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1.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198751

RESUMO

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


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Itália , Leucócitos Mononucleares/virologia , Lopinavir/uso terapêutico , Pulmão/citologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/terapia , Prognóstico , Estudos Prospectivos , Respiração Artificial/métodos , Ritonavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Taxa de Sobrevida , Vírion/metabolismo , Vírion/ultraestrutura
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 865-870, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148379

RESUMO

Objective To investigate dynamic changes of type 3 innate lymphoid cells (ILC3) in lungs of mice with bronchopulmonary dysplasia (BPD). Methods Forty newborn C57BL/6 mice were randomized into air group and the hyperoxia group, 20 mice in each group. C57BL/6 newborn mice were delivered by caesarean section on the 19th day of pregnancy and exposed to 850 mL/L O2 for replication of the BPD model. Five mice in each group were sacrificed 1 day, 3, 7, 14 days after they were born for procurement of fresh lung tissues. HE staining was used to observe the pathological changes of lung tissues. ELISA was used to detect the protein content of downstream cytokines interleukin-17 (IL-17), IL-22 and granulocyte-macrophage colony stimulating factor (GM-CSF) in lung homogenate. Flow cytometry was used for measuring the proportion of ILC3 in lymphocytes as well as the proportions of IL-17+ ILC3 and IL-22+ ILC3 in the lung. Results The proportion of ILC3 in lung tissues reached the peak on the 7th day after birth. In contrast with the air group, the proportion of ILC3 in the hyperoxia group was significantly elevated at the same time points. The protein content of IL-17 and IL-22 in the hyperoxia group went up significantly in comparison with those in the air group at the same time points, while the GM-CSF content in the hyperoxia group showed no significant changes. The proportions of IL-17+ILC3 and IL-22+ILC3 in the hyperoxia group significantly increased as compared with those in the air group at the same time points. Conclusion The secretion of IL-17 and IL-22 derived from ILC3 is associated with BPD.


Assuntos
Displasia Broncopulmonar/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Linfócitos/citologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hiperóxia , Imunidade Inata , Pulmão/citologia , Pulmão/imunologia , Pulmão/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Distribuição Aleatória
3.
Int J Mol Sci ; 21(21)2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33126657

RESUMO

Acute respiratory distress syndrome (ARDS) is characterized by massive inflammation, increased vascular permeability and pulmonary edema. Mortality due to ARDS remains very high and even in the case of survival, acute lung injury can lead to pulmonary fibrosis. The renin-angiotensin system (RAS) plays a significant role in these processes. The activities of RAS molecules are subject to dynamic changes in response to an injury. Initially, increased levels of angiotensin (Ang) II and des-Arg9-bradykinin (DABK), are necessary for an effective defense. Later, augmented angiotensin converting enzyme (ACE) 2 activity supposedly helps to attenuate inflammation. Appropriate ACE2 activity might be decisive in preventing immune-induced damage and ensuring tissue repair. ACE2 has been identified as a common target for different pathogens. Some Coronaviruses, including SARS-CoV-2, also use ACE2 to infiltrate the cells. A number of questions remain unresolved. The importance of ACE2 shedding, associated with the release of soluble ACE2 and ADAM17-mediated activation of tumor necrosis factor-α (TNF-α)-signaling is unclear. The roles of other non-classical RAS-associated molecules, e.g., alamandine, Ang A or Ang 1-9, also deserve attention. In addition, the impact of established RAS-inhibiting drugs on the pulmonary RAS is to be elucidated. The unfavorable prognosis of ARDS and the lack of effective treatment urge the search for novel therapeutic strategies. In the context of the ongoing SARS-CoV-2 pandemic and considering the involvement of humoral disbalance in the pathogenesis of ARDS, targeting the renin-angiotensin system and reducing the pathogen's cell entry could be a promising therapeutic strategy in the struggle against COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Sistema Renina-Angiotensina/fisiologia , Síndrome Respiratória Aguda Grave/patologia , Proteína ADAM17/metabolismo , Animais , Betacoronavirus , Permeabilidade Capilar/fisiologia , Humanos , Inflamação/patologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Pandemias , Edema Pulmonar/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
4.
Breast Cancer Res ; 22(1): 117, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126915

RESUMO

Severe coronavirus disease 2019 (COVID-19) causes a hyperactivation of immune cells, resulting in lung inflammation. Recent studies showed that COVID-19 induces the production of factors previously implicated in the reawakening of dormant breast cancer cells such as neutrophil extracellular traps (NETs). The presence of NETs and of a pro-inflammatory microenvironment may therefore promote breast cancer reactivation, increasing the risk of pulmonary metastasis. Further studies will be required to confirm the link between COVID-19 and cancer recurrence. However, an increased awareness on the potential risks for breast cancer patients with COVID-19 may lead to improved treatment strategies to prevent metastatic relapse.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/virologia , Infecções por Coronavirus/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/virologia , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Neoplasias da Mama/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Pandemias , Pneumonia/imunologia , Pneumonia/virologia , Pneumonia Viral/virologia , Microambiente Tumoral/imunologia
5.
Med Hypotheses ; 143: 110201, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017909

RESUMO

COVID-19 initially an epidemic caused by SARS-CoV-2 has turned out to be a life- threatening global pandemic with increased morbidity and mortality. The presence of cytokine storm has been linked with the pathogenesis of severe lung injury as evinced in COVID-19. Aquaporins (AQPs) are molecular water channels, facilitating water transport across the cell membrane in response to osmotic gradients. Impairment in alveolar fluid clearance due to altered functional expression of respiratory AQPs highlight their pathophysiological significance in pulmonary edema associated respiratory illness. Therefore, we hypothesize that targeted modulation of AQPs in lungs in the intervening period of time, could diminish the dreadful effects of inflammation- induced comorbidity in COVID-19.


Assuntos
Aquaporinas/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Edema Pulmonar/tratamento farmacológico , Animais , Betacoronavirus , Transporte Biológico , Comorbidade , Citocinas/metabolismo , Humanos , Inflamação , Pulmão/imunologia , Pulmão/virologia , Camundongos , Pandemias
6.
Mol Med ; 26(1): 95, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054759

RESUMO

Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.


Assuntos
Infecções por Coronavirus/imunologia , Epigênese Genética/imunologia , Fibrose Pulmonar Idiopática/imunologia , Mecanotransdução Celular/imunologia , Pneumonia Viral/imunologia , Embolia Pulmonar/imunologia , Insuficiência Respiratória/imunologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Fenômenos Biomecânicos , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Fibroblastos/imunologia , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/patologia , Mecanotransdução Celular/genética , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Embolia Pulmonar/genética , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Insuficiência Respiratória/virologia , Estresse Mecânico
7.
Clin Microbiol Rev ; 34(1)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33055229

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, introduced the third highly pathogenic coronavirus into humans in the 21st century. Scientific advance after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic and Middle East respiratory syndrome coronavirus (MERS-CoV) emergence enabled clinicians to understand the epidemiology and pathophysiology of SARS-CoV-2. In this review, we summarize and discuss the epidemiology, clinical features, and virology of and host immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2 and the pathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS). We especially highlight that highly pathogenic coronaviruses might cause infection-associated hemophagocytic lymphohistiocytosis, which is involved in the immunopathogenesis of human coronavirus-induced ARDS, and also discuss the potential implication of hemophagocytic lymphohistiocytosis therapeutics for combating severe coronavirus infection.


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/fisiopatologia , Interações Hospedeiro-Patógeno , Humanos , Período de Incubação de Doenças Infecciosas , Pulmão/imunologia , Pulmão/fisiopatologia , Pulmão/virologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/mortalidade , Linfo-Histiocitose Hemofagocítica/fisiopatologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Filogenia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Vírus da SARS/genética , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/fisiopatologia , Índice de Gravidade de Doença , Análise de Sobrevida
8.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105830

RESUMO

Inflammation is a biological response to the activation of the immune system by various infectious or non-infectious agents, which may lead to tissue damage and various diseases. Gut commensal bacteria maintain a symbiotic relationship with the host and display a critical function in the homeostasis of the host immune system. Disturbance to the gut microbiota leads to immune dysfunction both locally and at distant sites, which causes inflammatory conditions not only in the intestine but also in the other organs such as lungs and brain, and may induce a disease state. Probiotics are well known to reinforce immunity and counteract inflammation by restoring symbiosis within the gut microbiota. As a result, probiotics protect against various diseases, including respiratory infections and neuroinflammatory disorders. A growing body of research supports the beneficial role of probiotics in lung and mental health through modulating the gut-lung and gut-brain axes. In the current paper, we discuss the potential role of probiotics in the treatment of viral respiratory infections, including the COVID-19 disease, as major public health crisis in 2020, and influenza virus infection, as well as treatment of neurological disorders like multiple sclerosis and other mental illnesses.


Assuntos
Infecções por Coronavirus/terapia , Influenza Humana/terapia , Transtornos Mentais/terapia , Esclerose Múltipla/terapia , Pneumonia Viral/terapia , Probióticos/uso terapêutico , Infecções Respiratórias/terapia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Encéfalo/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Humanos , Imunomodulação , Influenza Humana/imunologia , Influenza Humana/microbiologia , Influenza Humana/virologia , Pulmão/imunologia , Transtornos Mentais/imunologia , Transtornos Mentais/microbiologia , Consórcios Microbianos/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Orthomyxoviridae/fisiologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Simbiose/imunologia
9.
Front Cell Infect Microbiol ; 10: 548582, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042873

RESUMO

Objective: The present study aimed at investigating the clinical risk factors for COVID-19 patients developing from moderate condition to severe condition, and providing reference for early intervention and prognosis. Methods: We collected the clinical data of 24 patients with moderate-to-severe COVID-19 who were admitted to the isolation ward of the First Affiliated Hospital of Bengbu Medical College from January, 2020 to February 20, 2020, and evaluated the data of clinical characteristics, blood test results, inflammatory index, chest CT imaging characteristics, and antiviral treatment, comparing this with the clinical data of 41 patients with moderate condition in the same period. From this comparison we thus summarized the current knowledge of potential risk factors for COVID-19 patients developing from moderate to severe condition. Results: (1) Clinical characteristics: The moderate-to-severe group and the moderate group in terms of combined common underlying diseases and respiratory frequency showed significant difference statistically (t-value were 13.32, 6.17, respectively, P < 0.05), while no significant difference between the two groups in gender, age, or clinical symptoms was statistically observed(P > 0.05). (2) Analysis of blood test results: The lymphocyte count and plasma albumin of the moderate-to-severe group were significantly lower than those of the moderate group (t-values were 4.16, 4.11, respectively, P < 0.05), and the blood glucose and urea of the moderate-to-severe group were significantly higher than those of the moderate group (t-value were 3.27, 4.19, respectively, P < 0.05). However, there was no significant difference in terms of white blood cell count (WBC), platelet count (PLT), and glutamic-pyruvic transaminase (GPT) (P > 0.05). (3) Comparison of inflammatory indicators: The level of IL-6 and CRP of the moderate-to-severe group were significantly higher than those of the moderate group (t-values were 2.84, 4.88, respectively, P < 0.05). (4) Imaging comparison: As for patients with moderate COVID-19, the imaging manifestations were the concurrence of ground-glass opacity, patchy shadow, and consolidation shadow in both lungs, diffuse ground-glass opacity in both lungs accompanied by air bronchogram, and large area consolidation of both lungs with pulmonary interstitial changes. The possibility for these patients to develop into severe condition increased, and the differences were statistically significant (t = 10.92, P < 0.05). (5) Clinical antiviral treatment: There was no statistically significant difference in the combination of two or three antiviral drugs between the two groups (χ2 = 0.05, P > 0.05). Conclusion: Current evidence suggested that the combination of common underlying diseases, respiratory frequency, lymphocyte count, blood glucose, albumin, urea level, inflammatory factors (CRP, IL-6), and imaging manifestations collectively contributed to the potential risk factors for the development of COVID-19 from moderate condition to severe condition. Particular attention should be paid to early detection and intervention during clinical work, which will be of vital significance to the ascent of the recovery rate as well as the reduction of mortality.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Betacoronavirus/fisiologia , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/imunologia , Progressão da Doença , Feminino , Hospitalização , Humanos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto Jovem
10.
Nat Commun ; 11(1): 5086, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033248

RESUMO

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Carga Viral
11.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 136-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093777

RESUMO

Background: Interstitial lung disease (ILD) is a common complication of primary Sjögren's syndrome (pSS). Because there is a paucity of literature on the management of pSS-associated ILD (pSS-ILD), this retrospective cohort study assessed the efficacy of azathioprine and mycophenolate therapy in adult patients with pSS-ILD. Methods: A retrospective cohort study was performed using electronic health records to identify adults meeting the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for pSS. The presence of pSS-ILD was confirmed by characteristic high-resolution computed tomography and/or histopathology findings. Sociodemographic, clinical, and pulmonary function test (PFT) data were abstracted for patients meeting the criteria and followed longitudinally from the date of their ILD diagnosis. PFT values were anchored on time of treatment start, and linear mixed-effects modeling was used to analyze changes in diffusion capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) before and after treatment initiation. Results: We identified 19 subjects who had pSS-ILD, of whom seven were treated with azathioprine and seven were treated with mycophenolate. Within the azathioprine treated group, FVC% slope change trended toward improvement from a rate of -9.8% per month pre-treatment to 2.1% per month post-treatment (p = 0.13). Within the mycophenolate treated group, FVC% slope change improved from a rate of 1.5% per month pre-treatment to 4.3% per month post-treatment (p = 0.02) and DLCO% slope changed from a rate of -3.8% to -1.3% per month (p = 0.01) after therapy start. Conclusions: Mycophenolate treatment was associated with significant improvement in PFTs of pSS-ILD patients over time, and azathioprine treatment followed a similar non-significanttrend. Additional prospective studies are needed to further evaluate these findings. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 136-147).


Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Azatioprina/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Imunossupressores/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Fatores de Tempo , Resultado do Tratamento
12.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 231-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093788

RESUMO

Background: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Objective: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. Methods: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. Results: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. Conclusion: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Antibacterianos/uso terapêutico , Progressão da Doença , Evolução Fatal , Volume Expiratório Forçado , Humanos , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Capacidade Vital
13.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037188

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Assuntos
Apoptose/imunologia , Betacoronavirus/patogenicidade , Caspase 8/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Necroptose/imunologia , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Animais , Caspase 8/genética , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 687-692, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958124

RESUMO

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


Assuntos
Asma , Modelos Animais de Doenças , Hipersensibilidade , Neutrófilos , Pyroglyphidae , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Regulação da Expressão Gênica/imunologia , Hipersensibilidade/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Pyroglyphidae/imunologia , Distribuição Aleatória
15.
Clin Immunol ; 220: 108576, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32866645

RESUMO

Upper respiratory tract is the primary site of SARS-CoV-2 replication. Releasing of pro and anti-inflammatory mediators plays an important role in the immunopathogenesis of Coronavirus Disease 2019 (COVID-19). The aim of this study was to evaluate the early inflammatory response in upper airway by measuring of IFN-γ, TGF-ß1 and RANTES at mRNA level. Forty five SARS-CoV-2 infected patients were enrolled, whose were divided in two groups: asymptomatic and symptomatic. Twenty healthy persons, SARS-CoV-2 negative were included as controls. Higher IFN-γ expression was detected in SARS-CoV-2 infected patients in comparison with controls (p = 0.0393). IFN-γ expression was increased in symptomatic patients (p = 0.0405). TGF-ß1 and RANTES expressions were lower in SARS-CoV-2 infected patients than controls (p < 0.0001; p = 0.0011, respectively). A significant correlation between IFN-γ and TGF-ß1 was observed in SARS-CoV-2 asymptomatic patients (r = +0.61, p = 0.0014). The findings suggest that imbalance between IFN-γ and TGF-ß1 expression could be an impact in clinical expression of SARS-CoV-2 infection.


Assuntos
Betacoronavirus/patogenicidade , Quimiocina CCL5/genética , Infecções por Coronavirus/imunologia , Interferon gama/genética , Pneumonia Viral/imunologia , RNA Mensageiro/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Doenças Assintomáticas , Betacoronavirus/imunologia , Estudos de Casos e Controles , Quimiocina CCL5/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferon gama/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Nasofaringe/imunologia , Nasofaringe/patologia , Nasofaringe/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , RNA Mensageiro/imunologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta1/imunologia
16.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
17.
Eur J Immunol ; 50(9): 1283-1294, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32910469

RESUMO

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Isotipos de Imunoglobulinas/sangue , Pulmão/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/classificação , Linfócitos B/virologia , Betacoronavirus/imunologia , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Proliferação de Células , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Estudos Transversais , Citocinas/genética , Citocinas/imunologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/imunologia , Humanos , Imunidade Humoral , Memória Imunológica , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Cultura Primária de Células , Índice de Gravidade de Doença , Análise de Sobrevida
18.
Anim Sci J ; 91(1): e13450, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32881233

RESUMO

Mycoplasma pneumonia of swine (MPS) is caused by Mycoplasma hyopneumoniae (M.hp) and is a common chronic respiratory disease of pigs. Recently, a genetically selected variant of the Landrace pig (Miyagino L2) has a lower incidence of pulmonary MPS lesions. We investigated the pathological and immunological characteristics of MPS resistance in these pigs (n = 24) by comparing with the normal landrace pig (control: n = 24). The pathological MPS lung lesion score in MPS-selected landrace pigs was significantly lower than in the control. The gene expression of interleukin (IL)-12p40, which acts as a chemoattractant and a component of the bioactive cytokines IL-12 and IL-23, was significantly higher at the hilar lymph nodes, lung, and spleen in MPS-selected landrace pigs than in control landrace pigs, and these were negatively correlated with the macroscopic MPS lung lesion score. In summary, we demonstrate that resistance against MPS in Miyagino L2 pigs is associated with IL-12p40 up-regulation, in comparison with normal landrace pigs without the MPS vaccine. In addition, a comparative study of macroscopic MPS lung lesions and IL-12p40 gene expression in lung and hilar lymph nodes may lead to beneficial selection traits for the genetic selection for MPS resistance in pigs.


Assuntos
Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/metabolismo , Pulmão/imunologia , Linfonodos/imunologia , Pneumonia Suína Micoplasmática/genética , Pneumonia Suína Micoplasmática/imunologia , Suínos/genética , Suínos/imunologia , Animais , Expressão Gênica , Predisposição Genética para Doença , Masculino , Característica Quantitativa Herdável , Seleção Genética , Regulação para Cima/genética
19.
PLoS One ; 15(9): e0239668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32970762

RESUMO

We developed an approach for substantial attenuation of Mycobacterium tuberculosis by prolonged culturing under gradually acidifying conditions. Bacteria subjected to acidification lost the capacity to form colonies on solid media, but readily resuscitated their growth in the murine host, providing a useful model to study in vivo development of infection mimicking latent and reactivation tuberculosis (TB) in humans. Here we characterize biomarkers of lung pathology and immune responses triggered by such attenuated bacteria in genetically TB-susceptible and resistant mice. In susceptible I/St mice, CFU counts in lungs and spleens were ~1.5-log higher than in resistant B6 mice, accompanied by diffuse pneumonia and excessive lung infiltration with highly activated CD44+CD62L- T-lymphocytes resulting in death between months 7-9 post challenge. B6 mice were characterized by development of local inflammatory foci, higher production of pro-inflammatory IL-6 and IL-11 cytokines and a more balanced T-cell activation in their lungs. CFU counts remained stable in B6 mice during the whole 18-mo observation period, and all mice survived. Thus, we established a mouse model of fatal reactivation TB vs. indefinite mycobacterial possession after identical challenge and characterized the features of immune responses in the lung tissue underlining these polar phenotypes.


Assuntos
Predisposição Genética para Doença , Interleucinas/metabolismo , Pulmão/imunologia , Ativação Linfocitária , Tuberculose Pulmonar/imunologia , Tuberculose Esplênica/imunologia , Animais , Carga Bacteriana , Células Cultivadas , Feminino , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Interleucinas/genética , Selectina L/genética , Selectina L/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Baço/imunologia , Baço/microbiologia , Linfócitos T/imunologia , Tuberculose Pulmonar/genética , Tuberculose Esplênica/genética
20.
Nucleic Acids Res ; 48(19): e109, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32978944

RESUMO

Transcriptome-wide association studies (TWASs) integrate expression quantitative trait loci (eQTLs) studies with genome-wide association studies (GWASs) to prioritize candidate target genes for complex traits. Several statistical methods have been recently proposed to improve the performance of TWASs in gene prioritization by integrating the expression regulatory information imputed from multiple tissues, and made significant achievements in improving the ability to detect gene-trait associations. Unfortunately, most existing multi-tissue methods focus on prioritization of candidate genes, and cannot directly infer the specific functional effects of candidate genes across different tissues. Here, we propose a tissue-specific collaborative mixed model (TisCoMM) for TWASs, leveraging the co-regulation of genetic variations across different tissues explicitly via a unified probabilistic model. TisCoMM not only performs hypothesis testing to prioritize gene-trait associations, but also detects the tissue-specific role of candidate target genes in complex traits. To make full use of widely available GWASs summary statistics, we extend TisCoMM to use summary-level data, namely, TisCoMM-S2. Using extensive simulation studies, we show that type I error is controlled at the nominal level, the statistical power of identifying associated genes is greatly improved, and the false-positive rate (FPR) for non-causal tissues is well controlled at decent levels. We further illustrate the benefits of our methods in applications to summary-level GWASs data of 33 complex traits. Notably, apart from better identifying potential trait-associated genes, we can elucidate the tissue-specific role of candidate target genes. The follow-up pathway analysis from tissue-specific genes for asthma shows that the immune system plays an essential function for asthma development in both thyroid and lung tissues.


Assuntos
Estudo de Associação Genômica Ampla , Modelos Estatísticos , Locos de Características Quantitativas , Transcriptoma , Asma/genética , Asma/imunologia , Predisposição Genética para Doença , Humanos , Pulmão/imunologia , Herança Multifatorial/genética , Especificidade de Órgãos , Glândula Tireoide/imunologia
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