , Pneumonia/etiologia , Complicações Infecciosas na Gravidez/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Betacoronavirus , Criança , Pré-Escolar , China , Infecções por Coronavirus/patologia , Feminino , Humanos , Lactente , Masculino , Pandemias , Pneumonia/patologia , Pneumonia Viral/patologia , Gravidez , Complicações Infecciosas na Gravidez/patologia , Estudos Retrospectivos , Adulto Jovem
3.
Chemosphere ; 248: 126035, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32014637

RESUMO

Epidemiologic studies show that there is a link between Bisphenol A (BPA) exposure and lung inflammation. Despite this, the molecular mechanisms are not entirely known. This study sought to determine whether exposure to BPA affected the development of ovalbumin (OVA) induced lung inflammation in adolescent female mice and whether the mechanism was related to mTOR-mediated autophagy pathway. Female 4-week-old C57BL/6 mice after one week of domestication were randomly divided into five groups (8/group): control group, OVA group, 0.1 µg mL-1 BPA + OVA group, 0.2 µg mL-1 BPA + OVA group and 0.4 µg mL-1 BPA + OVA group. BPA exacerbated airway hyperresponsiveness (AHR), induced the pathological changes in the lung, which also enhanced inflammatory cells and cytokine levels. In addition, BPA exposure affected expression of autophagy associated proteins and genes. This research results indicated that BPA aggravated OVA-induced lung inflammation and induced abnormal immune function in mice, and its mechanism was related to the activation of autophagy pathway by down-regulation expression of mTOR. These findings suggest that therapeutic strategies to target autophagy may offer a new approach for severe asthma therapy.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Fenóis/toxicidade , Pneumonia/induzido quimicamente , Animais , Asma/induzido quimicamente , Autofagia , Citocinas/metabolismo , Feminino , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina , Pneumonia/patologia , Hipersensibilidade Respiratória , Serina-Treonina Quinases TOR/metabolismo , Testes de Toxicidade
4.
Infection ; 48(2): 267-274, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32008182

RESUMO

OBJECTIVES: Current risk stratification in community-acquired pneumonia (CAP) does not incorporate the dynamic nature of CAP evolution. Study aim was to evaluate the predictive value of early blood pressure (BP) drop and its consideration within the CRB-65 score. METHODS: We performed a retrospective cohort study including consecutive adult hospitalized CAP patients 2013-2014 without documented treatment limitations or direct ICU admission. The CRB-65 score was calculated initially and re-calculated including any BP below the threshold (BP drop) within the first 24 h (CRB-65[BP24]). The primary endpoint was need for mechanical ventilation or vasopressors (MVVS) occurring after 24 h. Prognostic values were evaluated by uni- and multivariate and ROC curve analyses. RESULTS: 28/294 patients (9.5%) met the primary endpoint. Only 3 (11%) of them showed an initial BP of < 90 mmHg systolic or ≤ 60 mmHg diastolic, but 21 (75%) developed a BP drop within the first 24 h. 24/178 (13%) with and only 4/116 (3%) without any low BP during the first 24 h needed MVVS (p = 0.004). After multivariate analysis, the predictive value of BP drop was independent of other score parameters and biomarkers (all p < 0.01). In ROC analysis, the new CRB-65(BP24) showed a better prediction than the CRB-65 score (AUC 0.69 vs. 0.62, p = 0.04). 7/13 patients (54%) with MVVS despite an admission CRB-65 of 0 or 1 showed a BP drop. CONCLUSIONS: In the evaluated cohort, BP drop within the first 24 h was significantly associated with more need for MVVS in CAP, and its consideration improved the prognostic value of the CRB-65 score.


Assuntos
Pressão Sanguínea , Infecções Comunitárias Adquiridas/diagnóstico , Hospitalização/estatística & dados numéricos , Pneumonia/diagnóstico , Idoso , Estudos de Coortes , Infecções Comunitárias Adquiridas/mortalidade , Humanos , Estimativa de Kaplan-Meier , Pneumonia/mortalidade , Pneumonia/patologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
5.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L314-L322, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851532

RESUMO

Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-α, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosa-induced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.


Assuntos
Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/prevenção & controle , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/fisiologia , Proteína Amiloide A Sérica/metabolismo , Animais , Quimiocinas/metabolismo , Epitélio/patologia , Pulmão/irrigação sanguínea , Pulmão/microbiologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/patologia , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Pneumonia/complicações , Pneumonia/microbiologia , Pneumonia/patologia , Proteína Amiloide A Sérica/deficiência
6.
Adv Gerontol ; 32(4): 633-638, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31800194

RESUMO

The aim of the study was to determin the incidence, severity and prognostic significance of acute kidney injury (AKI) in elderly patients with community-acquired pneumonia (CAP). 122 older patients (≥60 years) with community-acquired pneumonia were examined. Acute kidney injury was diagnosed in 49 (40,2%) patients including 47 (95,9%) patients with AKI occurring prehospital. In patients with community-acquired pneumonia associated with acute kidney injury the clinical picture of AKI was harder. Also disturbance of consciousness, dyspnea, leg swelling, tachycardia, abnormal liver function tests such as hyperbilirubinemia and hypertransaminasemia were diagnosed more frequently in this group of patients. With the development of AKI increased in-hospital mortality: odds ratio of death among patients with CAP associated with AKI was 8,3 (95% CI 2,75-25,28). So, the development of AKI in elderly patients with CAP is an actual health problem requiring the development of preventive measures and drug therapy in patients with CAP and also mandatory monitoring of patients who have had acute kidney injury.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Lesão Renal Aguda/complicações , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/patologia , Idoso , Infecções Comunitárias Adquiridas/complicações , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/patologia , Humanos , Incidência , Pneumonia/complicações , Pneumonia/epidemiologia , Pneumonia/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco
7.
Immunity ; 51(5): 899-914.e7, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31732166

RESUMO

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.


Assuntos
Suscetibilidade a Doenças , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Biomarcadores , Contagem de Células , Suscetibilidade a Doenças/imunologia , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Isquemia/etiologia , Isquemia/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Células Musculares/imunologia , Células Musculares/metabolismo , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Pneumonia/etiologia , Pneumonia/metabolismo , Pneumonia/patologia
8.
BMC Infect Dis ; 19(1): 843, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615438

RESUMO

BACKGROUND: In recent years, some rare fungi have been increasingly recognized as new human pathogens. Here we reported the first fatal case of human severe pneumonia complicated by multiple organ dysfunction caused by Acrophialophora levis infection. However, its pathogenic mechanism and risk factors are unknown. Acrophialophora genus has only reported in six cases of human infection worldwide, but it has not been reported previously in China. CASE PRESENTATION: A 71-year-old male patient with severe pneumonia complicated with multiple organ dysfunction caused by A. levis infection. The fungal identification was based on micromorphology and sequence analysis of the internal transcriptional spacer (ITS) of ribosomal RNA genes recovered from lower respiratory tract secretions. The microbial characteristics, sensitivity to antifungal drugs of this isolated A. levis were studied. Anti-infective regimen, liposomal amphotericin B combined with tegacycline, was used to prevent infection. The next day, the fever decreased, body temperature fluctuated between 36.5 and 37.8 degree, cough and sputum decreased, and sputum volume decreased, with oxygen uptake for 5 L/min, blood oxygen saturation over 95%. After 17 days of treatment, CT reexamination showed that the lesions in the right lung and left upper lung were absorbed and pleural effusion was reduced. The next 8 days, the patient asked to return to the local hospital for treatment. The local hospital stopped using liposomal amphotericin B because of the absence of liposomal amphotericin B, and died of respiratory failure 2 days later. CONCLUSIONS: This study is the first to report the occurrence, risk factors, molecular determinants, microbial characteristics and susceptibility to antifungal agents of A. levis infection in China. In addition, six published cases of human infection with Acrophialophora were reviewed.


Assuntos
Ascomicetos/isolamento & purificação , Pneumonia/diagnóstico , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Humanos , Masculino , Derrame Pleural/etiologia , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
9.
Int J Nanomedicine ; 14: 7237-7247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564876

RESUMO

Background: The health hazards of silica nanoparticle (SiNP) are raising worldwide concern as SiNPs has become the second largest manufactured nanomaterial in global markets. However, insufficient data for the adverse health effects and safety evaluation of SiNPs are remaining a big question. Purpose: We evaluated the effects and related mechanism of SiNPs on pulmonary inflammation and collagen production through repeated intravenous administration in mice in a 45-day observation period. Methods: Morphological and ultrastructural change, ultradistribution of SiNPs in lungs were observed in ICR mice through intravenous administration. Oxidative damage, pro-inflammatory cytokines, hydroxyproline content, the marker of fibroblasts and epithelial-mesenchymal transition (EMT), and JAK2/STAT3 and TGF-ß1/Smad3 signaling pathways were detected to explore the lung injuries and related mechanism. Results: The results showed repeated intravenous exposure of SiNPs increased the weight of lung tissues and destroyed pulmonary histomorphological structure. The increased MDA content, depletion of SOD and GSH-Px in lungs were observed in SiNP-treated mice. The protein expressions of JAK2/STAT3 pathway were upregulated in lungs, and the levels of inflammatory cytokines TNF-α, IL-1ß, and IL-6 in serum and lungs were also elevated in SiNPs treated group. The increased hydroxyproline content indicated collagen accumulation in lungs of SiNP-treated mice. Meanwhile, the protein expressions of the marker of myofibroblast (a-SMA), the regulators in connective tissue remodeling (CTGF), TGF-ß, and p-Smad3 were all upregulated in lungs. In addition, we found intravenous administration of SiNPs-induced ultrastructural changes in type II alveolar epithelial cells but without downregulation of the protein expression of the key markers of epithelial cells (E-Cadherin). Conclusion: Our results revealed that oxidative stress and inflammation contributed to the collagen accumulation through activation of JAK2/STAT3 and TGF-ß/Smad3 pathways. It suggests that pulmonary aberrant inflammation and collagen accumulation induced by nanoparticles should be seriously considered for the safety application in diagnostics or therapeutics.


Assuntos
Colágeno/metabolismo , Janus Quinase 2/metabolismo , Nanopartículas/administração & dosagem , Pneumonia/patologia , Transdução de Sinais , Dióxido de Silício/administração & dosagem , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Administração Intravenosa , Animais , Caderinas/metabolismo , Citocinas/metabolismo , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos ICR , Modelos Biológicos , Miofibroblastos/metabolismo , Nanopartículas/ultraestrutura , Estresse Oxidativo , Fator de Transcrição STAT3/metabolismo
11.
Dis Markers ; 2019: 1089107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583025

RESUMO

The focus of sepsis has shifted from inflammation to organ dysfunction on the basis of a recent definition based on the sequential organ failure score (SOFA). A diagnostic and prognostic marker is necessary under this definition but is currently unknown. We enrolled 80 sepsis patients consecutively admitted to an intensive care unit through the emergency department and 80 healthy control patients who received routine health check-ups from August 2018 to January 2019. SEPSIS-3 criteria were used for the diagnosis of patients based on SOFA score ≥ 2 from the baseline along with evidence of infection. Concentrations of 28 cytokines, eight chemokines, and nine growth factors were measured on the day of diagnosis. Hierarchical cluster analysis was performed for molecules. The majority of infections were pneumonia (45% of patients) and urinary tract infections (40% of patients). Most of the measured molecules were increased in patients with sepsis. Area under receiver operating characteristic curve (AUROC) values were found to be as follows: hepatic growth factor (HGF), 0.899; interleukin-1 receptor antagonist (IL-1RA), 0.893; C-C motif ligand 5 (CCL5) 5, 0.887; C-X-C motif chemokine 10 (CXCL10), 0.851; CCL2, 0.840; and IL-6, 0.830. IL-1RA, IL-6, IL-8, IL-15, and CCL11 concentrations correlated with SOFA score with statistical significance. Prognosis multivariate analysis revealed an odds ratio of 0.968 for epidermal growth factor (EGF). Three clusters were formed, of which Clusters 2 and 3 were associated with nonsurvivors. Diagnosis of sepsis was performed using cytokines, chemokines, and growth factors. HGF revealed the highest diagnostic capability, and EGF predicted favorable prognosis among the tested molecules.


Assuntos
Citocinas/sangue , Fator de Crescimento de Hepatócito/sangue , Pneumonia/diagnóstico , Sepse/diagnóstico , Infecções Urinárias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Fator de Crescimento Epidérmico/sangue , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Razão de Chances , Escores de Disfunção Orgânica , Pneumonia/sangue , Pneumonia/mortalidade , Pneumonia/patologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/sangue , Sepse/mortalidade , Sepse/patologia , Análise de Sobrevida , Infecções Urinárias/sangue , Infecções Urinárias/mortalidade , Infecções Urinárias/patologia
12.
Life Sci ; 236: 116790, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31626791

RESUMO

AIMS: Although the bulk of research into the biology of serotonin 5-HT2A receptors has focused on its role in the CNS, selective activation of these receptors in peripheral tissues can produce profound anti-inflammatory effects. We previously demonstrated that the small molecule 5-HT2 receptor agonist (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] inhibits TNF-α-mediated proinflammatory signaling cascades and inflammation via 5-HT2A receptor activation and prevents the development of, and inflammation associated with, acute allergic asthma in a mouse ovalbumin (OVA) model. Here, we investigated the ability of (R)-DOI to reverse inflammation and symptoms associated with established asthma in a newly developed model of chronic asthma. METHODS: An 18-week ovalbumin challenge period was performed to generate persistent, chronic asthma in BALB/c mice. Four once daily intranasal treatments of (R)-DOI were administered one week after allergen cessation, with respiratory parameters being measured by whole-body plethysmography (WBP). Cytokine and chemokine levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in homogenized lung tissue, bronchoalveolar (BALF) fluid was analyzed for chemokine modulation by multiplex assays, and Periodic Acid-Schiff and Masson's Trichrome staining was performed to determine goblet cell infiltration and overall changes to lung morphology. KEY FINDINGS: 5-HT2 activation via (R)-DOI attenuates elevated airway hyperresponsiveness to methacholine, reduces pulmonary inflammation and mucus production, and reduces airway structural remodeling and collagen deposition by nearly 70%. SIGNIFICANCE: Overall, these data provide support for the therapeutic potential of (R)-DOI and 5-HT2 receptor activation for the treatment of asthma, and identifies (R)-DOI as a novel therapeutic compound against pulmonary fibrosis.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Anfetaminas/farmacologia , Asma/tratamento farmacológico , Pneumonia/prevenção & controle , Receptores 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Remodelação das Vias Aéreas/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Doença Crônica , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Hipersensibilidade/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Pneumonia/imunologia , Pneumonia/patologia
13.
BMC Res Notes ; 12(1): 584, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533801

RESUMO

OBJECTIVE: The aim of this study was to compare in vivo effect of five pharmacological options on inflammation and pulmonary fibrosis induced by paraquat. METHODS: 54 Wistar SPF rats were used. After 2 h post-intoxication with paraquat ion, groups of 9 animals were randomly assigned to (1) cyclophosphamide plus dexamethasone (2) low molecular weight heparin (3) unfractionated heparin (4) vitamin C every 24 h, (5) atorvastatin or (6) placebo with intraperitoneal saline. Lung inflammation, alveolar injury, hepatocyte damage, hepatic regeneration, acute tubular necrosis and kidney congestion were evaluated. RESULTS: In the control group 100% of animals presented moderate and severe lung inflammation, while in the groups with atorvastatin and intratracheal heparin this proportion was lower (55.5%; CI 26.6-81.3%) (p = 0.025). A lower degree of moderate or severe hepatic regeneration was evident in the treatment groups with atorvastatin (p = 0.009). In this study was demonstrated that statins and heparin might have a protective effect in the paraquat-induced destructive phase. More evidence is needed to evaluated of dose-response effects of these drugs before to study in clinical trials.


Assuntos
Tratamento Farmacológico/métodos , Pulmão/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Atorvastatina/farmacologia , Ciclofosfamida/farmacologia , Dexametasona/farmacologia , Quimioterapia Combinada , Heparina/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Pulmão/patologia , Paraquat/toxicidade , Pneumonia/patologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/induzido quimicamente , Ratos Wistar , Resultado do Tratamento
14.
Part Fibre Toxicol ; 16(1): 35, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533843

RESUMO

BACKGROUND: Li-ion batteries (LIB) are increasingly used worldwide. They are made of low solubility micrometric particles, implying a potential for inhalation toxicity in occupational settings and possibly for consumers. LiCoO2 (LCO), one of the most used cathode material, induces inflammatory and fibrotic lung responses in mice. LCO also stabilizes hypoxia-inducible factor (HIF) -1α, a factor implicated in inflammation, fibrosis and carcinogenicity. Here, we investigated the role of cobalt, nickel and HIF-1α as determinants of toxicity, and evaluated their predictive value for the lung toxicity of LIB particles in in vitro assays. RESULTS: By testing a set of 5 selected LIB particles (LCO, LiNiMnCoO2, LiNiCoAlO2) with different cobalt and nickel contents, we found a positive correlation between their in vivo lung inflammatory activity, and (i) Co and Ni particle content and their bioaccessibility and (ii) the stabilization of HIF-1α in the lung. Inhibition of HIF-1α with chetomin or PX-478 blunted the lung inflammatory response to LCO in mice. In IL-1ß deficient mice, HIF-1α was the upstream signal of the inflammatory lung response to LCO. In vitro, the level of HIF-1α stabilization induced by LIB particles in BEAS-2B cells correlated with the intensity of lung inflammation induced by the same particles in vivo. CONCLUSIONS: We conclude that HIF-1α, stabilized in lung cells by released Co and Ni ions, is a mechanism-based biomarker of lung inflammatory responses induced by LIB particles containing Co/Ni. Documenting the Co/Ni content of LIB particles, their bioaccessibility and their capacity to stabilize HIF-1α in vitro can be used to predict the lung inflammatory potential of LIB particles.


Assuntos
Cobalto/toxicidade , Células Epiteliais/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/efeitos dos fármacos , Óxidos/toxicidade , Pneumonia/induzido quimicamente , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Técnicas de Cultura de Células , Linhagem Celular , Citocinas/análise , Relação Dose-Resposta a Droga , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Exposição por Inalação , Íons , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Pneumonia/imunologia , Pneumonia/patologia
15.
Biomed Pharmacother ; 119: 109390, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520916

RESUMO

Gubenfangxiao decoction (GBFXD) is a traditional Chinese medicine formula derived from Yupingfengsan, an ancient formula widely used to treat respiratory diseases. In recent years, GBFXD has been applied to efficaciously and safely treat asthma. However, the mechanism of GBFXD is still not fully elucidated. The aim of this study was to employ the label-free proteomic method to explore the protective mechanism of GBFXD in respiratory syncytial virus (RSV)-ovalbumin (OVA) induced chronic persistent asthmatic mice. After RSV-OVA challenge, mice were orally administered GBFXD at a dose of 36 g/kg accompanied with OVA nasal spray once every 3 days for 28 days. The label-free proteomics-based liquid chromatography-tandem mass spectrometry method was used to explore the differentially abundant proteins (DAPs) in the serum from model mice compared with that in control mice (M:C), and in GBFXD-treated mice compared with that in model mice (G:M). The mass spectrometry proteomics data have been deposited to the ProteomeXchange with identifier PXD013244. A total of 69 significant DAPs were identified including 39 in M:C, 46 in G:M, and 16 common differential proteins. Bioinformatics analysis revealed that the DAPs of M:C were mainly involved in inflammatory response and were related to lipid metabolism. However, the DAPs of G:M mostly participated in stress response, inflammatory response, and epithelial cell proliferation. Serum levels of Apoa-1, Apoc-1, Cfd, and Lrg1, EGFR and Lrg1 in the lungs were consistent with the results of proteomic analysis. Apoa-1 and Apoc-1 were closely related to cholesterol transport, lipid metabolism balance, and airway epithelial integrity; Cfd participated in immune response, affecting the occurrence and development of inflammation; EGFR and Lrg1 were involved in epithelial cell proliferation, influencing the process of airway remodeling. In summary, these results indicated that GBFXD may affect inflammatory and immune response of asthma by regulating cholesterol transport and complement factor activation. Furthermore, it could repair damaged airway epithelium and avoid airway remodeling to prevent and treat asthma.


Assuntos
Proteínas Sanguíneas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Proteômica , Animais , Asma/sangue , Asma/complicações , Doença Crônica , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Imunoglobulina E/sangue , Pulmão/patologia , Camundongos , Pneumonia/sangue , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Substâncias Protetoras/farmacologia , Mapas de Interação de Proteínas , Reprodutibilidade dos Testes , Coloração e Rotulagem
16.
Anim Sci J ; 90(11): 1475-1483, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515907

RESUMO

The aim of this study was to identify the prevalence of pathological lesions in pigs from small-scale farms and to determine associations between pathological lesions and hematological parameters, and carcass and meat quality in slaughtered pigs. The study was conducted on 625 pigs (~115 kg) originating from 20 small-scale farms. Any signs of pneumonia, pleurisy, pericarditis, and liver milk spots were recorded as present or absent. Complete blood count was investigated. The following carcass quality parameters were measured: live, hot and cold carcass weights, cooling loss, dressing percentage, backfat thickness, and meatiness. Meat pH and temperature were measured 45 min postmortem. Of the 625 examined pigs, 41.8% had pneumonia, 23.5% pleurisy, 2.7% pericarditis, and 29.9% liver milk spots. The presence of pathological lesions in slaughtered pigs adversely affected hematological parameters, reduced live, hot and cold carcass weights, and meatiness and had deleterious effects on meat quality (higher pH45min and higher prevalence of dark, firm and dry meat). In conclusion, this study showed a high prevalence of pathological lesions in slaughtered pigs, indicating serious health problems in smallholder pig production systems. The presence of single and, especially, multiple pathological lesions in slaughtered pigs negatively affected hematological parameters, and carcass and meat quality.


Assuntos
Matadouros/estatística & dados numéricos , Qualidade dos Alimentos , Hepatopatias/epidemiologia , Hepatopatias/veterinária , Pericardite/epidemiologia , Pericardite/veterinária , Pleurisia/epidemiologia , Pleurisia/veterinária , Pneumonia/epidemiologia , Pneumonia/veterinária , Doenças dos Suínos/epidemiologia , Animais , Fazendas/estatística & dados numéricos , Hepatopatias/patologia , Pericardite/patologia , Pneumonia/patologia , Prevalência , Suínos , Doenças dos Suínos/patologia
17.
BMJ Case Rep ; 12(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31519721

RESUMO

Antisynthetase syndrome is a rare autoimmune disease and represents a distinct entity within the idiopathic inflammatory myopathies. Its variable systemic manifestations are composed of myositis, interstitial lung disease, non-erosive arthritis, fever, Raynaud's phenomenon, hyperkeratotic skin changes and the presence of antibodies against aminoacyl-transfer-RNA-synthetases. Interstitial lung disease is the major determinant of morbidity and mortality. The role of lung biopsy remains controversial but it might be considered on an individual basis and may provide information regarding prognosis and treatment response. An integrated clinical, radiological and pathological approach to interstitial lung disease has to be emphasised. Due to the rarity of the disease, no standardised treatment guidelines for antisynthetase syndrome exist. We discuss a patient with anti-Jo1-autoantibody antisynthetase syndrome with proximal myositis and severe, rapid onset, interstitial lung disease with a histopathological pattern of organising pneumonia on surgical lung biopsy and good response to early combined immunosuppressive treatment with corticosteroids, mycophenolate mofetil and rituximab.


Assuntos
Terapia Combinada/métodos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Miosite/tratamento farmacológico , Pneumonia/patologia , Administração Intravenosa , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Aminoacil-tRNA Sintetases/imunologia , Autoanticorpos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Pessoa de Meia-Idade , Miosite/imunologia , Miosite/patologia , Pneumonia/etiologia , Rituximab/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento
18.
BMC Res Notes ; 12(1): 497, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405369

RESUMO

OBJECTIVE: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality. RESULTS: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.


Assuntos
Agranulocitose/induzido quimicamente , Alemtuzumab/efeitos adversos , Hemorragia Cerebral/induzido quimicamente , Fatores Imunológicos/efeitos adversos , Listeriose/induzido quimicamente , Insuficiência de Múltiplos Órgãos/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pneumonia/induzido quimicamente , Adulto , Agranulocitose/mortalidade , Agranulocitose/patologia , Alemtuzumab/administração & dosagem , Hemorragia Cerebral/mortalidade , Hemorragia Cerebral/patologia , Evolução Fatal , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Listeriose/microbiologia , Listeriose/mortalidade , Listeriose/patologia , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Pneumonia/microbiologia , Pneumonia/mortalidade , Pneumonia/patologia
19.
Life Sci ; 235: 116794, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31465731

RESUMO

Amongst the various forms of lung injury; pulmonary fibrosis remains the most intricate form with limited therapeutic options to both the patient and the physicians. Bleomycin (BLM) is a chemotherapeutic agent used for the treatment of various carcinomas; however, its therapeutic value is significantly limited by its associated pulmonary fibrosis. The current study highlights the prominent antioxidant, anti-inflammatory and anti-fibrotic effect of crocin against BLM-induced pulmonary fibrosis. Intratracheal BLM instillation induced significant biochemical, structural, functional and vascular pulmonary injury. BLM instillation increased oxidant load with quenching of antioxidant defenses together with increase inflammatory and fibrotic cytokines expression. Crocin significantly attenuated BLM-induced lung injury and its effect was comparable to the standard anti-fibrotic; halofuginone. The observed anti-inflammatory and anti-fibrotic and antioxidant impacts are thought to be embroiled in the therapeutic impacts of crocin. Down-regulation of TLR4, IL-10 expression is the major pathway involved in the observed anti-inflammatory effects and finally, down-regulation of tissue expression of TNF-α and TGF-ß1 is the major pathways implicated in the observed anti-fibrotic activities and modulation of Nrf2 and HO-1 pathways is the main mechanism involved in the observed antioxidant effects.


Assuntos
Bleomicina/toxicidade , Carotenoides/farmacologia , Pneumonia/prevenção & controle , Artéria Pulmonar/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/prevenção & controle , Animais , Antibióticos Antineoplásicos , Masculino , Pneumonia/induzido quimicamente , Pneumonia/patologia , Artéria Pulmonar/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/patologia
20.
Ecotoxicol Environ Saf ; 183: 109500, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31450033

RESUMO

Exposure to diesel engine exhaust (DEE) impairs lung function. But the underlying mechanisms are still not fully understood. The aim of this study was to investigate the effects of long-term DEE exposure on lung inflammation and the underlying mechanisms. Sprague-Dawley male rats were exposed to DEE with 3 mg/m3 of diesel exhaust particles (DEP) for 12 weeks. Then urine, blood, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for the determination of biochemistry indexes, DNA methylation status, and histological changes in the lung. The results showed that the metabolites of polycyclic aromatic hydrocarbons (PAHs) 2-hydroxyphenanthrene (2-OHPh) and 9-OHPh, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) level were higher in urine of DEE-exposed rats than control group. The level of proinflammatory cytokines IL-8, IL-6, and TNF-α was significantly higher in serum (1.8, 3.5, and nearly 1.0-fold increase, respectively), BALF (2.2, 3.8, and 2.0-fold increase, respectively) and lung tissues (3.5, 4.3, and 2.4-fold increase, respectively) of DEE-exposed rats than control group. While the level of clara cell secretory protein (CC16) and pulmonary surfactant protein D (SP-D) with anti-inflammatory property was obviously lower in serum (reduction of 29% and 38%, respectively), BALF (reduction of 50% and 46%, respectively) and lung tissues (reduction of 50% and 55%, respectively) of DEE-exposed rats than control group. Exposure to DEE also resulted in significant increases in total white blood cell (WBC), neutrophil, eosinophil, and lymphocyte number in BALF. Airway inflammation and remolding were apparent in DEE group. The methylation level of CCAAT/enhancer-binding protein alpha (C/EBPα) promoter was markedly increased (about 3.2-fold increase), and its mRNA and protein expression were significantly decreased (about 62% and 68% decrease, respectively) in the lungs of DEE-exposed rats compared with the group. Further, cell experiments were performed to investigate the relationship between C/EBPα and CC16, and CC16 function under DEP conditions. The results showed that DEP inhibited CC16 expression via methylation of C/EBPα promoter, and the increase of CC16 level significantly relieved the proinflammatory effects caused by DEP exposure. In conclusion, our data indicated that long-term exposure to DEE can cause lung inflammation, at least in part via methylation of C/EBPα promoter, and inhibition of CC16 expression.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/genética , Exposição por Inalação/efeitos adversos , Pneumonia/induzido quimicamente , Emissões de Veículos/toxicidade , Animais , Citocinas/metabolismo , Metilação de DNA/efeitos dos fármacos , Masculino , Pneumonia/metabolismo , Pneumonia/patologia , Hidrocarbonetos Policíclicos Aromáticos/urina , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Uteroglobina/genética , Uteroglobina/metabolismo
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