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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2019.tde-16102019-144432
Document
Author
Full name
Karla Barroso Feitosa
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Costa, Soraia Kátia Pereira (President)
Lima, Wothan Tavares de
Pedreira Filho, Walter dos Reis
Silva, Carla Lima da
Title in Portuguese
Caracterização do mecanismo de ativação da via de sinalização do receptor da resposta inata TLR4 nas ações deletérias do poluente ambiental 1,2-naftoquinona.
Keywords in Portuguese
1,2-naftoquinona
Inflamação alérgica
Molecula de adesão
Quimiotaxia
Remodelamento pulmonar
TLR4
Abstract in Portuguese
O aumento da poluição do ar ambiente (PAA) correlaciona-se com uma alta incidência de efeitos adversos na saúde da população, resultando em maior número de óbitos causados por complicações respiratórias e cardiovasculares, particularmente, em individuos susceptiveis (ex.: neonatos). Resultados do grupo mostram que camundongos neonatos C57Bl/6, quando expostos ao PAA 1,2-naftoquinona (1,2-NQ), um dos contaminantes do MP eliminado na exaustão do diesel, exibem maior susceptibilidade à asma, paralelo ao aumento da resposta humoral e células Th2 / Th17, via mecanismo regulado por receptores da resposta inata TLR4. Os objetivos deste estudo consistem em: i) Avaliar os efeitos da exposição precoce à 1,2-NQ sobre a mecânica respiratória, além de caracterizar mecanismos celulares envolvidos na exacerbação dessa resposta em animais selvagens e nocautes TLR4, ii) Averiguar e validar em PMN obtidos de voluntários, a influência da 1,2-NQ sobre a funcionalidade dessas células e o papel dos TLR4. Camundongos selvagens e nocautes TLR4 (2 22 g) foram usados, expostos à 1,2-NQ, e os parâmetros funcionais e celulares avaliados. PMN foram obtidos do sangue periférico de voluntários sadios, e submetido ao teste de quimiotaxia em microplacas. Camundongos selvagens expostos à 1,2-NQ exibem alteração estrutural (remodelamento) no pulmão, caracterizada por aumento na produção de muco e da área/espessura da musculatura lisa peri-bronquica, que intensificou a hiperresponsividade das vias aéreas frente à MCh. No epitelio pulmonar dos animais selvagens expostos à 1,2-NQ, o desafio antigênico aumentou a imunorreatividade para ICAM, VCAM-1 e PECAM-1, sendo esse efeito (exceto PECAM-1) supresso em animais nocautes TLR4. A incubação da 1,2-NQ com os PMN humano não afetou a quimiotaxia frente ao fMLP. A 1,2-NQ favoreceu per se a quimiotaxia dos eosinófilos e aumentou a migração frente à eotaxina. Esse efeito foi bloqueado pelo LPS-RS. Conclui-se que os receptores TLR4 regulam a funcionabilidade dos PMN, sendo esse efeito controlado pela imunorregulação das ICAM-1 e VCAM-1 (mas não PECAM), atuando como feedback (+) na exacerbação da eosinofilia alérgica em pulmão de camundongos expostos à 1,2-NQ na fase neonatal. Em PMN humano, a 1,2-NQ regula a quimiotaxia e o mecanismo pode e o TLR4 está envolvido na resposta.
Title in English
Characterization of the activation mechanism involved in the TLR4 signaling pathway during the deleterious actions of the environmental pollutant 1,2-naphthoquinone.
Keywords in English
1,2-naphthoquinone
Adhesion molecule
Asthma
Chemotaxi
Pulmonary remodelin
TLR4
Abstract in English
The increase in ambient air pollution (PAA) correlates with the higher incidence of adverse effects on the population health, resulting in a higher number of deaths due to respiratory and cardiovascular diseases, particularly in susceptible individuals (eg neonates). Previous results from our group show that neonates C57Bl / 6 mice, when exposed to 1,2- naphthoquinone (1,2-NQ), one of the MP contaminants eliminated in diesel exhaust, exhibit a greater susceptibility to allergic lung inflammation, concomitantly with increased humoral response and Th2 / Th17 cells population, via mechanism dependent on the innate TLR4 response. The aims of this study are: i) To evaluate the effects of early exposure to 1,2-NQ on respiratory mechanics, besides characterizing cellular mechanisms involved in the exacerbation of this response in wild animals and TLR4 knockouts; ii) To verify and validate in PMN obtained from volunteers, the influence of 1,2-NQ on the functionality of these cells and the role of TLR4. Both wild mice (WT) and TLR4 knockouts (KO; 2-22 g) were used, and inhaled with the 1,2-NQ. The functional and cellular parameters were evaluated. PMN were isolated from the blood of healthy volunteers and submitted to chemotaxis on microplates. Wild mice exposed to 1,2-NQ exhibit structural alteration (remodeling) in the lung, characterized by increased production of mucus and increased area / peri-bronchial smooth muscle thickness, which led to airways hyperresponsiveness to MCh. In the lung epithelium of WT mice exposed to 1,2-NQ, the antigen challenge (OVA) increased the immunoreactivity for ICAM, VCAM-1 and PECAM-1, and this effect (except PECAM-1) was suppressed in TLR4 KO mice. Incubation of 1,2-NQ with human PMN did not affect the chemotaxis of cells against fMLP, although per se favored chemotaxis of eosinophils and increase eotaxin- induced chemotaxis. It is concluded that TLR4 receptors regulate PMN function, and this effect is controlled by the immunoregulation of ICAM-1 and VCAM-1 (but not PECAM), acting as feedback (+) in the exacerbation of allergic eosinophilia in the lung of mice exposed to 1,2-NQ in the neonatal phase. In human PMN, the 1,2-NQ regulates chemotaxis and TLR4 is envolved in response.
 
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Release Date
2023-10-24
Publishing Date
2019-10-29
 
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