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1.
Life Sci ; 273: 119302, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662427

RESUMO

Src homolog and collagen homolog (SHC) proteins are adaptor proteins bound to cell surface receptors that play an important role in signal transduction and related diseases. As an important member of the SHC protein family, SHC1 regulates cell proliferation and apoptosis, reactive oxygen species (ROS) production, and oxidative stress. Three isomeric proteins namely, p46shc, p52shc, and p66shc, are produced from the same SHC1 gene locus. All the three proteins are found in the liver, and are widely expressed in various hepatic cells. SHC1 has been proven to be associated with acute and chronic liver injuries of different etiologies, and plays important roles in liver fibrosis and hepatocellular carcinoma (HCC). Therefore, this review summarizes recent studies that discuss and explore the role of SHC1 in the occurrence and progression of liver diseases. We also provide a theoretical basis for future studies.


Assuntos
Lesão Pulmonar Aguda/patologia , Lesão Pulmonar/patologia , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Lesão Pulmonar Aguda/metabolismo , Animais , Humanos , Lesão Pulmonar/metabolismo , Isoformas de Proteínas , Transdução de Sinais
2.
Life Sci ; 274: 119341, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33716059

RESUMO

The COVID-19 pandemic surges on as vast research is produced to study the novel SARS-CoV-2 virus and the disease state it induces. Still, little is known about the impact of COVID-19-induced microscale damage in the lung on global lung dynamics. This review summarizes the key histological features of SARS-CoV-2 infected alveoli and links the findings to structural tissue changes and surfactant dysfunction affecting tissue mechanical behavior similar to changes seen in other lung injury. Along with typical findings of diffuse alveolar damage affecting the interstitium of the alveolar walls and blood-gas barrier in the alveolar airspace, COVID-19 can cause extensive microangiopathy in alveolar capillaries that further contribute to mechanical changes in the tissues and may differentiate it from previously studied infectious lung injury. Understanding microlevel damage impact on tissue mechanics allows for better understanding of macroscale respiratory dynamics. Knowledge gained from studies into the relationship between microscale and macroscale lung mechanics can allow for optimized treatments to improve patient outcomes in case of COVID-19 and future respiratory-spread pandemics.


Assuntos
/complicações , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Ventilação Pulmonar , /isolamento & purificação , /transmissão , Humanos
3.
PLoS One ; 16(2): e0247510, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33626084

RESUMO

Angiotensin converting enzyme 2 (ACE2) is the putative functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current literature on the abundance and distribution of ACE2 protein in the human respiratory tract is controversial. We examined the effect of age and lung injury on ACE2 protein expression in rodent and non-human primate (NHP) models. We also examined ACE2 expression in human tissues with and without coronavirus disease 19 (COVID-19). ACE2 expression was detected at very low levels in preterm, but was absent in full-term and adult NHP lung homogenates. This pattern of ACE2 expression contrasted with that of transmembrane protease serine type 2 (TMPRSS2), which was significantly increased in full-term newborn and adult NHP lungs compared to preterm NHP lungs. ACE2 expression was not detected in NHP lungs with cigarette smoke-induced airway disease or bronchopulmonary dysplasia. Murine lungs lacked basal ACE2 immunoreactivity, but responded to hyperoxia, bacterial infection, and allergen exposure with new ACE2 expression in bronchial epithelial cells. In human specimens, robust ACE2 immunoreactivity was detected in ciliated epithelial cells in paranasal sinus specimens, while ACE2 expression was detected only in rare type 2 alveolar epithelial cells in control lungs. In autopsy specimens from patients with COVID-19 pneumonia, ACE2 was detected in rare ciliated epithelial and endothelial cells in the trachea, but not in the lung. There was robust expression of ACE2 expression in F344/N rat nasal mucosa and lung specimens, which authentically recapitulated the ACE2 expression pattern in human paranasal sinus specimens. Thus, ACE2 protein expression demonstrates a significant gradient between upper and lower respiratory tract in humans and is scarce in the lung. This pattern of ACE2 expression supports the notion of sinonasal epithelium being the main entry site for SARS-CoV-2 but raises further questions on the pathogenesis and cellular targets of SARS-CoV-2 in COVID-19 pneumonia.


Assuntos
/biossíntese , Lesão Pulmonar/enzimologia , Fatores Etários , Células Epiteliais Alveolares/metabolismo , Animais , Animais Recém-Nascidos , /metabolismo , Feminino , Expressão Gênica , Humanos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Papio papio , Mucosa Respiratória/enzimologia , Mucosa Respiratória/metabolismo , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Transcriptoma
4.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33574054

RESUMO

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65-year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.


Assuntos
/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pneumonia/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , /imunologia , Diagnóstico Diferencial , Humanos , /efeitos adversos , Imunoterapia/efeitos adversos , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/virologia , Masculino , Nasofaringe/metabolismo , Nasofaringe/patologia , Metástase Neoplásica , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
5.
Viruses ; 13(2)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499234

RESUMO

Respiratory viruses such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a constant threat to public health given their ability to cause global pandemics. Infection with either virus may lead to aberrant host responses, such as excessive immune cell recruitment and activation, dysregulated inflammation, and coagulopathy. These may contribute to the development of lung edema and respiratory failure. An increasing amount of evidence suggests that lung endothelial cells play a critical role in the pathogenesis of both viruses. In this review, we discuss how infection with influenza or SARS-CoV-2 may induce endothelial dysfunction. We compare the effects of infection of these two viruses, how they may contribute to pathogenesis, and discuss the implications for potential treatment. Understanding the differences between the effects of these two viruses on lung endothelial cells will provide important insight to guide the development of therapeutics.


Assuntos
Endotélio/virologia , Influenzavirus A/patogenicidade , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , /patogenicidade , Plaquetas/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio/metabolismo , Endotélio/patologia , Armadilhas Extracelulares/imunologia , Humanos , Junções Intercelulares/patologia , Lesão Pulmonar/terapia
6.
Respir Res ; 22(1): 32, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514373

RESUMO

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.


Assuntos
/patologia , Lesão Pulmonar/patologia , Pulmão/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Autopsia , Demografia , Progressão da Doença , Feminino , Humanos , Infarto/epidemiologia , Infarto/patologia , Lesão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Trombose/etiologia , Trombose/patologia , Adulto Jovem
7.
Int J Mol Sci ; 22(2)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478107

RESUMO

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define any possible specific pattern. Histopathologic alterations are principally found within lungs and blood vessels, and these abnormalities also seem to have the highest clinical impact. Nevertheless, many of the morphological data collected so far are non-specific, fickle, and possibly associated with other co-existing factors. The aim of this minireview is to describe the main histopathological features related to COVID-19 and the mechanism known as "cytokine storm".


Assuntos
/imunologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , /metabolismo , Autopsia , Síndrome da Liberação de Citocina , Citocinas/sangue , Humanos , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/patologia , /isolamento & purificação
8.
Nicotine Tob Res ; 22(Suppl 1): S96-S99, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33320257

RESUMO

Implications In this commentary, we describe the evidence-based approach used to identify the primary cause of EVALI and to curb the 2019 outbreak. We also discuss future research opportunities and public health practice considerations to prevent a resurgence of EVALI.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Lesão Pulmonar/etiologia , Vaping/efeitos adversos , Vaping/epidemiologia , Surtos de Doenças , Humanos , Lesão Pulmonar/patologia , Estados Unidos/epidemiologia
9.
Nat Commun ; 11(1): 5778, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188196

RESUMO

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.


Assuntos
Plaquetas/patologia , Vasos Sanguíneos/patologia , Quimiotaxia , Inflamação/patologia , Pneumonia/sangue , Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo , Adulto , Animais , Movimento Celular , Microambiente Celular , Modelos Animais de Doenças , Fibrinogênio/metabolismo , Humanos , Lipopolissacarídeos , Lesão Pulmonar/microbiologia , Lesão Pulmonar/patologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Camundongos Endogâmicos C57BL , Microvasos/patologia , Pneumonia/microbiologia , Pseudópodes/metabolismo
10.
Front Immunol ; 11: 2063, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013872

RESUMO

Background: Cases of excessive neutrophil counts in the blood in severe coronavirus disease (COVID-19) patients have drawn significant attention. Neutrophil infiltration was also noted on the pathological findings from autopsies. It is urgent to clarify the pathogenesis of neutrophils leading to severe pneumonia in COVID-19. Methods: A retrospective analysis was performed on 55 COVID-19 patients classified as mild (n = 22), moderate (n = 25), and severe (n = 8) according to the Guidelines released by the National Health Commission of China. Trends relating leukocyte counts and lungs examined by chest CT scan were quantified by Bayesian inference. Transcriptional signatures of host immune cells of four COVID19 patients were analyzed by RNA sequencing of lung specimens and BALF. Results: Neutrophilia occurred in 6 of 8 severe patients at 7-19 days after symptom onset, coinciding with lesion progression. Increasing neutrophil counts paralleled lesion CT values (slope: 0.8 and 0.3-1.2), reflecting neutrophilia-induced lung injury in severe patients. Transcriptome analysis revealed that neutrophil activation was correlated with 17 neutrophil extracellular trap (NET)-associated genes in COVID-19 patients, which was related to innate immunity and interacted with T/NK/B cells, as supported by a protein-protein interaction network analysis. Conclusion: Excessive neutrophils and associated NETs could explain the pathogenesis of lung injury in COVID-19 pneumonia.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Armadilhas Extracelulares/genética , Ativação de Neutrófilo/genética , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Teorema de Bayes , Infecções por Coronavirus/virologia , Feminino , Humanos , Contagem de Leucócitos , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Infiltração de Neutrófilos/imunologia , Pandemias , Pneumonia Viral/virologia , Mapas de Interação de Proteínas/imunologia , RNA Viral/genética , Estudos Retrospectivos , Transcriptoma
11.
Signal Transduct Target Ther ; 5(1): 240, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060566

RESUMO

The COVID-19 pandemic has emerged as a global health emergency due to its association with severe pneumonia and relative high mortality. However, the molecular characteristics and pathological features underlying COVID-19 pneumonia remain largely unknown. To characterize molecular mechanisms underlying COVID-19 pathogenesis in the lung tissue using a proteomic approach, fresh lung tissues were obtained from newly deceased patients with COVID-19 pneumonia. After virus inactivation, a quantitative proteomic approach combined with bioinformatics analysis was used to detect proteomic changes in the SARS-CoV-2-infected lung tissues. We identified significant differentially expressed proteins involved in a variety of fundamental biological processes including cellular metabolism, blood coagulation, immune response, angiogenesis, and cell microenvironment regulation. Several inflammatory factors were upregulated, which was possibly caused by the activation of NF-κB signaling. Extensive dysregulation of the lung proteome in response to SARS-CoV-2 infection was discovered. Our results systematically outlined the molecular pathological features in terms of the lung response to SARS-CoV-2 infection, and provided the scientific basis for the therapeutic target that is urgently needed to control the COVID-19 pandemic.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Lesão Pulmonar/genética , Pneumonia Viral/genética , Proteoma/genética , Proteômica/métodos , Síndrome Respiratória Aguda Grave/genética , Idoso , Autopsia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ontologia Genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Masculino , Redes e Vias Metabólicas , Anotação de Sequência Molecular , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteoma/metabolismo , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais
12.
Toxicol Lett ; 334: 4-13, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949624

RESUMO

Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3ß level and elevated the active ß-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.


Assuntos
Poluentes Radioativos do Ar/toxicidade , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Pulmão , Radônio/toxicidade , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta à Radiação , Humanos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Produtos de Decaimento de Radônio/toxicidade , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 240-244, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981279

RESUMO

Objective: To investigate the inflammatory mechanism of nasal instillation of fine particulate matter (PM2.5)on hippocampal tissue injury in mice.Methods: Thirty C57BL/6J mice were randomly divided into 3 groups(n=10):control group, low-dose group, high-dose group. The nasal instillation doses of PM2.5 in the low-dose group and the high-dose group were 1.5 mg/kg BW and 7.5 mg/kg BW, respectively, and the control group was given saline with an equal volume. Saline was sprayed once every other time for 12 times. The serum levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were determined by ELISA method. HE staining and electron microscopy were used to observe the pathological changes and ultrastructure of lung tissue and hippocampus. The inflammatory cytokine levels in hippocampus were detected by antibody chip technique. Results: There was no significant effect of PM2.5 nasal instillation on serum TNF-α, IL-1ß and IL-6 levels (P>0.05), and there was no obvious pathological changes in lung tissue structure. In hippocampus, low-dose and high-dose PM2.5 exposure could lead to disordered neuronal arrangement in the hippocampal CA3 region, and there were neurological changes around the neuron cells and ultrastructural changes such as edema around small blood vessels. Compared with the control group, the levels of inflammatory cytokines such as CX3CL1, CSF2 and TECK in the low-dose group were increased significantly (P <0.05), while sTNFR1 was decreased significantly (P<0.05); the inflammatory factors CX3CL1, CSF2, and TCA-3 were significantly increased in the high-dose group (P<0.05), while leptin, MIG, and FASLG were significantly decreased (P<0.05). Conclusion: Nasal instillation of PM2.5 can induce tissue damage in the hippocampus of mice, and its mechanism of action may be the olfactory brain pathway. The increasing of TNF-α and IL-6 and the decreasing of sTNFR1 and FASLG may be involved in inflammatory mechanisms.


Assuntos
Lesões Encefálicas , Hipocampo , Material Particulado , Administração Intranasal , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/fisiopatologia , Citocinas/sangue , Hipocampo/efeitos dos fármacos , Hipocampo/lesões , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Material Particulado/toxicidade
14.
PLoS One ; 15(9): e0238140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881943

RESUMO

Vitamin E acetate (VEA) is strongly linked to the outbreak of electronic-cigarette or vaping product use-associated lung injury (EVALI). It has been proposed that VEA decomposition to ketene-a respiratory poison that damages lungs at low ppm levels-may play a role in EVALI. However, there is no information available on the temperature at which VEA decomposes and how this correlates with the vaping process. We have studied the temperature-dependent kinetics of VEA decomposition using quantum chemical and statistical mechanical modelling techniques, developing a chemical kinetic model of the vaping process. This model predicts that, under typical vaping conditions, the use of VEA contaminated e-cigarette products is unlikely to produce ketene at harmful levels. However, at the high temperatures encountered at low e-cigarette product levels, which produce 'dry hits', ketene concentrations are predicted to reach acutely toxic levels in the lungs (as high as 30 ppm). We therefore hypothesize that dry hit vaping of e-cigarette products containing VEA contributes to EVALI.


Assuntos
Etilenos/metabolismo , Cetonas/metabolismo , Lesão Pulmonar/patologia , Vaping/efeitos adversos , Vitamina E/metabolismo , Etilenos/química , Etilenos/toxicidade , Humanos , Cetonas/química , Cetonas/toxicidade , Cinética , Lesão Pulmonar/induzido quimicamente , Temperatura , Vitamina E/química
15.
Life Sci ; 260: 118426, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937159

RESUMO

AIMS: Tobacco smoking is a major health problem associated with lung and liver damage. Lung and liver damage secondary to tobacco smoking is mediated through nicotine-induced oxidative stress. Therefore, we hypothesized that antioxidant treatment with tiron may improve nicotine-induced lung and liver damage. MATERIALS AND METHODS: Rats were divided into six groups, a control, nicotine (10 mg/kg/day, i.p.; for 8 weeks) and tiron (100 or 200 mg/kg/day, i.p.; for 8 weeks) with or without nicotine administration. KEY FINDINGS: Tiron improved survival rate and attenuated lung and liver damage as reflected by decreased total and differential cell counts, lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) and decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum; also histopathological examination confirmed the protective effect of tiron in lung and liver tissues of nicotine treated rats. Tiron attenuated dyslipidemia, which is associated with nicotine. These ameliorative effects of tiron may be mainly due to its antioxidant effect as proved by a significant decrease in malondialdehyde (MDA) content, reactive oxygen species (ROS) and total nitrite/nitrate (NOx) levels, and increase in reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) activities. This is likely related to suppression of protein levels of NADPH oxidase enzyme (NOX1), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α); and up-regulation of protein levels of nuclear factor erythroid-2 (Nrf2). SIGNIFICANCE: This makes tiron (synthetic analogue of vitamin E) good candidate for future use to minimize nicotine's hazards among smokers.


Assuntos
Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Lesão Pulmonar/prevenção & controle , Nicotina/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Peso Corporal/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Contagem de Células , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Enzimas/sangue , L-Lactato Desidrogenase/metabolismo , Lipídeos/sangue , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/mortalidade , Lesão Pulmonar/patologia , Masculino , NADPH Oxidase 1/sangue , NADPH Oxidase 1/metabolismo , NF-kappa B/sangue , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley
16.
J Am Heart Assoc ; 9(18): e017368, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896206

RESUMO

E-cigarette or vaping product use-associated lung injury was recognized in the United States in the summer of 2019 and is typified by acute respiratory distress, shortness of breath, chest pain, cough, and fever, associated with vaping. It can mimic many of the manifestations of coronavirus disease 2019 (COVID-19). Some investigators have suggested that E-cigarette or vaping product use-associated lung injury was due to tetrahydrocannabinol or vitamin E acetate oil mixed with the electronic cigarette liquid. In experimental rodent studies initially designed to study the effect of electronic cigarette use on the cardiovascular system, we observed an E-cigarette or vaping product use-associated lung injury-like condition that occurred acutely after use of a nichrome heating element at high power, without the use of tetrahydrocannabinol, vitamin E, or nicotine. Lung lesions included thickening of the alveolar wall with foci of inflammation, red blood cell congestion, obliteration of alveolar spaces, and pneumonitis in some cases; bronchi showed accumulation of fibrin, inflammatory cells, and mucus plugs. Electronic cigarette users should be cautioned about the potential danger of operating electronic cigarette units at high settings; the possibility that certain heating elements may be deleterious; and that E-cigarette or vaping product use-associated lung injury may not be dependent upon tetrahydrocannabinol, vitamin E, or nicotine.


Assuntos
Dronabinol/toxicidade , Vapor do Cigarro Eletrônico/toxicidade , Sistemas Eletrônicos de Liberação de Nicotina , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Pneumonia/induzido quimicamente , Vaping/efeitos adversos , Vitamina E/toxicidade , Animais , Exposição por Inalação , Pulmão/patologia , Lesão Pulmonar/patologia , Modelos Animais , Óleos , Pneumonia/patologia , Ratos , Medição de Risco
17.
Dtsch Arztebl Int ; 117(29-30): 500-506, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32865490

RESUMO

BACKGROUND: The histomorphological changes of lung damage in severe coronavirus disease 2019 (COVID-19) have not yet been adequately characterized. In this article, we describe the sequence of pathological changes in COVID-19 and discuss the implications for approaches to treatment. METHODS: Standardized autopsies were performed on thirteen patients who had died of COVID-19. The findings were analyzed together with clinical data from the patients' medical records. RESULTS: Most (77%) of the deceased patients were men. Their median age at death was 78 years (range, 41-90). Most of them had major pre-existing chronic diseases, most commonly arterial hypertension. The autopsies revealed characteristic COVID-19-induced pathological changes in the lungs, which were regarded as the cause of death in most patients. The main histological finding was sequential alveolar damage, apparently due in large measure to focal capillary microthrombus formation. Alveolar damage leads to the death of the patient either directly or by the induction of pulmonary parenchymal fibrosis. Diffuse lung damage was seen exclusively in invasively ventilated patients. CONCLUSION: Autopsies are crucial for the systematic assessment of new diseases such as COVID-19: they provide a basis for further investigations of disease mechanisms and for the devising of potentially effective modes of treatment. The autopsy findings suggest that focal damage of the microvascular pulmonary circulation is a main mechanism of lethal lung disease due to the SARS-CoV-2 virus. It may also be a cause of persistent lung damage in patients who recover from severe COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Pneumonia Viral/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Índice de Gravidade de Doença
19.
Life Sci ; 259: 118249, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798558

RESUMO

AIMS: We aimed to evaluate the effect of Dexmedetomidine (Dex) on immunology function of macrophages and inflammatory reactions in non-ventilated lung tissues from both humans and rats. MAIN METHODS: Patients scheduled for lung lobectomy were randomly assigned to traditional anesthesia group or Dex anesthesia group, 15 subjects in each group. CD68, CD86 and CD206 were used to mark activate and polarized macrophages using immunofluorescence staining in human lung tissues. Sprague-Dawley rats were used to set lung injury model and randomly divided into Control group, one-lung ventilation group (CLI group) and CLI + Dex group. Lung tissues and bronchoalveolar lavage fluid (BALF) from non-ventilated lungs were collected. The acquired lung tissues were subjected to hematoxylin-eosin (H&E) staining and the inflammatory cells in BALF were calculated. Levels of cytokines and chemokines were detected by enzyme-linked immunosorbent assays (ELISA). KEY FINDINGS: Results from humans showed that anesthesia with Dex decreased the number of both CD68 positive cells and CD86 positive cells and down-regulated level of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1) in human lung. Results from rats demonstrated that treatment with Dex reversed the increased inflammatory cells in lung and the increased levels of TNF-α, interleukin-1ß (IL-ß), MCP-1 and chemokine (C-X-C motif) ligand 1 (CXCL1) resulted from non-ventilation; Dex increased the anti-inflammatory cytokine interleukin-10 (IL-10) in BALF from non-ventilated lung. SIGNIFICANCE: This study showed that Dex modulated the activation and immunological function of macrophages in non-ventilated lung and revealed a protective role in collapsed lung injury.


Assuntos
Dexmedetomidina/farmacologia , Lesão Pulmonar/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Idoso , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Dexmedetomidina/metabolismo , Feminino , Humanos , Pulmão/citologia , Pulmão/metabolismo , Lesão Pulmonar/patologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Life Sci ; 259: 118286, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810508

RESUMO

AIMS: To investigate the role of CX3CR1 in hyperoxic lung injury induced pulmonary fibrosis. MATERIALS AND METHODS: Hyperoxic lung injured mice were used as the disease model. Pulmonary fibrosis was determined by H&E and Masson's staining. Autophagy was investigated by western blot, immunofluorescence staining, and transmission electron microscopy. KEY FINDINGS: We observed that increased CX3CR1 expression corresponded with increased pulmonary fibrosis. Additionally, silencing of CX3CR1 significantly alleviated the fibrosis when compared to the control. We observed that exposure of mouse to hyperoxic environment increased macrophage levels along with an increased CD11b expression in the lung tissues. Subsequently, we also observed an increased expression of LC3-II and decreased p62 expression in hyperoxic mice models, suggesting the potential role of hyperoxia induced autophagy. CD11b and LC3/CX3CR1 were expressed and co-localized in a manner indicating CX3CR1 indeed does regulate macrophage autophagy in the hyperoxic lung injury model. We observed a decrease in hyperoxia-associated fibrosis, along with a decrease in autophagy when we used 3-MA (autophagy inhibitor) in our hyperoxic lung injury model. To elucidate the pathway through which CX3CR1 regulated autophagy, we further analyzed the Akt1 pathway. Our experimental results indicated that the Akt1 inhibitor (A-674563) did significantly decrease macrophage autophagy and fibrosis in hyperoxic mice models. SIGNIFICANCE: Thus, our data indicates a novel role of CX3CR1 in regulation of macrophage autophagy and promotion of pulmonary fibrosis in hyperoxic lung injured mice.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Autofagia/fisiologia , Western Blotting , Receptor 1 de Quimiocina CX3C/antagonistas & inibidores , Modelos Animais de Doenças , Hiperóxia/patologia , Pulmão/metabolismo , Lesão Pulmonar/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/patologia
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