ABSTRACT
OBJECTIVE: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1. METHODS: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h. RESULTS: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours. CONCLUSIONS: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.
Subject(s)
Infant, Premature , NF-kappa B , Humans , Infant, Newborn , Asphyxia , Biomarkers , Hypoxia , NF-kappa B/metabolism , Proto-Oncogene Proteins c-akt , Vascular Endothelial Growth Factor Receptor-1ABSTRACT
Abstract Objective: Given the high proliferative activity of germinal matrix and its direct correlation with hypoxemia, it is necessary to investigate the possible molecular regulation pathways, to understand the existing clinical relationship between the hypoxic-ischemic insult and the biomarkers NF-kB, AKT-3, Parkin, TRK-C and VEGFR-1. Methods: A hundred and eighteen germinal matrix samples of the central nervous system of patients who died in the first 28 days of life were submitted to histological and immunohistochemistry analysis to identify the tissue immunoexpression of those biomarkers related to asphyxia, prematurity, and death events within 24h. Results: A significantly increased tissue immunoexpression of NF-kB, AKT-3 and Parkin was observed in the germinal matrix of preterm infants. In addition, significantly decreased tissue immunoexpression of VEGFR-1 and NF-kB was observed in patients who experienced asphyxia followed by death within 24 hours. Conclusions: The results suggest a direct involvement between the hypoxic-ischemic insult and NF-kB and VEGFR-1 markers since a decreased immunoexpression of these biomarkers was observed in asphyxiated patients. Furthermore, it is suggested that there was not enough time for VEGFR-1 to be transcribed, translated and expressed on the surface of the plasma membrane. This temporality can be observed in the relationship between NF-kB expression and the survival time of individuals who died within 24 hours, suggesting that this factor is essential for the production of VEGFR-1 and, therefore, to carry out the necessary remodeling effect to neovascularize the affected region.
RESUMO Objetivo: Dada a alta atividade proliferativa da matriz germinativa e sua correlação direta com a hipoxemia, é necessário investigar as possíveis vias de regulação molecular para entender a relação clínica existente entre o insulto hipóxico-isquêmico e os biomarcadores NF-kB, AKT -3, Parkina, TRK-C e VEGFR-1. Métodos: Cento e dezoito amostras de matriz germinativa do sistema nervoso central de pacientes que faleceram nos primeiros 28 dias de vida foram submetidas a análise histológica e imuno-histoquímica para identificar a imunoexpressão tecidual desses biomarcadores relacionados a eventos de asfixia, prematuridade e óbito em 24 horas. Resultados: Observou-se uma imunoexpressão tecidual significativamente aumentada de NF-kB, AKT-3 e Parkin na matriz germinativa de prematuros. Além disso, constatou-se uma imunoexpressão tecidual significativamente diminuída de VEGFR-1 e de NF-kB em pacientes que apresentaram asfixia seguida de morte em 24 horas. Conclusões: Os resultados sugerem o envolvimento direto entre o insulto hipóxico-isquêmico e os marcadores NF-kB e VEGFR-1, visto que se observou uma imunoexpressão diminuída destes biomarcadores nos pacientes asfixiados. Além disso, sugere-se que não houve tempo suficiente para que o VEGFR-1 fosse transcrito, traduzido e expresso na superfície da membrana plasmática. Essa temporalidade pode ser observada na relação entre a expressão de NF-kB e o tempo de vida dos indivíduos que morreram em 24 horas, o que sugere que esse fator é essencial para a produção do VEGFR-1 e, portanto, para realizar o efeito remodelador necessário para neovascularizar a região afetada.
ABSTRACT
Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.
