RESUMO
An active epidemiological investigation of COVID-19 cases in the Setagaya ward of Tokyo revealed that household transmission was the main route of infection spread. This study aimed to identify the factors affecting household transmission in patients diagnosed with COVID-19 and their cohabitants, during the wild type virus (December 2020) and alpha variant epidemic (May 2021). Index case factors significantly associated with household transmission for both wild type (WT) and alpha variant (AV), were at least 3 days from onset to diagnosis (WT: risk ratio [RR] 1.44, 95% confidence interval [CI] 1.16-1.79/AV: RR 1.66, CI 1.32-2.08), and a household size of three or more people (WT: RR 1.37, CI 1.10-1.72/AV: RR 1.29, CI 1.05-1.59). There were also significant differences in age ≥ 65 (RR 2.39, CI 1.26-4.54) and symptomatic at diagnosis (RR 3.05, CI 1.22-7.63) in index cases of WT. Among cohabitants, factors associated with household transmission for both strains were being the spouse/partner of the index case (WT: RR 1.68, CI 1.21-1.82/AV: RR 1.97, CI 1.59-2.43) and at least 3 days from onset to diagnosis of the index case (WT: RR 1.48, CI 1.34-2.10/ AV: RR 1.86, CI1.52-2.28). Early diagnosis and isolation are effective for preventing household transmission.
RESUMO
Prostaglandin E2 (PGE2) is a critical factor in the pathogenesis of dioxin-induced neonatal hydronephrosis. Since the PGE2 receptor has four subtypes, EP1 - EP4, this study was aimed to challenge the hypothesis that at least one of the four subtypes is responsible for the pathogenesis of dioxin-induced hydronephrosis. To this end, we used mouse pups, with a C57BL/6 J background, genetically lacking EP1, EP2, or EP3, and wild-type pups in whom EP4 was suppressed by administering ONO-AE3-208 (ONO), an EP4 antagonist, from postnatal day 1 (PND 1) to PND 13. To expose the pups to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via lactation, the dams were administered TCDD at an oral dose of 20 µg/kg on PND 1. The pups' urine and kidneys were collected on PND 14 for urinalysis and histological examination, respectively. We found that the incidence of hydronephrosis was 80% in the EP1+/+ group, but was markedly reduced to 28.6% in the EP1-/- group despite the fact that PGE2 concentration in the urine was similarly increased in the both groups. In contrast, the incidence of hydronephrosis was 80% and 100% in the EP2+/+ and EP2-/-groups, respectively, and 88.9% and 100% in the EP3+/+ and EP3-/- groups, respectively. With regard to EP4, the incidence of hydronephrosis in vehicle (saline)-treated groups and ONO-treated was 88.9% and 100%, respectively. Therefore, we concluded that among PGE2 receptor subtypes, EP1 plays a predominant role in the onset of TCDD-induced neonatal hydronephrosis in mouse pups.
Assuntos
Hidronefrose/induzido quimicamente , Hidronefrose/fisiopatologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Prostaglandina E Subtipo EP2/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Prostaglandina E Subtipo EP2/genéticaRESUMO
Dioxin is a ubiquitous environmental pollutant that induces toxicity when bound to the aryl hydrocarbon receptor (AhR). Significant differences in susceptibility of mouse strains to dioxin toxicity are largely accounted for by the dissociation constant of binding to dioxins of AhR subtypes encoded by different alleles. We showed that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), components of a prostanoid synthesis pathway, play essential roles in the onset of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hydronephrosis of neonatal mice. Although C57BL/6J and BALB/cA mice harbor AhR receptors highly responsive to TCDD, they were found by chance to differ significantly in the incidence of TCDD-induced hydronephrosis. Therefore, the goal of the present study was to determine the molecular basis of this difference in susceptibility to TCDD toxicity. For this purpose, we administered C57BL/6J and BALB/cA dams' TCDD at an oral dose of 15 or 80 µg/kg on postnatal day (PND) 1 to expose pups to TCDD via lactation, and the pups' kidneys were collected on PND 7. The incidence of hydronephrosis in C57BL/6J pups (64%) was greater than in BALB/cA pups (0%, p < 0.05), despite similarly increased levels of COX-2 mRNA. The incidence of hydronephrosis in these mouse strains paralleled the levels of renal mPGES-1 mRNA and early growth response 1 (Egr-1) that modulates mPGES-1 gene expression, as well as PGE2 concentrations in urine. Although these mouse strains possess AhR alleles tightly bound to TCDD, their difference in incidence and severity of hydronephrosis can be explained, in part, by differences in the expression of mPGES-1 and Egr-1.
Assuntos
Dinoprostona/biossíntese , Hidronefrose/induzido quimicamente , Rim/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Animais , Animais Recém-Nascidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hidronefrose/genética , Hidronefrose/metabolismo , Hidronefrose/patologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Rim/metabolismo , Rim/patologia , Lactação , Exposição Materna , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Prostaglandina-E Sintases , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo , Índice de Gravidade de Doença , Especificidade da Espécie , Fatores de TempoRESUMO
Hydronephrosis is a common disease characterized by dilation of the renal pelvis and calices, resulting in loss of kidney function in the most severe cases. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces nonobstructive hydronephrosis in mouse neonates through upregulation of prostaglandin E2 (PGE2) synthesis pathway consisting of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) by a yet unknown mechanism. We here studied possible involvement of cytosolic phospholipase A2α (cPLA2α) in this mechanism. To this end, we used a cPLA2α-null mouse model and found that cPLA2α has a significant role in the upregulation of the PGE2 synthesis pathway through a noncanonical pathway of aryl hydrocarbon receptor. This study is the first to demonstrate the predominant role of cPLA2α in hydronephrosis. Elucidation of the pathway leading to the onset of hydronephrosis using the TCDD-exposed mouse model will deepen our understanding of the molecular basis of nonobstructive hydronephrosis in humans.
Assuntos
Dinoprostona/biossíntese , Fosfolipases A2 do Grupo IV/metabolismo , Hidronefrose/patologia , Animais , Ciclo-Oxigenase 2/biossíntese , Citocromo P-450 CYP1A1/genética , Modelos Animais de Doenças , Feminino , Expressão Gênica , Fosfolipases A2 do Grupo IV/genética , Hidronefrose/induzido quimicamente , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Oxirredutases Intramoleculares/biossíntese , Oxirredutases Intramoleculares/genética , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dibenzodioxinas Policloradas , Prostaglandina-E Sintases , RNA Mensageiro/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/genética , Regulação para CimaRESUMO
INTRODUCTION: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17ß-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls. METHODS: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERß selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry. RESULTS: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc. CONCLUSION: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.
Assuntos
Estradiol/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Transdução de Sinais/efeitos dos fármacos , Idoso , Western Blotting , Células Cultivadas , Cromatografia Líquida , Antagonistas do Receptor de Estrogênio/farmacologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibronectinas/biossíntese , Fibronectinas/efeitos dos fármacos , Fibrose/metabolismo , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Espectrometria de Massas em TandemRESUMO
Hydronephrosis induced in the kidney of neonatal mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via lactation is a sensitive and characteristic hallmark of TCDD teratogenicity. We previously found that cyclooxygenase-2 (COX-2) activity induced in mouse neonate kidneys by lactational TCDD exposure is required for this toxicity. COX-2 is an inducible form of cyclooxygenase and is responsible for producing prostaglandins (PGs) and thromboxane. PGE(2), a prostaglandin, is elevated in TCDD-exposed mouse pups. In this study, we investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible form of PGE(2) synthase, in TCDD-induced hydronephrosis. A dose of 10 µg TCDD/kg to dams increased mPGES-1 messenger RNA abundance, urinary PGE(2) levels, and the incidence of hydronephrosis in mPGES-1 wild-type pups. In homozygous mPGES-1 knockout (KO) mice, in contrast, TCDD-induced hydronephrosis was suppressed, demonstrating an essential role of mPGES-1 in the response. Lack of the mPGES-1 gene also suppressed urinary PGE(2) level to near the basal level in TCDD-exposed pups. In conclusion, mPGES-1 upregulation upon lactational TCDD exposure is a causal factor for TCDD-induced hydronephrosis in mouse neonates.
Assuntos
Hidronefrose/induzido quimicamente , Oxirredutases Intramoleculares/metabolismo , Rim/efeitos dos fármacos , Lactação , Exposição Materna , Dibenzodioxinas Policloradas/toxicidade , Animais , Animais Recém-Nascidos , Dinoprostona/urina , Feminino , Hidronefrose/enzimologia , Hidronefrose/genética , Hidronefrose/prevenção & controle , Oxirredutases Intramoleculares/deficiência , Oxirredutases Intramoleculares/genética , Rim/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandina-E Sintases , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
Polychlorinated biphenyls (PCBs) are a group of persistent pollutants that are detected in maternal serum and umbilical cord, suggesting that fetal exposure also needs to be considered. The effects of dioxin-like PCB congeners 3,3',4,4'-tetrachlorobiphenyl (PCB77) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) and a non-dioxin-like compound 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) on the expression of endothelial nitric oxide synthase (eNOS), known to maintain blood flow to the fetus, in human umbilical vein endothelial cells (HUVECs) were investigated. The mRNA levels of eNOS, aryl hydrocarbon receptor (AhR) and cytochrome P450 (CYP) 1A1 in cells treated with 5 microM PCBs for 24 hours were analysed by real-time RT-PCR. Cells were also treated with alpha-naphthoflavone (alpha NF), an AhR antagonist or ICI 182780, an estrogen receptor (ER) antagonist, one hour prior to PCB exposure, to observe the effects of these receptors on eNOS modulation. Each PCB increased the eNOS mRNA level by 4.5-fold that was markedly inhibited by alphaNF. ERs were also suspected of altering eNOS levels because ICI 182780 treatment resulted in a decrease in the eNOS level. These results suggest that the eNOS mRNA expression increases due to the action of PCBs related to both AhR and ERs in HUVECs, and that maternal PCB exposure could influence fetal circulation.