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1.
BMJ Open ; 12(4): e060771, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35450917

RESUMO

OBJECTIVE: To evaluate the association between use of proton pump inhibitors (PPIs) and risk of pneumonia in children. DESIGN: Nationwide register-based self-controlled case series study. SETTING: Sweden, July 2006 to December 2016. PARTICIPANTS: Children aged <18 years who were treated with PPIs and had a hospitalisation or hospital emergency care visit for pneumonia within 1 year before and 2 years after PPI initiation. MAIN OUTCOMES AND MEASURES: The primary analysis examined the risk of pneumonia during the risk period (ongoing PPI treatment), the pre-exposure period (≤30 days preceding PPI treatment) and the postexposure period (days 1-365 after PPI discontinuation), comparing to the unexposed period. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% CIs. RESULTS: A total of 2356 cases of pneumonia were included. Compared with the unexposed period, the risk of pneumonia was significantly increased during ongoing PPI treatment, with an adjusted IRR of 1.40 (95% CI 1.21 to 1.62). The risk of pneumonia was also increased in the pre-exposure period (adjusted IRR, 1.80, 95% CI 1.51 to 2.13), but not in the postexposure period (adjusted IRR 0.98, 95% CI 0.89 to 1.08). Dividing the risk period by time since treatment initiation, the increased risk of pneumonia was highest in the first 30 days (adjusted IRR 1.63, 95% CI 1.35 to 1.97), remained during days 31-90 (adjusted IRR 1.32, 95% CI 1.04 to 1.69), but waned in days ≥91 (IRR 1.06, 95% CI 0.79 to 1.41). CONCLUSIONS AND RELEVANCE: An increased risk of pneumonia was observed both immediately before and immediately after PPI initiation. This pattern of association can likely be explained by an underlying risk of pneumonia due to factors transiently present at the time around PPI initiation. Thus, our findings do not support a causal relationship between PPI use and risk of pneumonia.


Assuntos
Pneumonia , Inibidores da Bomba de Prótons , Estudos de Casos e Controles , Criança , Humanos , Pneumonia/induzido quimicamente , Pneumonia/epidemiologia , Inibidores da Bomba de Prótons/efeitos adversos , Fatores de Risco , Suécia/epidemiologia
2.
Front Immunol ; 13: 874459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464414

RESUMO

Silica is an essential substrate of various materials, and inhaling silica induces pulmonary diseases potentially associated with macrophage pyroptosis. Utilizing silica of micro- and nano- sizes, we explored the role of macrophage pyroptosis in silica-induced pulmonary inflammation. Under the transmission electron microscopy, we found that the internalization of silica nanoparticle induced membrane rupture and increased the number of intracellular vacuoles, and both sizes of silica could suppress cell viability and proliferation. Also, silica-exposed macrophages generated higher levels of ROS, together with the upregulated expression of NLRP3, ASC, Caspase-1, GSDMD, IL-1ß, and IL-6. However, the expression of these proteins was suppressed after removing ROS or NLRP3. In addition, we found increased expression of TLR4 and NF-κB responsible for silica recognition and pyroptosis priming after silica exposure. For in vivo studies, we established animal model by intratracheally instilling 5 mg of silica into mice with/without NLRP3 inhibition. Four weeks later, we found diffused infiltration of inflammatory cells and enhanced collagen hyperplasia partially reversed by additional treatment with MCC950, so as the expression of pyroptotic molecules and proinflammatory cytokines. In particular, the dual immunofluorescent staining showed co-expression of macrophage-specific biomarker F4/80 and NLRP3 within the cells, and silica of nano-size showed more potent toxicity and pathogenicity than that of the micro-sized particles both in vitro and in vivo. To sum up, macrophage pyroptosis is an upstream event of silica-induced pulmonary inflammation promoted by ROS through the TLR4/NLRP3/NF-κB signaling axis.


Assuntos
Pneumonia , Piroptose , Animais , Inflamassomos/metabolismo , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/metabolismo , Dióxido de Silício/toxicidade , Receptor 4 Toll-Like/metabolismo
3.
Front Immunol ; 13: 830631, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464480

RESUMO

Immune checkpointty inhibitors (ICIs), particularly those targeting programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), enhance the antitumor effect by restoring the function of the inhibited effector T cells and produce durable responses in a large variety of metastatic and late patients with non-small-cell lung cancer. Although often well tolerated, the activation of the immune system results in side effects known as immune-related adverse events (irAEs), which can affect multiple organ systems, including the lungs. The occurrence of severe pulmonary irAEs, especially checkpoint inhibitor pneumonitis (CIP), is rare but has extremely high mortality and often overlaps with the respiratory symptoms and imaging of primary tumors. The development of CIP may be accompanied by radiation pneumonia and infectious pneumonia, leading to the simultaneous occurrence of a mixture of several types of inflammation in the lungs. However, there is a lack of authoritative diagnosis, grading criteria and clarified mechanisms of CIP. In this article, we review the incidence and median time to onset of CIP in patients with non-small-cell lung cancer treated with PD-1/PD-L1 blockade in clinical studies. We also summarize the clinical features, potential mechanisms, management and predictive biomarkers of CIP caused by PD-1/PD-L1 blockade in non-small-cell lung cancer treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Antígeno B7-H1 , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/patologia , Pneumonia/induzido quimicamente , Pneumonia/etiologia , Receptor de Morte Celular Programada 1
4.
Artigo em Inglês | MEDLINE | ID: mdl-35381532

RESUMO

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour post-injection, rats received nebulized treatments consisting of egg lecithin emulsified O3, Budesonide and Montelukast, and blends of O3 and Melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n = 3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-ß, and IL-10 were attenuated in all O3FA groups. IL-1ß was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress such as COVID-19.


Assuntos
COVID-19 , Ácidos Graxos Ômega-3 , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Animais , COVID-19/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Lipopolissacarídeos , Masculino , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Ratos , Ratos Wistar
5.
Soins Gerontol ; 27(154): 43-45, 2022.
Artigo em Francês | MEDLINE | ID: mdl-35393035

RESUMO

The prescription of lubricating laxatives (paraffin oil) is widespread in geriatrics because of the frequency of constipation. These molecules can cause serious adverse effects such as lipoid pneumonia, especially in subjects with swallowing disorders.


Assuntos
Laxantes , Pneumonia , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Humanos , Laxantes/efeitos adversos , Lipídeos/uso terapêutico , Óleo Mineral/efeitos adversos , Pneumonia/induzido quimicamente
6.
Artigo em Inglês | MEDLINE | ID: mdl-35457683

RESUMO

The Chinese community-acquired pneumonia (CAP) Diagnosis and Treatment Guideline 2020 recommends quinolone antibiotics as the initial empirical treatment options for CAP. However, patients with pulmonary tuberculosis (PTB) are often misdiagnosed with CAP because of the similarity of symptoms. Moxifloxacin and levofloxacin have inhibitory effects on mycobacterium tuberculosis as compared with nemonoxacin, resulting in delayed diagnosis of PTB. Hence, the aim of this study is to compare the cost-effectiveness of nemonoxacin, moxifloxacin and levofloxacin in the treatment of CAP and to determine the value of these treatments in the differential diagnosis of PTB. Primary efficacy data were collected from phase II-III randomized, double-blind, multi-center clinical trials comparing nemonoxacin to moxifloxacin (CTR20130195) and nemonoxacin to levofloxacin (CTR20140439) for the treatment of Chinese CAP patients. A decision tree was constructed to compare the cost-utility among three groups under the perspective of healthcare system. The threshold for willingness to pay (WTP) is 1-3 times GDP per capita ($11,174-33,521). Scenarios including efficacy and cost for CAP patients with a total of 6% undifferentiated PTB. Sensitivity and scenario analyses were performed to test the robustness of basic analysis. The costs of nemonoxacin, moxifloxacin, and levofloxacin were $903.72, $1053.59, and $1212.06 and the outcomes were 188.7, 188.8, and 188.5 quality-adjusted life days (QALD), respectively. Nemonoxacin and moxifloxacin were dominant compared with levofloxacin, and the ICER of moxifloxacin compared with nemonoxacin was $551,643, which was much greater than WTP; therefore, nemonoxacin was the most cost-effective option. Regarding patients with PTB who were misdiagnosed with CAP, taking nemonoxacin could save $290.76 and $205.51 when compared with moxifloxacin and levofloxacin and resulted in a gain of 2.83 QALDs. Our findings demonstrate that nemonoxacin is the more economical compared with moxifloxacin and levofloxacin, and non-fluoroquinolone antibiotics are cost-saving and utility-increasing compared to fluoroquinolones in the differential diagnosis of PTB, which can help healthcare system in making optimal policies and help clinicians in the medication of patients.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Quinolonas , Tuberculose Pulmonar , Antibacterianos/uso terapêutico , Infecções Comunitárias Adquiridas/tratamento farmacológico , Análise Custo-Benefício , Fluoroquinolonas/uso terapêutico , Humanos , Levofloxacino/uso terapêutico , Moxifloxacina/uso terapêutico , Pneumonia/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Tuberculose Pulmonar/tratamento farmacológico
7.
Toxins (Basel) ; 14(4)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35448876

RESUMO

Glucocorticoid-resistant asthma, which predominates with neutrophils instead of eosinophils, is an increasing health concern. One potential source for the induction of neutrophil-predominant asthma is aerosolized lipopolysaccharide (LPS). Cyanobacteria have recently caused significant tidal blooms, and aerosolized cyanobacterial LPS has been detected near the cyanobacterial overgrowth. We hypothesized that cyanobacterial LPS contributes to lung inflammation by increasing factors that promote lung inflammation and neutrophil recruitment. To test this hypothesis, c57Bl/6 mice were exposed intranasally to LPS from the cyanobacterium member, Geitlerinema sp., in vivo to assess neutrophil infiltration and the production of pro-inflammatory cytokines and chemokines from the bronchoalveolar fluid by ELISA. Additionally, we exposed the airway epithelial cell line, A549, to Geitlerinema sp. LPS in vitro to confirm that airway epithelial cells were stimulated by this LPS to increase cytokine production and the expression of the adhesion molecule, ICAM-1. Our data demonstrate that Geitlerinema sp. LPS induces lung neutrophil infiltration, the production of pro-inflammatory cytokines such as Interleukin (IL)-6, Tumor necrosis factor-alpha, and Interferongamma as well as the chemokines IL-8 and RANTES. Additionally, we demonstrate that Geitlerinema sp. LPS directly activates airway epithelial cells to produce pro-inflammatory cytokines and the adhesion molecule, Intercellular Adhesion Molecule-1 (ICAM-1), in vitro using the airway epithelial cell line, A549. Based on our findings that use Geitlerinema sp. LPS as a model system, the data indicate that cyanobacteria LPS may contribute to the development of glucocorticoid-resistant asthma seen near water sources that contain high levels of cyanobacteria.


Assuntos
Asma , Cianobactérias , Pneumonia , Animais , Asma/patologia , Quimiocinas/metabolismo , Cianobactérias/metabolismo , Citocinas/metabolismo , Glucocorticoides/metabolismo , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/toxicidade , Pulmão/patologia , Camundongos , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/patologia
8.
Food Chem Toxicol ; 163: 112923, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35318090

RESUMO

It is currently understood that tobacco smoking is a major cause of pulmonary disease due to pulmonary/lung inflammation. However, due to a highly dynamic market place and an abundance of diverse products, less is known about the effects of e-cigarette (E-cig) use on the lung. In addition, varieties of E-cig liquids (e-liquids), which deliver nicotine and numerous flavor chemicals into the lungs, now number in the 1000s. Thus, a critical need exists for safety evaluations of these E-cig products. Herein, we employed a "2-stage in vivo screening platform" (zebrafish to mouse) to assess the safety profiles of e-liquids. Using the zebrafish, we collected embryo survival data after e-liquid exposure as well as neutrophil migration data, a key hallmark for a pro-inflammatory response. Our data indicate that certain e-liquids induce an inflammatory response in our zebrafish model and that e-liquid exposure alone results in pro-inflammatory lung responses in our C57BL/6J model, data collected from lung staining and ELISA analysis, respectively, in the mouse. Thus, our platform can be used as an initial assessment to ascertain the safety profiles of e-liquid using acute inflammatory responses (zebrafish, Stage 1) as our initial metric followed by chronic studies (C57BL/6J, Stage 2).


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Pneumonia , Vaping , Animais , Estudos de Viabilidade , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Vaping/efeitos adversos , Peixe-Zebra
10.
Clin Imaging ; 86: 31-37, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35325631

RESUMO

BACKGROUND: Immune checkpoint inhibitor-related pneumonia (ICIP) is an independent risk factor for immunotherapy-related death. PURPOSE: To evaluate the ICIP, dynamic observation of computed tomography (CT) images of lung cancer patients with ICIP was conducted to study the relationship between the occurrence of ICIP and clinical information. MATERIAL AND METHODS: CT images and clinical information of lung cancer patients (n = 76) from two hospitals who received immune checkpoint inhibitor (ICI) treatment were collected. A total of 49 cases were enrolled after screening according to the inclusion and exclusion criteria. We performed statistical analysis on the imaging features and clinical information. RESULTS: Analysis of imaging characteristics revealed two types of ICIP: the limited-onset type and diffuse-onset type. The median onset time of limited-onset ICIP was significantly earlier than that of diffuse-onset ICIP (1.5 months vs. 2.8 months; p = 0.045). Statistical analysis based on differences within the group showed that the clinical ICIP grade and immunotherapy response rate of limited-onset cases were statistically significant (p = 0.003) and the imaging/clinical ICIP grade and the outcome of ICIP were statistically significant (p = 0.031/0.007). The immunotherapy strategy of diffuse-onset cases and the response rate of immunotherapy were statistically significant (p = 0.016). CONCLUSIONS: This study suggests that pre-existing lung lesions can be one of the possible predisposing factors for ICIP and describes the development of ICIP through continuous imaging. Our findings indicate pre-existing lung lesions as a referential monitoring target for the onset and progression of ICIP for clinical practice.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Estudos Retrospectivos
11.
Biochem Biophys Res Commun ; 601: 38-44, 2022 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-35228119

RESUMO

Lung inflammation and fibrosis are common side effects of radiotherapy that can lead to serious reduction in the quality of life of patients. However, no effective treatment is available, and the mechanisms underlying its pathophysiology are poorly understood. Irradiation increases formyl peptide receptor 2 (FPR2) expression in lung tissue, and FPR2 agonists are known to promote the uptake of apoptosis cells, referred to as efferocytosis that is a hallmark of the resolution of inflammation. Herein, in a mouse model of radiation-induced lung injury (RILI), efferocytosis was induced by injecting apoptotic cells into the lung through the trachea, and its correlation with FPR expression and the effect of efferocytosis and FPR expression on RILI were assessed. Interestingly, when apoptotic cells were injected into the lung, the radiation-induced increase in FPR2 expression was further amplified. In the mouse model of RILI, apoptotic cell instillation reduced the volume of the damaged lung and prevented the decrease in lung function. Additionally, the expression of inflammatory cytokines, fibrosis-related markers, and oxidative stress-related markers was reduced by apoptotic cell instillation. Co-administration of apoptotic Jurkat cells and WRW4, the FPR2 antagonist, reversed these effects. These findings suggest that efferocytosis induced by apoptotic cell instillation and enhanced FPR2 expression attenuate RILI, thereby alleviating lung inflammation and fibrosis.


Assuntos
Pulmão , Pneumonia , Lesões por Radiação , Animais , Apoptose/efeitos da radiação , Fibrose , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Camundongos , Fagocitose , Pneumonia/induzido quimicamente , Qualidade de Vida , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo
12.
Mol Immunol ; 145: 80-87, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35305534

RESUMO

BACKGROUND: For a long time, Siraitia grosvenorii fruit extract (SGFE) and its dominant compounds, mogroside V(MV) were both reported to have therapeutic effects on allergic pneumonia, while previous studies only stay on phenotype and mechanism of the two active ingredients, hardly have any studies compared the two ingredients on the effect of liver metabolic, and revealed the relationship between mechanism and liver metabolism. OBJECTIVE: Here we elucidated and compared the curative mechanisms of SGFE and MV on allergic pneumonia through liver metabolomics. METHODS: We established allergic pneumonia mice using ovalbumin, then treated the mice with SGFE, MV and positive drug of Suhuang Zhike Jiaonang. The effects of the drugs were evaluated by detecting inflammatory cytokines, pathological examination and liver oxidative stress biomarkers. We explored the metabolic features between SGFE and MV through liver metabolomics consequently. RESULTS: At phenotype, we confirmed that MV and SGFE both inhibited the expression of inflammatory cytokines including interleukins-5 (IL-5), IL-13, IL-17 and OVA-induced immunoglobulin E, which can also relieve inflammatory cells infiltration and mesenchymal thickening in lung tissue compared with positive drug. In addition, both of them can alleviate oxidative stress damage in liver, while MV showed a superior effect than SGFE. In metabolomic analysis, the two ingredients were found to ameliorate inflammatory and oxidative reaction mainly in controlling pathways of Riboflavin metabolism and Glutathione metabolism. While SGFE were found to control other metabolic pathways such as Phenylalanine metabolism, Sphingolipid metabolism, Glycerollipid metabolism, Glycine, serine and threonine metabolism and Arginine and proline metabolism. CONCLUSION: From the results we can infer that the minor ingredients except MV in SGFE contribute poor function to the treatment of allergic pneumonia and MV may be the main functional constituent that relieve allergic pneumonia in SGFE. This study will be beneficial to figuring out a systematic theory of Siraitia grosvenorii active ingredients and proposing a guidance for pharmacology development.


Assuntos
Frutas , Pneumonia , Animais , Citocinas , Fígado , Camundongos , Extratos Vegetais/farmacologia , Pneumonia/induzido quimicamente , Triterpenos
14.
Immunohorizons ; 6(3): 224-242, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35273098

RESUMO

Protein kinase D1 (PKD1), a ubiquitously expressed serine/threonine kinase, regulates diverse cellular processes such as oxidative stress, gene expression, cell survival, vesicle trafficking, Ag receptor signaling, and pattern recognition receptor signaling. We found previously that exposure to hypersensitivity pneumonitis (HP) inciting Ag Saccharopolyspora rectivirgula leads to the activation of PKD1 in a MyD88-dependent manner in various types of murine cells in vitro and in the mouse lung in vivo. However, it is currently unknown whether PKD1 plays a role in the S. rectivirgula-induced HP. In this study, we investigated contributions of PKD1 on the S. rectivirgula-induced HP using conditional PKD1-insufficient mice. Compared to control PKD1-sufficient mice, PKD1-insufficient mice showed substantially suppressed activation of MAPKs and NF-κB, expression of cytokines and chemokines, and neutrophilic alveolitis after single intranasal exposure to S. rectivirgula The significantly reduced levels of alveolitis, MHC class II surface expression on neutrophils and macrophages, and IL-17A and CXCL9 expression in lung tissue were observed in the PKD1-insufficient mice repeatedly exposed to S. rectivirgula for 5 wk. PKD1-insuficient mice exposed to S. rectivirgula for 5 wk also showed reduced granuloma formation. Our results demonstrate that PKD1 plays an essential role in the initial proinflammatory responses and neutrophil influx in the lung after exposure to S. rectivirgula and substantially contribute to the development of HP caused by repeated exposure to S. rectivirgula Our findings suggest that PKD1 can be an attractive new molecular target for therapy of S. rectivirgula-induced HP.


Assuntos
Alveolite Alérgica Extrínseca , Pneumonia , Proteína Quinase C/metabolismo , Alveolite Alérgica Extrínseca/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Proteínas Quinases , Saccharopolyspora
15.
N Engl J Med ; 386(12): 1143-1154, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35320644

RESUMO

BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Doenças Pulmonares Intersticiais/induzido quimicamente , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos
16.
Lung ; 200(2): 269-275, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35199228

RESUMO

PURPOSE: Anesthetics are required for procedures that deliver drugs/biologics, infectious/inflammatory agents, and toxicants directly to the lungs. However, the possible confounding effects of anesthesia on lung inflammation and injury are underreported. Here, we evaluated the effects of two commonly used anesthetic regimens on lung inflammatory responses to ozone in mice. METHODS: We tested the effects of brief isoflurane (Iso) or ketamine/xylazine/atipamezole (K/X/A) anesthesia prior to ozone exposure (4 h, 3 ppm) on lung inflammatory responses in mice. Anesthesia regimens modeled those used for non-surgical intratracheal instillations and were administered 1-2 h or 24 h prior to initiating ozone exposure. RESULTS: We found that Iso given 1-2 h prior to ozone inhibited inflammatory responses in the lung, and this effect was absent when Iso was given 23-24 h prior to ozone. In contrast, K/X/A given 1-2 h prior to ozone increased lung and systemic inflammation. CONCLUSION: Our results highlight the need to comprehensively evaluate anesthesia as an experimental variable in the assessment of lung inflammation in response to ozone and other inflammatory stimuli.


Assuntos
Anestesia , Ozônio , Pneumonia , Animais , Humanos , Inflamação/induzido quimicamente , Pulmão , Camundongos , Ozônio/toxicidade , Pneumonia/induzido quimicamente
17.
Toxicol Appl Pharmacol ; 440: 115930, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35202710

RESUMO

Benzalkonium chloride (BKC) is a prototypical quaternary ammonium disinfectant. Previously, we suggested a no lethal dose level (0.005%) and an LD50 range (0.5-0.05%) of BKC following a single pharyngeal aspiration. Herein, we exposed BKC repeatedly by pharyngeal aspiration for 14 days (0.005 and 0.01%, female mice, total five times with interval of two days, 5 mice/group) and 28 days (0, 0.001, 0.005, and 0.01%, male and female mice, weekly, 16 mice/sex/group). Death following 14 days-repeated exposure did not occur. Meanwhile, chronic pathological lesions were observed in the lung tissues of mice exposed to BKC for 28 days. The total number of bronchial alveolar lavage cells increased, and pulmonary homeostasis of immunologic messenger molecules was disturbed. Following, we investigated BKC-induced cellular responses using human bronchial epithelial cells. The cytotoxicity increased rapidly with concentration. Lysosomal volume, NO production, and lipid peroxidation increased in BKC-treated cells, whereas intracellular ROS level decreased accompanying structural and functional damage of mitochondria. We also found that BKC affected the expression level of immune response, DNA damage, and amino acid biosynthesis-related molecules. More interestingly, lamellar body- and autophagosome-like structures were notably observed in cells exposed to BKC, and necrotic and apoptotic cell death were identified accompanying cell accumulation in the G2/M phase. Therefore, we suggest that repeated respiratory exposure of BKC causes pulmonary inflammation and lung tissue damage and that dead and damaged cells may contribute to the inflammatory response. In addition, the formation process of lamellar body-like structures may function as a key toxicity mechanism.


Assuntos
Pneumonia , Surfactantes Pulmonares , Animais , Compostos de Benzalcônio/toxicidade , Feminino , Homeostase , Pulmão , Masculino , Camundongos , Pneumonia/induzido quimicamente
18.
J Pediatr Hematol Oncol ; 44(2): e500-e502, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35200223

RESUMO

Pulmonary fibrosis caused by bleomycin-induced pneumonia (BIP) is the most important side effect limiting the use of bleomycin and is mainly treated with corticosteroids. However, 1% to 4% of patients do not respond to corticosteroid therapy. Idiopathic pulmonary fibrosis and BIP develop by similar pathophysiological mechanisms. Nintedanib is a tyrosine kinase inhibitor used successfully in the treatment of idiopathic pulmonary fibrosis and there is no information about its use in BIP treatment. Here, we would like to present a 13-year-old boy with Hodgkin lymphoma who developed BIP after 2 cycles of ABVD (Adriamycin, bleomycin, vinblastine, and dacarbazine) and 4 cycles of BAECOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), whose respiratory failure impaired despite corticosteroid therapy, but was successfully treated with nintedanib.


Assuntos
Doença de Hodgkin , Fibrose Pulmonar Idiopática , Pneumonia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina , Criança , Dacarbazina , Doxorrubicina , Etoposídeo , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis , Masculino , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Prednisona/uso terapêutico , Vimblastina , Vincristina
19.
Commun Biol ; 5(1): 162, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35210549

RESUMO

T helper 17 (Th17) cells develop in response to T cell receptor signals (TCR) in the presence of specific environments, and produce the inflammatory cytokine IL17A. These cells have been implicated in a number of inflammatory diseases and represent a potential target for ameliorating such diseases. The kinase ITK, a critical regulator of TCR signals, has been shown to be required for the development of Th17 cells. However, we show here that lung inflammation induced by Saccharopolyspora rectivirgula (SR) induced Hypersensitivity pneumonitis (SR-HP) results in a neutrophil independent, and ITK independent Th17 responses, although ITK signals are required for γδ T cell production of IL17A. Transcriptomic analysis of resultant ITK independent Th17 cells suggest that the SR-HP-induced extrinsic inflammatory signals may override intrinsic T cell signals downstream of ITK to rescue Th17 responses in the absence of ITK. These findings suggest that the ability to pharmaceutically target ITK to suppress Th17 responses may be dependent on the type of inflammation.


Assuntos
Alveolite Alérgica Extrínseca , Pneumonia , Proteínas Tirosina Quinases , Células Th17 , Alveolite Alérgica Extrínseca/enzimologia , Alveolite Alérgica Extrínseca/imunologia , Alveolite Alérgica Extrínseca/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/imunologia , Pneumonia/metabolismo , Proteínas Tirosina Quinases/imunologia , Células Th17/enzimologia , Células Th17/imunologia , Células Th17/metabolismo
20.
Artigo em Inglês | MEDLINE | ID: mdl-35210765

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP). METHODS: A propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥40 years with ≥1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions. RESULTS: A total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 µg; propionate 710 µg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 µg), irrespective of definition (sensitive HR 1.38 95% CI 1.14-1.68; specific HR 1.31 95% CI 1.05-1.62). CONCLUSION: In the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.


Assuntos
Pneumonia , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Adulto , Beclometasona , Estudos de Coortes , Fluticasona , Fumarato de Formoterol , Humanos , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Resultado do Tratamento
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