RESUMO
Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAH) and can be a dominant contributor to ultrafine urban particulate matter (PM). Exposure to ultrafine PM is correlated with respiratory infections and asthmatic symptoms in young children. The lung undergoes substantial growth, alveolarization, and cellular maturation within the first years of life, which may be impacted by environmental pollutants such as PM. PAHs in PM can serve as ligands for the aryl hydrocarbon receptor (AhR) that induces expression of certain isozymes in the cytochrome P-450 superfamily, such as CYP1A1 and CYP1B1, localized in specific lung cell types. Although AhR activation and induction has been widely studied, its context within PM exposure and impact on the developing lung is poorly understood. In response, we have developed a replicable ultrafine premixed flame particle (PFP) generating system and used in vitro and in vivo models to define PM effects on AhR activation in the developing lung. We exposed 7-day neonatal and adult rats to a single 6-h PFP exposure and determined that PFPs cause significant parenchymal toxicity in neonates. PFPs contain weak AhR agonists that upregulate AhR-xenobiotic response element activity and expression and are capable inducers of CYP1A1 and CYP1B1 expression in both ages with different spatial and temporal patterns. Neonatal CYP1A1 expression was muted and delayed compared with adults, possibly because of differences in the enzyme maturation. We conclude that the inability of neonates to sufficiently adapt in response to PFP exposure may, in part, explain their susceptibility to PFP and urban ultrafine PM.
Assuntos
Sistema Enzimático do Citocromo P-450/biossíntese , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Material Particulado/farmacologia , Silicones/farmacologia , Animais , Animais Recém-Nascidos , Hidrocarboneto de Aril Hidroxilases/biossíntese , Células Cultivadas , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1B1 , Indução Enzimática , Humanos , Pulmão/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Hidrocarboneto Arílico/metabolismo , Células U937 , Regulação para Cima/efeitos dos fármacosRESUMO
How the aryl hydrocarbon receptor (AhR) regulates dendritic-cell (DC) differentiation is unknown. We show that activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused enhanced differentiation from immature DCs (IDCs) to mature DCs (MDCs) in the bone-marrow-derived DCs (BMDC) from B6 wild-type mice but not in the BMDCs from AhR-null mice as indicated by the expression of CD11c and class II major histocompatibility complex (MHC). Enhanced maturation of BMDCs was associated with elevated levels of CD86 and an increased AhR-dependent nuclear accumulation of nuclear factor-kappa-light-chain enhancer of activated B cell (NF-κB) member RelB in BMDCs. The expression of interleukin (IL) 10 and chemokine DC-CK1 was suppressed, whereas that of CXCL2, CXCL3 and IL-22 was significantly increased in AhR-activated BMDCs. Furthermore, TCDD induced expression of the regulatory enzymes indoleamine 2,3-dioxygenase (IDO1) and indoleamine 2,3-dioxygenase-like 1 (IDO2). Increased expression of IDO2 was associated with coexpression of the cell-surface marker CCR6. Interestingly, mRNA expression of the chemokine receptor CCR6 was drastically decreased in AhR-null IDCs and MDCs. Overall, these data demonstrate that AhR modifies the maturation of BMDCs associated with the induction of the regulatory enzyme IDO and altered expression of cytokine, chemokines and DC-specific surface markers and receptors.
Assuntos
Células Dendríticas/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , NF-kappa B/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Quimiocinas/genética , Quimiocinas/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Receptores CCR6/metabolismo , Transdução de Sinais/genética , Ativação Transcricional/genética , Interleucina 22RESUMO
COVID-19 cases have surpassed the 109 + million markers, with deaths tallying up to 2.4 million. Tens of thousands of papers regarding COVID-19 have been published along with countless bibliometric analyses done on COVID-19 literature. Despite this, none of the analyses have focused on domain entities occurring in scientific publications. However, analysis of these bio-entities and the relations among them, a strategy called entity metrics, could offer more insights into knowledge usage and diffusion in specific cases. Thus, this paper presents an entitymetric analysis on COVID-19 literature. We construct an entity-entity co-occurrence network and employ network indicators to analyze the extracted entities. We find that ACE-2 and C-reactive protein are two very important genes and that lopinavir and ritonavir are two very important chemicals, regardless of the results from either ranking.