RESUMEN
Background: India's abrupt nationwide Covid-19 lockdown internally displaced millions of migrant workers, who returned to distant rural homes. Documenting their labour market reintegration is a critical aspect of understanding the economic costs of the pandemic for India's poor. In a country marked by low and declining female labour force participation, identifying gender gaps in labour market reintegration - as a marker of both women's vulnerability at times of crisis and setbacks in women's agency - is especially important. Yet most studies of pandemic-displaced internal migrants in India are small, rely on highly selected convenience samples, and lack a gender focus. Methods: Beginning in April 2020 we enrolled roughly 4,600 displaced migrants who had, during the lockdown, returned to two of India's poorest states into a cohort observational study which tracked enrolees through July 2021. Survey respondents were randomly selected from the states' official databases of return migrants, with sampling stratified by state and gender. 85% of enrolees (3950) were working prior to the pandemic. Our difference-in-means analysis uses three survey waves conducted in July to August 2020, January to March 2021, and June to July 2021. Our analysis focuses on a balanced panel of 1780 previously working enrolees (the 45% of respondents present in the first wave that also participated in the subsequent two survey rounds). Primary outcomes of interest include labour market re-entry, earnings, and measures of vulnerability by gender. Findings: Before the March 2020 national lockdown, 98% (95% CI [97,99]) of workers were employed in the non-agricultural sector. In July 2020, one month after the end of the lockdown, incomes plummet, with both genders earning roughly 17% of their pre-pandemic incomes. 47% (95% CI [45,49]) were employed in agriculture and 37% (95% CI [35,39]) were unemployed. Remigration is critical to regaining income - by January 2021, male re-migrants report earnings on par with their pre-pandemic incomes, while men remaining in rural areas earn only 23% (95% CI [19,27]) of their pre-pandemic income. Remigration benefits women to a lesser extent - female re-migrants regain no more than 65% (95% CI [57,73]) of their pre-pandemic income at any point. Yet men and women struggle to remigrate throughout - by July 2021, no more than 63% (95% CI [60,66]) of men and 55% (95% CI [51,59]) of women had left their home villages since returning. Gender gaps in income recovery largely reflect higher rates of unemployment among women, both among those remaining in rural areas (9 percentage points (95% CI [6,13]) higher than men across waves) and among those who remigrate (13 percentage points (95% CI [9,17]) higher than men across waves). As a result, we observe gender gaps in well-being: relative to male counterparts, women across waves were 7 percentage points (95% CI [4,10]) more likely to report reduced consumption of essential goods and fared 6 percentage points (95% CI [4,7]) worse on a food insecurity index. Interpretation: Displaced migrants of both genders experienced persistent hardships for over a year after the initial pandemic lockdown. Women fare worse, driven by both lower rates of remigration and lower rates of labour market re-entry both inside and outside home villages. Some women drop out of the labour force entirely, but most unemployed report seeking or being available to work. In short, pandemic-induced labour market displacement has far-reaching, long-term consequences for migrant workers, especially women. Funding: Survey costs were funded by research grants from IZA/FCDO Gender, Growth, and Labour Markets in Low Income Countries Programme, J-PAL Jobs and Opportunity Initiative, and the Evidence-based Measures of Empowerment for Research on Gender Equality (EMERGE) program at University of California San Diego.
RESUMEN
In addition to immune cells, airway epithelial cells can contribute to and shape the immune response in the lung by secreting specific cytokines. IL-6 is a key factor in determining the effector fate of CD4(+) T cells. Here we show that under basal conditions, the IL-6 gene is already highly expressed in lung epithelial cells, but not in immune cells resident in the lung. However, upon exposure of the lungs to fungal allergens, the direct contact of ß-glucans present in the fungus cell wall with lung epithelial cells is sufficient to trigger the rapid synthesis and secretion of IL-6 protein. This posttranscriptional regulation of IL-6 in response to fungal extracts is mediated by the p38 mitogen-activated protein kinase pathway. The inhalation of ß-glucans with a nonallergenic antigen is sufficient to provide an adjuvant effect that leads to mucous hyperplasia in the airways. Thus, ß-glucans may constitute a common determinant of the fungal and plant-derived allergens responsible for some of the pathological features in allergic asthma.
Asunto(s)
Alérgenos/inmunología , Aspergillus fumigatus/inmunología , Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Epiteliales/inmunología , Regulación de la Expresión Génica/inmunología , Interleucina-6/inmunología , Mucosa Respiratoria/inmunología , beta-Glucanos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Alérgenos/química , Alérgenos/farmacología , Animales , Aspergillus fumigatus/química , Asma/metabolismo , Asma/patología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Células Cultivadas , Células Epiteliales/metabolismo , Células Epiteliales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Noqueados , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , beta-Glucanos/química , beta-Glucanos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
RATIONALE: The opportunistic pathogen Pseudomonas aeruginosa causes both acute and chronic lung infections and is particularly problematic in patients with cystic fibrosis and those undergoing mechanical ventilation. Decreased lung function contributes significantly to morbidity and mortality during P. aeruginosa infection, and damage inflicted by P. aeruginosa virulence factors contributes to lung function decline. OBJECTIVES: We sought to describe direct contribution of a bacterial phospholipase C/sphingomyelinase, PlcHR, to alteration of host lung physiology and characterize a potential therapeutic for protection of lung function. METHODS: We infected C57Bl/6 mice with P. aeruginosa wild-type or isogenic plcHR deletion strains and measured lung function using computer-controlled ventilators. For in vivo testing, miltefosine was delivered intraperitoneally 1 hour after infection. Infection and respiratory endpoints were at 24 hours after infection. MEASUREMENTS AND MAIN RESULTS: P. aeruginosa wild-type infection caused significant lung function impairment, whereas the effects of a ΔplcHR strain infection were much less severe. Surfactometry analysis of bronchoalveolar lavage fluid indicated that PlcHR decreased pulmonary surfactant function. Miltefosine has structural similarity to the PC and sphingomyelin substrates of PlcHR, and we found that it inhibits the cleavage of these choline-containing lipids in vitro. Miltefosine administration after P. aeruginosa infection limited the negative effects of PlcHR activity on lung function. CONCLUSIONS: We have directly linked production of a single virulence factor in P. aeruginosa with effects on lung function, and demonstrated that the inhibitor miltefosine protects lung function from PlcHR-dependent surfactant dysfunction.
Asunto(s)
Fibrosis Quística/microbiología , Infecciones por Pseudomonas/microbiología , Infecciones del Sistema Respiratorio/etiología , Animales , Antifúngicos/administración & dosificación , Antifúngicos/farmacología , Líquido del Lavado Bronquioalveolar/química , Fibrosis Quística/complicaciones , Modelos Animales de Enfermedad , Humanos , Inyecciones Intraperitoneales , Pulmón/efectos de los fármacos , Pulmón/microbiología , Pulmón/fisiología , Ratones , Ratones Endogámicos C57BL , Infecciones Oportunistas/microbiología , Fosforilcolina/administración & dosificación , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/patogenicidad , Respiración Artificial/efectos adversos , Infecciones del Sistema Respiratorio/microbiologíaRESUMEN
Indoleamine 2,3-dioxygenase (IDO) suppresses the functions of CD4(+) T cells through its ability to metabolize the essential amino acid tryptophan. Although the activity of IDO is required for the immunosuppression of allergic airway disease by the Toll-Like-Receptor 9 (TLR9) agonist, oligonucleotides comprised of cytosine and guanine nucleotides linked by phosphodiester bonds (CpG) DNA, it is unclear whether IDO expression by resident lung epithelial cells is sufficient to elicit these effects. Therefore, we created a transgenic mouse inducibly overexpressing IDO within nonciliated airway epithelial cells. Upon inhalation of formalin-fixed Aspergillus fumigatus hyphal antigens, the overexpression of IDO from airway epithelial cells of these mice reduced the number of CD4(+) T cells within the inflamed lung and impaired the capacity of antigen-specific splenic CD4(+) effector T cells to secrete the cytokines IL-4, IL-5, IL-13, and IFN-γ. Despite these effects, allergic airway disease pathology was largely unaffected in mice expressing IDO in airway epithelium. In support of the concept that dendritic cells are the major cell type contributing to the IDO-inducing effects of CpG DNA, mice expressing TLR9 only in the airway epithelium did not augment IDO expression subsequent to the administration of CpG DNA. Furthermore, the systemic depletion of CD11c(+) cells rendered mice incapable of CpG DNA-induced IDO expression. Our results demonstrate that an overexpression of IDO within the airway epithelium represents a novel mechanism by which the number of CD4(+) T cells recruited to the lung and their capacity to produce cytokines can be diminished in a model of allergic airway disease, and these results also highlight the critical role of dendritic cells in the antiasthmatic effects of IDO induction by CpG DNA.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Pulmón/enzimología , Activación de Linfocitos , Aspergilosis Pulmonar/enzimología , Mucosa Respiratoria/enzimología , Animales , Antígenos Fúngicos/inmunología , Aspergillus fumigatus/inmunología , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/inmunología , Broncoconstricción , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/microbiología , Línea Celular Transformada , Proliferación Celular , Técnicas de Cocultivo , Citocinas/metabolismo , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Femenino , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Quinurenina/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/fisiopatología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Oligodesoxirribonucleótidos/farmacología , Aspergilosis Pulmonar/inmunología , Aspergilosis Pulmonar/microbiología , Aspergilosis Pulmonar/fisiopatología , Ratas , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/deficiencia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo , Regulación hacia Arriba , Uteroglobina/genética , Uteroglobina/metabolismoRESUMEN
BACKGROUND: Nitrogen dioxide (NO2) is an air pollutant associated with poor respiratory health, asthma exacerbation, and an increased likelihood of inhalational allergies. NO2 is also produced endogenously in the lung during acute inflammatory responses. NO2 can function as an adjuvant, allowing for allergic sensitization to an innocuous inhaled antigen and the generation of an antigen-specific Th2 immune response manifesting in an allergic asthma phenotype. As CD11c+ antigen presenting cells are considered critical for naïve T cell activation, we investigated the role of CD11c+ cells in NO2-promoted allergic sensitization. METHODS: We systemically depleted CD11c+ cells from transgenic mice expressing a simian diphtheria toxin (DT) receptor under of control of the CD11c promoter by administration of DT. Mice were then exposed to 15 ppm NO2 followed by aerosolized ovalbumin to promote allergic sensitization to ovalbumin and were studied after subsequent inhaled ovalbumin challenges for manifestation of allergic airway disease. In addition, pulmonary CD11c+ cells from wildtype mice were studied after exposure to NO2 and ovalbumin for cellular phenotype by flow cytometry and in vitro cytokine production. RESULTS: Transient depletion of CD11c+ cells during sensitization attenuated airway eosinophilia during allergen challenge and reduced Th2 and Th17 cytokine production. Lung CD11c+ cells from wildtype mice exhibited a significant increase in MHCII, CD40, and OX40L expression 2 hours following NO2 exposure. By 48 hours, CD11c+MHCII+ DCs within the mediastinal lymph node (MLN) expressed maturation markers, including CD80, CD86, and OX40L. CD11c+CD11b- and CD11c+CD11b+ pulmonary cells exposed to NO2 in vivo increased uptake of antigen 2 hours post exposure, with increased ova-Alexa 647+ CD11c+MHCII+ DCs present in MLN from NO2-exposed mice by 48 hours. Co-cultures of ova-specific CD4+ T cells from naïve mice and CD11c+ pulmonary cells from NO2-exposed mice produced IL-1, IL-12p70, and IL-6 in vitro and augmented antigen-induced IL-5 production. CONCLUSIONS: CD11c+ cells are critical for NO2-promoted allergic sensitization. NO2 exposure causes pulmonary CD11c+ cells to acquire a phenotype capable of increased antigen uptake, migration to the draining lymph node, expression of MHCII and co-stimulatory molecules required to activate naïve T cells, and secretion of polarizing cytokines to shape a Th2/Th17 response.
Asunto(s)
Alérgenos , Asma/inmunología , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/inmunología , Polaridad Celular , Pulmón/inmunología , Óxido Nítrico/inmunología , Administración por Inhalación , Animales , Asma/prevención & control , Antígeno CD11b/metabolismo , Antígeno CD11c/genética , Movimiento Celular , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Genes Codificadores de los Receptores de Linfocitos T , Factor de Crecimiento Similar a EGF de Unión a Heparina , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Óxido Nítrico/administración & dosificación , Ovalbúmina/inmunología , Fragmentos de Péptidos/inmunología , Fenotipo , Factores de TiempoRESUMEN
BACKGROUND: Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFalpha and IL-1beta, rather than as regulatory cytokine. OBJECTIVE: To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease. METHODS: Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects. RESULTS: The levels of the proinflammatory biomarkers TNFalpha and IL-1beta were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p < 0.01). Hierarchical regression analysis in the total study cohort indicates that the relationship between asthma and lung function could be mediated by IL-6. Among Th2 cytokines only IL-13 (p < 0.05) was also elevated in the asthmatic group, and positively correlated with IL-6 levels (rS = 0.53, p < 0.05). CONCLUSIONS: In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.
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Asma/inmunología , Citocinas/inmunología , Interleucina-6/inmunología , Pulmón/inmunología , Neumonía/inmunología , Hipersensibilidad Respiratoria/inmunología , Adulto , Femenino , Humanos , Masculino , Neumonía/complicacionesRESUMEN
Allergic asthma is caused by inhaled allergens and is characterized by airway eosinophilia, as well as mucus hypersecretion, which can lead to airflow obstruction. Despite the association of increased IL-6 levels with human atopic asthma, the contribution of IL-6 to the development of allergic airway inflammation triggered by inhaled allergens remains unclear. In this study, we examined the role of IL-6 in a mouse model of allergic airway inflammation induced by direct airway exposure to extracts of Aspergillus fumigatus, a common allergen in humans. We show that inhaled A. fumigatus extracts rapidly trigger the production of IL-6 in the airways. IL-6 appears to be dispensable for the recruitment of eosinophils to the lung during the development of allergic airway inflammation. However, IL-6 is essential for mucus hypersecretion by airway epithelial cells triggered in response to inhaled A. fumigatus Ags. Impaired mucus production caused by IL-6 deficiency correlates with a severe reduction in the levels of IL-13, a major inducer of mucin glycoproteins. Thus, IL-6 is a key regulator of specific hallmark features of allergic airway inflammation and it could be a potential target for pulmonary diseases that are associated with goblet cell metaplasia and mucus hypersecretion.
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Alérgenos/inmunología , Antígenos Fúngicos/inmunología , Interleucina-6/inmunología , Mucinas/biosíntesis , Sistema Respiratorio/inmunología , Animales , Aspergillus fumigatus/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Hipersensibilidad , Inflamación , Interleucina-6/biosíntesis , Ratones , Moco/metabolismoRESUMEN
Allergic airway disease is characterized by eosinophilic inflammation, mucus hypersecretion and increased airway resistance. Fungal antigens are ubiquitous within the environment and are well known triggers of allergic disease. Bacterial products are also frequently encountered within the environment and may alter the immune response to certain antigens. The consequence of simultaneous exposure to bacterial and fungal products on the lung adaptive immune response has not been explored. Here, we show that oropharyngeal aspiration of fungal lysates (Candida albicans, Aspergillus fumigatus) promotes airway eosinophilia, secretion of Th2 cytokines and mucus cell metaplasia. In contrast, oropharyngeal exposure to bacterial lysates (Pseudomonas aeruginosa) promotes airway inflammation characterized by neutrophils, Th1 cytokine secretion and no mucus production. More importantly, administration of bacterial lysates together with fungal lysates deviates the adaptive immune response to a Th1 type associated with neutrophilia and diminished mucus production. The immunomodulatory effect that bacterial lysates have on the response to fungi is TLR4 independent but MyD88 dependent. Thus, different types of microbial products within the airway can alter the host's adaptive immune response and potentially impact the development of allergic airway disease to environmental fungal antigens.
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Antígenos Fúngicos/inmunología , Bacterias/inmunología , Extractos Celulares/inmunología , Eosinófilos/inmunología , Hipersensibilidad/inmunología , Metaplasia/inmunología , Neutrófilos/inmunología , Animales , Antígenos Fúngicos/metabolismo , Aspergillus fumigatus/inmunología , Candida albicans/inmunología , Extractos Celulares/farmacología , Citocinas/biosíntesis , Citocinas/inmunología , Eosinófilos/citología , Eosinófilos/microbiología , Hipersensibilidad/microbiología , Factores Inmunológicos/inmunología , Factores Inmunológicos/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Pulmón/inmunología , Pulmón/patología , Masculino , Metaplasia/microbiología , Ratones , Ratones Endogámicos C57BL , Moco/inmunología , Moco/metabolismo , Factor 88 de Diferenciación Mieloide/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/citología , Neutrófilos/microbiología , Pseudomonas aeruginosa/inmunología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/microbiología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/microbiología , Receptor Toll-Like 4/inmunologíaRESUMEN
OBJECTIVES: To evaluate the association between plasma granulocyte colony-stimulating factor (G-CSF) levels and clinical outcomes including mortality in patients with acute lung injury (ALI), and to determine whether lower tidal volume ventilation was associated with a more rapid decrease in plasma G-CSF over time in patients with ALI. DESIGN: Retrospective measurement of G-CSF levels in plasma samples that were collected prospectively as part of a large multicenter clinical trial. SETTING: Intensive care units in ten university centers. PATIENTS: The study included 645 patients enrolled in the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for ALI. MEASUREMENTS AND MAIN RESULTS: Baseline plasma levels of G-CSF were associated with an increased risk of death and a decrease in ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, age, and sex (Odds ratio death 1.2/log10 increment G-CSF, 95% confidence interval 1.01 to 1.4). Stratification of G-CSF levels into quartiles revealed a strong association between the highest levels of G-CSF and an increased risk of death and decreased ventilator-free days and organ failure-free days in multivariate analyses controlling for ventilation strategy, Acute Physiology and Chronic Health Evaluation III score, Pao2/Fio2 ratio, creatinine, and platelet count (p < 0.05). Subgroup multivariate analysis of patients with sepsis as their risk factor for ALI revealed a U-shaped association between mortality and G-CSF levels such that risk increased linearly from the second through fourth (highest) quartiles, yet also increased in the first (lowest) quartile. G-CSF levels decreased over time in both tidal volume groups, and there was no statistical difference in the extent of decrease between ventilator strategies. CONCLUSIONS: In patients with ALI, plasma G-CSF levels are associated with morbidity and mortality, but these levels are not influenced by tidal volume strategy. In patients with sepsis-related ALI, a bimodal association between baseline plasma G-CSF levels and subsequent morbidity and mortality from this disease was found.
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Lesión Pulmonar Aguda/sangre , Factor Estimulante de Colonias de Granulocitos/sangre , Síndrome de Dificultad Respiratoria/sangre , Lesión Pulmonar Aguda/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Síndrome de Dificultad Respiratoria/mortalidad , Estudios RetrospectivosRESUMEN
Activation of Th2 CD4(+) T cells is necessary and sufficient to elicit allergic airway disease, a mouse model with many features of human allergic asthma. Effectively controlling the activities of these cells could be a panacea for asthma therapy. Blood-feeding parasites have devised remarkable strategies to effectively evade the immune response. For example, ticks such as Ixodes scapularis, which must remain on the host for up to 7 days to feed to repletion, secrete immunosuppressive proteins. Included among these proteins is the 15-kDa salivary protein Salp15, which inhibits T cell activation and IL-2 production. Our objective for these studies was to evaluate the T cell inhibitory properties of Salp15 in a mouse model of allergic asthma. BALB/cJ mice were Ag sensitized by i.p. injection of OVA in aluminum hydroxide, with or without 50 mug of Salp15, on days 0 and 7. All mice were challenged with aerosolized OVA on days 14-16 and were studied on day 18. Compared with control mice sensitized with Ag, mice sensitized with Ag and Salp15 displayed significantly reduced airway hyperresponsiveness, eosinophilia, Ag-specific IgG1 and IgE, mucus cell metaplasia, and Th2 cytokine secretion in vivo and by CD4(+) T cells restimulated with Ag in vitro. Our results demonstrate that Salp15 can effectively prevent the generation of a Th2 immune response and the development of experimental asthma. These studies, and those of others, support the notion that a lack of ectoparasitism may contribute to the increasing prevalence of allergic asthma.
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Adyuvantes Inmunológicos/uso terapéutico , Asma/prevención & control , Ixodes/inmunología , Proteínas y Péptidos Salivales/uso terapéutico , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/metabolismo , Animales , Asma/inmunología , Asma/patología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/prevención & control , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/parasitología , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/administración & dosificación , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/uso terapéutico , Interleucina-13/antagonistas & inhibidores , Interleucina-13/biosíntesis , Interleucina-4/antagonistas & inhibidores , Interleucina-4/biosíntesis , Interleucina-5/antagonistas & inhibidores , Interleucina-5/biosíntesis , Ratones , Ratones Endogámicos BALB C , Moco/inmunología , Moco/metabolismo , Moco/parasitología , Proteínas y Péptidos Salivales/administración & dosificación , Proteínas y Péptidos Salivales/metabolismoRESUMEN
CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(-/-) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(-/-) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(-/-) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(-/-) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(-/-) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Citocromo P-450 CYP2E1/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Etanol/toxicidad , Hígado/efectos de los fármacos , Hígado/enzimología , Pentanoles/toxicidad , Acetaminofén , Alanina Transaminasa/sangre , Animales , Benzoquinonas/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/deficiencia , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/biosíntesis , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glucurónidos/metabolismo , Glutatión/metabolismo , Hidroxilación , Iminas/metabolismo , Hígado/patología , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Ratones , Ratones Noqueados , Índice de Severidad de la Enfermedad , Testosterona/metabolismo , Troleandomicina/farmacologíaRESUMEN
Cystic fibrosis (CF) lung disease is characterized by persistent airway inflammation and airway infection that ultimately leads to respiratory failure. Aspergillus sp. are present in the airways of 20-40% of CF patients and are of unclear clinical significance. In this study, we demonstrate that CF transmembrane conductance regulator (CFTR)-deficient (CFTR knockout, Cftr(tm1Unc-)TgN(fatty acid-binding protein)CFTR) and mutant (DeltaF508) mice develop profound lung inflammation in response to Aspergillus fumigatus hyphal Ag exposure. CFTR-deficient mice also develop an enhanced Th2 inflammatory response to A. fumigatus, characterized by elevated IL-4 in the lung and IgE and IgG1 in serum. In contrast, CFTR deficiency does not promote a Th1 immune response. Furthermore, we demonstrate that CD4+ T cells from naive CFTR-deficient mice produce higher levels of IL-4 in response to TCR ligation than wild-type CD4+ T cells. The Th2 bias of CD4+ T cells in the absence of functional CFTR correlates with elevated nuclear levels of NFAT. Thus, CFTR is important to maintain the Th1/Th2 balance in CD4+ T cells.