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1.
J Thromb Haemost ; 22(1): 188-198, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37748582

RESUMO

BACKGROUND: During infection, neutrophil extracellular traps (NETs) are associated with severity of pulmonary diseases such as acute respiratory disease syndrome. NETs induce subsequent immune responses, are directly cytotoxic to pulmonary cells, and are highly procoagulant. Anticoagulation treatment was shown to reduce in-hospital mortality, indicating thromboinflammatory complications. However, data are sparsely available on the involvement of NETs in secondary events after virus clearance, which can lead to persistent lung damage and postacute sequelae with chronic fatigue and dyspnea. OBJECTIVES: This study focuses on late-phase events using a murine model of viral lung infection with postacute sequelae after virus resolution. METHODS: C57BL/6JRj mice were infected intranasally with the betacoronavirus murine coronavirus (MCoV, strain MHV-A95), and tissue samples were collected after 2, 4, and 10 days. For NET modulation, mice were pretreated with OM-85 or GSK484 and DNase I were administered intraperitoneally between days 2 to 5 and days 4 to 7, respectively. RESULTS: Rapid, platelet-attributed thrombus formation was followed by a second, late phase of thromboinflammation. This phase was characterized by negligible virus titers but pronounced tissue damage, apoptosis, oxidative DNA damage, and presence of NETs. Inhibition of NETs during the acute phase did not impact virus burden but decreased lung cell apoptosis by 67% and oxidative stress by 94%. Prevention of neutrophil activation by immune training before virus infection reduced damage by 75%, NETs by 31%, and pulmonary thrombi by 93%. CONCLUSION: NETs are detrimental inducers of tissue damage during respiratory virus infection but do not contribute to virus clearance.


Assuntos
Infecções por Coronavirus , Coronavirus , Armadilhas Extracelulares , Trombose , Animais , Camundongos , Neutrófilos , Tromboinflamação , Modelos Animais de Doenças , Inflamação/complicações , Trombose/complicações , Camundongos Endogâmicos C57BL , Pulmão , Infecções por Coronavirus/complicações
2.
Nat Cell Biol ; 25(12): 1833-1847, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37945904

RESUMO

MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.


Assuntos
Neoplasias da Mama , Epigênese Genética , Receptor alfa de Estrogênio , Amplificação de Genes , Proteínas Proto-Oncogênicas c-maf , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Cromatina , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Proteínas Proto-Oncogênicas c-maf/genética
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