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1.
Medicine (Baltimore) ; 98(48): e18131, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770246

RESUMO

Anaplastic lymphoma kinase (ALK) inhibitor-related pneumonitis (ALK-IIP) is relatively rare but sometimes fatal, so the timely diagnosis of ALK-IIP is important for enabling prompt management. However, the detailed radiologic characteristics and clinical course of ALK-IIP are still unclear. This study was performed to investigate the clinical and radiologic characteristics and risk factors of ALK-IIP in patients with non-small cell lung cancer (NSCLC).A total of 250 NSCLC patients who had been treated with ALK inhibitors were retrospectively enrolled. Chest computed tomography (CT) was classified into 4 CT patterns using the 2013 guideline for idiopathic interstitial pneumonia: cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis (HP), acute interstitial pneumonia (AIP), and nonspecific interstitial pneumonia. Clinical characteristics including toxicity grading and treatment course were analyzed in regarding to CT patterns. Clinical characteristics were compared between patients with ALK-IIP and without ALK-IIP.ALK-IIP was identified in 11 patients (4.4%). The most common CT pattern was the COP pattern (n = 7, 63.6%) and followed by HP and AIP patterns (both, n = 2, 18.2%). ALK-IIP showed pneumonitis toxicity grade ranged from 1 to 4, and AIP pattern had the highest toxicity grade, followed by HP and COP patterns (median grade: 3.5, 2.5, 1). All of the patients with the COP pattern were successfully treated, while half of patients with the AIP pattern died during treatment. The smoking history and extrathoracic metastasis were more frequent in patients with ALK-IIP (P < .005). The smoking history was associated with a higher incidence of ALK-IIP (odds ratio: 3.586, 95% confidence interval: 1.058-13.432, P = .049).ALK-IIP showed a spectrum of chest CT patterns, which reflected the toxicity grades. The COP pattern was the most common CT pattern of ALK-IIP, and patients with ALK-IIP of the COP pattern were successfully treated. ALK inhibitors should be used with caution in NSCLC patients with smoking history.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/diagnóstico por imagem , Inibidores de Proteínas Quinases/efeitos adversos , Tomografia Computadorizada por Raios X , Adulto , Idoso , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/induzido quimicamente , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Estudos Retrospectivos , Fatores de Risco
2.
Toxicol Lett ; 317: 59-67, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577921

RESUMO

Toluene-diisocyanate (TDI) is mainly used in the manufacturing process of polyurethane foams, and is a potent inducer of occupational asthma characterized by airway inflammation and airway hyperreactivity. Thymic stromal lymphopoietin (TSLP) plays an important role in the development of asthma, and correlating with the differentiation of Th2 and Th17 cells. However, the role of TSLP in TDI-induced asthma remains unclear. In this study, 96 TDI-exposed workers as well as a mouse model of TDI-induced asthma were investigated. The air exposure assessment result of TDI in the workplace showed that workers were exposed to inhalation of a very high concentration of TDI, approximately 8 times the recommended level, leading to a decrease in pulmonary function and an increase in inflammatory cells, as well as TSLP and IgE levels in the supernatant of sputum obtained from exposed workers. In order to further investigate the role of TSLP in the pathogenesis of TDI-induced asthma, a mouse model of TDI-induced asthma was also employed. Histopathological analysis of mouse lung and bronchus showed an obvious infiltration of inflammatory cells around the bronchus. The levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in bronchoalveolar lavage fluid (BALF), the expression levels of TSLP protein and ROR-γt and IL-17 mRNA in mouse lung tissues were also significantly increased. However, after treatment with TSLP neutralizing antibody (TSLP-Ab), the degree of pulmonary and bronchial inflammation in mice was significantly alleviated, and the levels of inflammatory cells, IFN-γ, IL-4 and IL-17 in BALF, and the expression levels of ROR-γt and IL-17 mRNA in lung tissue were significantly decreased. Our data shows that TSLP plays an important role in the pathogenesis of TDI-induced asthma, and that TSLP-Ab can effectively alleviate TDI-induced airway inflammation of asthma.


Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos Neutralizantes/farmacologia , Asma/prevenção & controle , Citocinas/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pneumonia/prevenção & controle , Tolueno 2,4-Di-Isocianato/efeitos adversos , Adulto , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunoglobulina E/imunologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Exposição por Inalação/efeitos adversos , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Intern Med ; 58(20): 3019-3023, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611510

RESUMO

A 54-year-old man started to take oren-gedoku-to (coptis detoxifying decoction) because he was experiencing chronic hot flashes, night sweats and insomnia. He developed a high fever from the day of intake. At day 17, he stopped taking oren-gedoku-to because of malaise and chills, and he was admitted to our hospital. Drug-induced pneumonitis was suspected, and all drugs were stopped. Consequently, his symptoms, laboratory data and chest X-ray findings markedly improved. The results of a lymphocyte stimulation test were positive for oren-gedoku-to and one of its components, ougon (Baikal skullcap). Based on these findings, we diagnosed him with pneumonitis caused by ougon.


Assuntos
Medicamentos de Ervas Chinesas/efeitos adversos , Pneumonia/induzido quimicamente , Coptis , Humanos , Masculino , Pessoa de Meia-Idade
4.
Pneumologie ; 73(10): 582-585, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31499560

RESUMO

A 35-year-old male patient presented to the emergency department with complains of fever, dyspnea and petechiae. The chest X-ray revealed signs of bipulmonary infiltration. 5 days ago, an illicit silicone injection was performed into the penis for cosmetic reasons. Due to progressive respiratory failure the patient required mechanical ventilation. Bronchoalveolar lavage revealed diffuse alveolar hemorrhage. Silicone pneumonitis with a severe acute respiratory failure based on silicone embolization syndrome was diagnosed. Prone positioning, lung-protective ventilation and corticosteroid therapy were initiated. The patient was discharged from ICU after 19 days. In an outpatient follow up, lung function was fully recovered. CONCLUSION: Silicone pneumonitis should be considered in case of fever, respiratory distress and alveolar hemorrhage linked to cosmetic procedures. High dose corticosteroid therapy and lung-protective ventilation strategies may help for complete recovery of lung function.


Assuntos
Pneumonia/induzido quimicamente , Insuficiência Respiratória/induzido quimicamente , Silicones/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Lavagem Broncoalveolar , Humanos , Masculino , Pneumonia/tratamento farmacológico , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto , Insuficiência Respiratória/terapia , Silicones/administração & dosagem , Resultado do Tratamento
5.
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
6.
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
7.
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
8.
Mediators Inflamm ; 2019: 3427053, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379467

RESUMO

Occupational exposure to crystalline silica (CS) results in a persistent pulmonary inflammatory response that eventually leads to abnormal tissue repair, disability, and death. The inflammatory-immune responses occur in the early stages of CS exposure, and both innate and adaptive immunity are involved. CD4+ T cells play a pivotal role in the pathogenesis of CS-induced pulmonary disease, which has no proven curative therapy. Dihydrotanshinone I (DHI), a natural product isolated from Salvia miltiorrhiza Bunge (Danshen), has anti-inflammatory and immunomodulatory properties. However, whether DHI has a protective effect on CS-induced lung disease, how it influences the Th immune response, and the potential underlying molecular mechanism(s) have not been fully clarified. In this study, DHI treatment of CS-exposed mice reduced the expression of proinflammatory cytokines and the infiltration of immune cells. It significantly ameliorated CS-induced pulmonary inflammation by attenuating T helper (Th)1 and Th17 responses, which were tightly related to the inhibition of STAT1 and STAT3. DHI significantly altered Th2 cytokines but not the Th2 nuclear transcription factor. Furthermore, our study found that DHI treatment also affected regulatory T cell activity in CS-injured mice. Taken together, our findings indicated that DHI could modulate Th responses and alleviate CS-induced pulmonary inflammation, suggesting a novel application of DHI in CS-induced pulmonary disease.


Assuntos
Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Dióxido de Silício/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Feminino , Citometria de Fluxo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/metabolismo
9.
Environ Res ; 177: 108661, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442789

RESUMO

BACKGROUND: Ethanol vehicles release exhaust gases that contribute to the formation of secondary organic aerosols (SOA). OBJECTIVE: To determine in vivo toxicity resulting from exposure to SOA derived from vehicles using different ethanol-gasoline blends (E0, E10, E22, E85W, E85S, E100). METHODS: Exhaust emissions from vehicles using ethanol blends were delivered to a photochemical chamber and reacted to produce SOA. The aerosol samples were collected on filters, extracted, and dispersed in an aqueous solutions and intratracheally instilled into Sprague Dawley rats in doses of 700 µg/0.2 ml. After 45 min and 4 h pulmonary and cardiac chemiluminescence (CL) was measured to estimate the amount of reactive oxygen species (ROS) produced in the lungs and heart. Inflammation was measured by differential cell count in bronchoalveolar lavages (BAL). RESULTS: Statistically and biologically significant differences in response to secondary particles from the different fuel formulations were detected. Compared to the control group, animals exposed to SOA from gasoline (E0) showed a significantly higher average CL in the lungs at 45 min. The highest CL averages in the heart were observed in the groups exposed to SOA from E10 and pure ethanol (E100) at 45 min. BAL of animals exposed to SOA from E0 and E85S had a significant increased number of macrophages at 45 min. BAL neutrophil count was increased in the groups exposed to E85S (45 min) and E0 (4 h). Animals exposed to E0 and E85W had increased BAL lymphocyte count compared to the control and the other exposed groups. DISCUSSION: Our results suggest that SOA generated by gasoline (E0), followed by ethanol blends E85S and E85W, substantially induce oxidative stress measured by ROS generation and pulmonary inflammation measured by the recruitment of white blood cells in BAL.


Assuntos
Poluentes Atmosféricos/toxicidade , Pneumonia/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Emissões de Veículos/toxicidade , Animais , Etanol , Gasolina , Coração/efeitos dos fármacos , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Macrófagos/citologia , Neutrófilos/citologia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
10.
Ecotoxicol Environ Saf ; 182: 109425, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31295660

RESUMO

BACKGROUND: Inhalation of fine particulate matter (PM2.5) induces the occurrence of lung inflammation and fibrosis, but its molecular mechanism remains unclear. Resveratrol (RES) is known to have anti-inflammatory properties in many pulmonary diseases. Here, we aimed to investigate the effect of long-term "real-world" ambient PM exposure on lung inflammation and fibrosis and further explore the protective effect and mechanism of RES. METHODS AND RESULTS: RES (50 and 100 mg/kg.bw) was administered to C57BL/6J mice that were exposed to ambient PM for 5 months. The control group breathed filtered air without RES, and the PM group was exposed to PM without RES. The inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and lung fibrosis were evaluated by enzyme-linked immune sorbent assay (ELISA) kits and Masson's trichrome staining. The real-time PCR and Western blot analysis were used to determine the signal pathway. In vivo, PM exposure markedly elevated the levels of inflammatory cytokines and TGF-ß1 in BALF, induced lung fibrosis. Meanwhile, PM exposure triggered autophagy process and activated the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in lung. Also, RES treatment abolished PM-induced lung inflammation and fibrosis, and inhibited autophagic process and NLRP3 inflammasome activation. In vitro, PM2.5-induced cytotoxicity in BEAS-2B cells dose-dependently. Besides, RES alleviated PM2.5-induced cytotoxicity, inhibited autophagic process and NLRP3 inflammasome activity and decreased IL-1ß production in BEAS-2B cells. CONCLUSION: Long-term PM exposure induced lung inflammation and fibrosis, and RES intervention alleviated these adverse effects via inhibiting autophagy-related NLRP3 inflammasome activation.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose/tratamento farmacológico , Material Particulado/toxicidade , Pneumonia/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Citocinas/metabolismo , Inibidores Enzimáticos/uso terapêutico , Inflamassomos/metabolismo , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/induzido quimicamente , Proteínas , Fibrose Pulmonar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1
11.
Environ Pollut ; 253: 507-515, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31330343

RESUMO

Black carbon (BC) can combine with organic matter and form secondary pollutants known as aged BC. BC and aged BC can cause respiratory system inflammation and induce lesions at relevant sites, but the underlying mechanism has remained unknown. To gain insight into the potential mechanisms, we focused on macrophages and transforming growth factor ß-activated kinase 1 (TAK1) which are a crucial factor in inflammation. Our research aims to determine the role of TAK1 in macrophages in pulmonary inflammation induced by particulate matter. In this study, BC and 1,4-naphthoquinone were mixed to model aged BC (1,4NQ-BC) in atmosphere. BC induced mice lung inflammation model, lung macrophage knock-down TAK1 animal model and primary macrophage knock-down TAK1 model were used to explore whether TAK1 in macrophage is a critical role in the process of inflammation. The results showed that the expressions of inflammatory cytokines (IL-1ß, IL-6, IL-33) mRNA were significantly increased and the phosphorylation of MAPK and NF-κB signaling pathway related proteins were enhanced in RAW 264.7 cell lines. In vivo studies revealed that the indicators of pulmonary inflammation (pathology, inflammatory cell numbers) and related cytokines (IL-1ß, IL-6, IL-33) mRNA expressions in CD11c-Map3k7-/- animals were significantly lower than wild-type animals after mice were instilled particles. In mice primary macrophages, the expressions of IL-6, IL-33 mRNA were inhibited after TAK1 gene was knock-down. These results unequivocally demonstrated that TAK1 plays a crucial role in BC induced lung inflammation in mice, and we can infer that BC and 1,4NQ-BC cause these inflammatory responses by stimulating pulmonary macrophages.


Assuntos
Poluentes Atmosféricos/toxicidade , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Pneumonia/induzido quimicamente , Fuligem/toxicidade , Animais , Carbono/metabolismo , Citocinas/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Interleucina-1beta/metabolismo , Interleucina-33/metabolismo , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosforilação , Pneumonia/metabolismo , Células RAW 264.7
12.
Drug Discov Ther ; 13(3): 164-167, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31257354

RESUMO

Immune checkpoint inhibitors are associated with a wide spectrum of immune-related adverse events (irAEs) that are typically transient but are sometimes severe or even fatal. No consensus exists for the treatment of severe immune-mediated pneumonitis that is refractory to corticosteroids. Here, we report an autopsy case of pembrolizumab-induced pneumonitis that was transiently improved using infliximab. A 67-year-old male with advanced lung adenocarcinoma developed pneumonitis two weeks after a single dose of first-line pembrolizumab. The pneumonitis was refractory to corticosteroids, and the patient required mechanical ventilation. Addition of a single dose of infliximab rapidly improved the respiratory status and chest CT showed resolution of ground-glass opacities in the right upper and middle lobes. However, the patient died from re-exacerbation of pneumonitis 17 days after infliximab administration. The autopsy confirmed organizing phase diffuse alveolar damage in the right lower lobe, while the right upper lobe remained almost intact consistent with the CT findings, which is suggestive of the therapeutic effect of infliximab. The half-life of infliximab is 7-12 days, and a second dose of infliximab two weeks after the first dose is sometimes required for the treatment of gastrointestinal toxicity induced by anti-CTLA4 antibodies. Although the current guidelines do not recommend repeated administration of infliximab for immune-mediated pneumonitis, the present case suggests that repeated infliximab therapy may be beneficial in the treatment of immune-mediated pneumonitis.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Infliximab/administração & dosagem , Pneumonia/tratamento farmacológico , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Autopsia , Evolução Fatal , Humanos , Infliximab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
13.
Rev Bras Enferm ; 72(3): 760-766, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31269143

RESUMO

OBJECTIVE: To evaluate the risk factors related to Klebsiella pneumoniae carbapenemase infection after renal transplantation. METHODS: This was a retrospective epidemiological (case-control) study, conducted from October 2011 to march 2016. Transplanted patients with infection by this bacteria during hospitalization were selected as cases. The controls were paired by age, sex, type of donor and transplant time. The proportion of cases and controls was 1:2. RESULTS: Thirty hundred and five patients were included in the study (45 cases and 90 controls). The risk factors found for infection by KPC were: time of hospitalization after the transplant (OR: 4.82; CI95% 2.46-9.44), delayed kidney function (OR: 5.60; CI95% 1.91-11.01) and previous infectious for another microorganism ( OR: 34.13 CI95% 3.52-132.00). CONCLUSION: The risk of acquisition of this bacterium was directly related to invasive procedures and exposure to the hospital environment. The findings reinforce the importance of prevention measures and control of infection by this microorganism.


Assuntos
Proteínas de Bactérias/efeitos adversos , Transplante de Rim/efeitos adversos , Infecções por Klebsiella/etiologia , Pneumonia/etiologia , beta-Lactamases/efeitos adversos , Adulto , Proteínas de Bactérias/metabolismo , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Transplante de Rim/métodos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/metabolismo , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/patogenicidade , Masculino , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , beta-Lactamases/metabolismo
14.
Clin Nucl Med ; 44(10): 806-807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306191

RESUMO

A 49-year-old patient with metastatic melanoma was treated with nivolumab (Opdivo). An early F-FDG PET/CT after 2 cycles showed a progressive metabolic disease. A 4-month optimal follow-up F-FDG PET/CT showed a complete metabolic response. The treatment was stopped after 22 cycles because of immunotherapy-related pneumonitis. After discontinuation of treatment, PET/CT examinations demonstrated a metabolic complete remission during 2 years. The metabolic pattern on early PET was suggestive of pseudoprogression, which is a rare phenomenon reflecting an activation of inflammatory cells within the tumor microenvironment causing lesions to increase in size and to accumulate FDG until a sufficient immune response is developed.


Assuntos
Fluordesoxiglucose F18 , Melanoma/tratamento farmacológico , Melanoma/patologia , Nivolumabe/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Feminino , Humanos , Melanoma/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico
15.
Mol Immunol ; 112: 163-174, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31153046

RESUMO

Exposure to airborne particulate matter (PM) not only causes lung inflammation and chronic respiratory diseases, but also increases the incidence and mortality of cardiopulmonary diseases. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation has been shown to play a critical role in the formation of many chronic disorders. On the other hand, carbon monoxide (CO) has been shown to possess anti-inflammatory and antioxidant effects in many tissues and organs. Here, we investigated the effects and mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that PM induced C-reactive protein (CRP) expression, NLRP3 inflammasome activation, IL-1ß secretion, and caspase-1 activation, which were inhibited by pretreatment with CORM-2. In addition, transfection with siRNA of Toll-like receptor 2 (TLR2) or TLR4 and pretreatment with an antioxidant (N-acetyl-cysteine, NAC), the inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or a mitochondria-specific superoxide scavenger (MitoTEMPO) reduced PM-induced inflammatory responses. CORM-2 also inhibited PM-induced NADPH oxidase activity and NADPH oxidase- and mitochondria-derived ROS generation. However, pretreatment with inactivate CORM-2 (iCORM-2) had no effects on PM-induced inflammatory responses. Finally, we showed that CORM-2 inhibited PM-induced CRP, NLRP3 inflammasome, and ASC protein expression in the lung tissues of mice and IL-1ß levels in the serum of mice. PM-enhanced leukocyte count in bronchoalveolar lavage fluid in mice was reduced by CORM-2. The results of this study suggested a protective role of CORM-2 in PM-induced lung inflammation by inhibiting the TLR2 and TLR4/ROS-NLRP3 inflammasome-CRP axial.


Assuntos
Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organometálicos/farmacologia , Pneumonia/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Monóxido de Carbono/efeitos adversos , Caspase 1/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Material Particulado/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos
16.
J Chemother ; 31(5): 290-293, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215358

RESUMO

Streptococcus pneumoniae is the main pathogen in invasive, life-threatening diseases such as bacteremia, meningitis, and pneumonia. We describe three cases of breakthrough pneumococcal severe life-threatening infections, including two meningitis and one bloodstream infection in patients treated with cefixime for otitis, sinusitis and pneumonia, respectively. Cefixime does not seem to be fully effective in treating invasive pneumococcal diseases. Because penicillin non-susceptibility might be linked to cefixime failure, the prompt knowledge of susceptibility to penicillin in S. pneumoniae might be very useful. Furthermore, MIC of cefixime should be measured because values >0.5 mg/L might be related to failure.


Assuntos
Bacteriemia/epidemiologia , Cefixima/efeitos adversos , Meningite/epidemiologia , Infecções Pneumocócicas/tratamento farmacológico , Pneumonia/epidemiologia , Streptococcus pneumoniae/efeitos dos fármacos , Adolescente , Adulto , Antibacterianos/efeitos adversos , Bacteriemia/induzido quimicamente , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Meningite/induzido quimicamente , Infecções Pneumocócicas/microbiologia , Pneumonia/induzido quimicamente , Prognóstico , Adulto Jovem
17.
EBioMedicine ; 45: 553-562, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31204278

RESUMO

BACKGROUND: The Single immunoglobin interleukin-1 (IL-1)-related receptor (Sigirr), also known as IL-1R8, has been shown to exhibit broad anti-inflammatory effects against inflammatory diseases including acute lung injury, while molecular regulation of IL-1R8/Sigirr protein stability has not been reported. This study is designed to determine whether stabilization of IL-1R8/Sigirr by a deubiquitinating enzyme (DUB) is sufficient to suppress inflammatory responses and lessen lung inflammation. METHODS: A molecular signature of ubiquitination and degradation of IL-1R8/Sigirr was determined using a receptor ligation chase model. The anti-inflammatory effects on USP13 were investigated. USP13 knockout mice were evaluated for stabilization of IL-1R8/Sigirr and disease phenotype in an acute lung injury model. FINDINGS: IL-1R8/Sigirr degradation is mediated by the ubiquitin-proteasome system, through site-specific ubiquitination. This effect was antagonized by the DUB USP13. USP13 levels correlate directly with IL-1R8/Sigirr, and both proteins were reduced in cells and tissue from mice subjected to inflammatory injury by the TLR4 agonist lipopolysaccharide (LPS). Knockdown of USP13 in cells increased IL-1R8/Sigirr poly-ubiquitination and reduced its stability, which enhanced LPS-induced TLR4 signaling and cytokine release. Likewise, USP13-deficient mice were highly susceptible to LPS or Pseudomonas aeruginosa models of inflammatory lung injury. IL-1R8/Sigirr overexpression in cells or by pulmonary viral transduction attenuated the inflammatory phenotype conferred by the USP13-/- genotype. INTERPRETATION: Stabilization of IL-1R8/Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation. FUND: This study was supported by the US National Institutes of Health (R01HL131665, HL136294 to Y.Z., R01 GM115389 to J.Z.).


Assuntos
Endopeptidases/genética , Pneumopatias/genética , Pneumonia/genética , Receptores de Interleucina-1/genética , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos/uso terapêutico , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Camundongos , Camundongos Knockout , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia/terapia , Estabilidade Proteica , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética
18.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067702

RESUMO

PM2.5 is particulate matter with a diameter of 2.5 µm or less. Airway macrophages are the key players regulating PM2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1ß, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Interleucina-10/genética , Pneumonia/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Arginase/genética , Biomarcadores , Polaridade Celular/efeitos dos fármacos , Citocinas/genética , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Peso Molecular , Material Particulado/efeitos adversos , Fosforilação/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/patologia , Ratos
19.
Sci Total Environ ; 677: 524-529, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31063895

RESUMO

Epidemiological evidence has shown that air pollution is associated with chronic obstructive pulmonary disease (COPD). The objective of this study was to investigate the effects of air pollution on patients with COPD and pneumonia. A case-control study of patients who had undergone thoracentesis for pleural effusion drainage in a hospital was recruited for this study. COPD and non-COPD patients with pneumonia respectively served as the case and control groups. Increases in particulate matter of <2.5 µm in aerodynamic diameter (PM2.5) and NO2 increased the risk of pneumonia in COPD patients (adjusted odd ratio (OR) = 4.136, 95% confidence interval (CI) = 1.740-9.832 for PM2.5; adjusted OR = 1.841, 95% CI = 1.117-3.036 for NO2). COPD patients with pneumonia had higher levels of CD14 in pleural effusion than did non-COPD with pneumonia (p < 0.05). An increase in CD14 of the pleural effusion increased the risk of pneumonia in COPD patients (adjusted OR = 1.126, 95% CI = 1.009-1.256). We further observed that an increase in Cu and a decrease in Zn in the pleural effusion increased the risk of pneumonia in COPD patients (adjusted OR = 1.005, 95% CI = 1.000-1.010 for Cu; adjusted OR = 0.988, 95% CI = 0.978-0.997 for Zn). In conclusion, our results suggest that COPD patients had a high risk of pneumonia occurring due to air pollution exposure.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental , Pneumonia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Material Particulado/efeitos adversos , Pneumonia/induzido quimicamente , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
20.
Tuberculosis (Edinb) ; 116S: S118-S122, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31072690

RESUMO

Mycobacterium tuberculosis (MTB) is a pathogen that infects and kills millions yearly. The mycobacterium's cell wall glycolipid trehalose 6,6'-dimycolate (TDM) has been used historically to model MTB induced inflammation and granuloma formation. Alterations to the model can significantly influence the induced pathology. One such method incorporates intraperitoneal pre-exposure, after which the intravenous injection of TDM generates pathological damage effectively mimicking the hypercoagulation, thrombus formation, and tissue remodeling apparent in lungs of infected individuals. The purpose of these experiments is to examine the histological inflammation involved in the TDM mouse model that induces development of the hemorrhagic response. TDM induced lungs of C57BL/6 mice to undergo granulomatous inflammation. Further histological examination of the peak response demonstrated tissue remodeling consistent with hypercoagulation. The observed vascular occlusion indicates that obstruction likely occurs due to subendothelial localized activity leading to restriction of blood vessel lumens. Trichrome staining revealed that associated damage in the hypercoagulation model is consistent with intra endothelial cell accumulation of innate cells, bordered by collagen deposition in the underlying parenchyma. Overall, the hypercoagulation model represents a comparative pathological instrument for understanding mechanisms underlying development of hemorrhage and vascular occlusion seen during MTB infection.


Assuntos
Fatores Corda/metabolismo , Endotélio Vascular/patologia , Granuloma do Sistema Respiratório/patologia , Pulmão/irrigação sanguínea , Mycobacterium tuberculosis/metabolismo , Pneumonia/patologia , Tuberculose Pulmonar/patologia , Animais , Coagulação Sanguínea , Modelos Animais de Doenças , Endotélio Vascular/microbiologia , Feminino , Granuloma do Sistema Respiratório/sangue , Granuloma do Sistema Respiratório/induzido quimicamente , Granuloma do Sistema Respiratório/microbiologia , Pulmão/microbiologia , Camundongos Endogâmicos C57BL , Pneumonia/sangue , Pneumonia/induzido quimicamente , Pneumonia/microbiologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/induzido quimicamente , Tuberculose Pulmonar/microbiologia , Remodelação Vascular
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