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1.
J Exp Biol ; 2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39206582

RESUMO

Exposure to winter cold causes an increase in energy demands to meet the challenge of thermoregulation. In small rodents, this increase in cardiac output leads to a profound cardiac hypertrophy, 2-3x that typically seen with exercise training. The nature of this hypertrophy and its relevance to winter mortality remains unclear. Our goal was to characterize cold-induced cardiac hypertrophy and to assess its similarity to either exercise-induced (physiological) hypertrophy or the pathological hypertrophy of hypertension. We hypothesized that cold-induced hypertrophy will most closely resemble exercise-induced hypertrophy, but be another unique pathway for physiological cardiac growth. We found that cold-induced hypertrophy was largely reversed after return to warm temperatures. Further, metabolic rates were elevated while gene expression and mitochondrial enzyme activities indicative of pathology were absent. A gene expression panel comparing hearts of exercised and cold exposed mice further suggests that these activities are similar, although not identical. In conclusion, we found that chronic cold led to a phenotype that most closely resembled physiological hypertrophy, with enhanced metabolic rate, without induction of fetal genes , but with decreased expression of genes associated with fatty acid oxidation, suggesting that heart failure is not a cause of winter mortality in small rodents and identifying a novel approach for the study of cardiac growth.

2.
Environ Res ; 259: 119550, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-38964578

RESUMO

BACKGROUND: Despite growing literature on animal feeding operations (AFOs) including concentrated animal feeding operations (CAFOs), research on disproportionate exposure and associated health burden is relatively limited and shows inconclusive findings. OBJECTIVE: We systematically reviewed previous literature on AFOs/CAFOs, focusing on exposure assessment, associated health outcomes, and variables related to environmental justice (EJ) and potentially vulnerable populations. METHODS: We conducted a systematic search of databases (MEDLINE/PubMed and Web of Science) and performed citation screening. Screening of titles, abstracts, and full-text articles and data extraction were performed independently by pairs of reviewers. We summarized information for each study (i.e., study location, study period, study population, study type, study design, statistical methods, and adjusted variables (if health association was examined), and main findings), AFO/CAFO characteristics and exposure assessment (i.e., animal type, data source, measure of exposure, and exposure assessment), health outcomes or symptoms (if health association was examined), and information related to EJ and potentially vulnerable populations (in relation to exposure and/or health associations, vulnerable populations considered, related variables, and main findings in relation to EJ and vulnerable populations). RESULTS: After initial screening of 10,963 papers, we identified 76 eligible studies. This review found that a relatively small number of studies (20 studies) investigated EJ and vulnerability issues related to AFOs/CAFOs exposure and/or associated health outcomes (e.g., respiratory diseases/symptoms, infections). We found differences in findings across studies, populations, the metrics used for AFO/CAFO exposure assessment, and variables related to EJ and vulnerability. The most commonly used metric for AFO/CAFO exposure assessment was presence of or proximity to facilities or animals. The most investigated variables related to disparities were race/ethnicity and socioeconomic status. CONCLUSION: Findings from this review provide suggestive evidence that disparities exist with some subpopulations having higher exposure and/or health response in relation to AFO/CAFO exposure, although results varied across studies.


Assuntos
Criação de Animais Domésticos , Exposição Ambiental , Justiça Ambiental , Animais , Humanos
3.
Pediatr Allergy Immunol ; 35(6): e14173, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38873916

RESUMO

BACKGROUND: Little is known about the immune responses during acute asthma exacerbation. In this study, we examined immune responses in children following an acute asthma exacerbation. METHODS: We evaluated pro-inflammatory cytokine levels and gene expression profiles in blood samples from pediatric patients admitted for acute asthma exacerbation. Viral PCR was performed to differentiate between viral or non-viral-associated exacerbations. RESULTS: Following informed consent, clinical data were obtained from 20 children with asthma (median [interquartile range, IQR]: age 11.5 [8.0, 14.2]) years and 14 healthy age-matched controls (10.5 [7.0, 13.0]). Twelve had positive nasopharyngeal Polymerase chain reaction (PCR) for viral infection (11 rhinoviruses and 1 respiratory syncytial virus (RSV)). Nine were in the pediatric intensive care unit (PICU) and among them five required continuous positive airway pressure (CPAP). Mean (±SD) days on systemic steroids before drawing blood sample were 2.5 ± 1.6. Twelve had history of environmental allergies with 917 (274, 1396) IU/mL total IgE (median (IQR)). Compared with controls, IL-1RA and IL-10 levels were significantly increased and TNF-α significantly decreased in asthma subjects (p < .05 for all). RNA-seq analysis revealed 852 differentially expressed genes in subjects with asthma. Pathway analysis found upregulated genes and pathways involved in innate immune responses in subjects with asthma. Significantly reduced genes included pathways associated with T helper cell differentiation and activation. CONCLUSIONS: In acute asthma exacerbation, innate immune pathways remained increased while adaptive immune responses related to T helper cells are blunted and are independent of trigger or asthma severity. Our novel findings highlight the need to identify new therapies to target persistent innate immune responses to improve outcomes in acute asthma.


Assuntos
Asma , Citocinas , Imunidade Inata , Humanos , Asma/imunologia , Criança , Feminino , Masculino , Adolescente , Citocinas/sangue , Doença Aguda , Progressão da Doença , Estudos de Casos e Controles , Pré-Escolar
4.
Environ Health Perspect ; 131(8): 87018, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37616159

RESUMO

BACKGROUND: Concentrated animal feeding operations (CAFOs) emit pollutants that can cause negative impacts on human health. The concentration of hog production in North Carolina raises concerns regarding the disproportionate exposure of vulnerable communities to air pollution from CAFOs. OBJECTIVES: We investigated whether exposure to gaseous ammonia (NH3) and hydrogen sulfide (H2S) (in 2019) differs between subpopulations by examining demographics, including race/ethnicity, age, educational attainment, language proficiency, and socioeconomic status. METHODS: We used an Air Monitoring Station (AMS)/Environmental Protection Agency (EPA) Regulatory Model (AERMOD)-based Human Exposure Model (version 3) to estimate ambient concentrations of NH3 and H2S from hog farms in Duplin County and its surrounding counties in North Carolina and estimate subsequent exposures of communities within 50km of Duplin County, North Carolina, or the Duplin County Region. We combined estimated exposures with 2016 American Community Summary Census data, at the block group level, using spatial analysis to investigate whether exposures to these pollutants differ by race and ethnicity, age, income, education, and language proficiency. Based on these estimations, we assessed associated exposure risks to the impacted communities and used multivariable regression modeling to evaluate the relationship between average ammonia exposures from Duplin regional hog farms and the presence of vulnerable populations. RESULTS: The average [±standard deviation (SD)] annual estimated concentration of NH3 and H2S in the Duplin County Region is 1.75±2.81 µg/m3 and 0.0087±0.014 µg/m3, respectively. The maximum average annual ambient concentrations are estimated at 54.27±4.12 µg/m3 and 0.54±0.041 µg/m3 for NH3 and H2S, respectively. Our descriptive analysis reveals that people of low income, people of color, people with low educational attainment, and the linguistically isolated in the Duplin Region are disproportionately exposed to higher levels of pollutants than the average exposure for residents. Alternatively, our statistical results suggests that after adjusting for covariates, communities of color are associated with 1.70% (95% CI: -3.79, 0.44) lower NH3 concentrations per 1-SD increase. One-standard deviation increases in the adults with low educational attainment and children <19 years of age is associated with 1.26% (95% CI: -0.77, 3.33) and 1.20% (95% CI: -0.62, 3.05) higher NH3 exposure per 1-SD increase, respectively. DISCUSSION: Exposures to NH3 and H2S differed by race and ethnicity, educational attainment, language proficiency, and socioeconomic status. The observed associations between exposure to CAFO-generated pollutants and sociodemographic indicators differed among demographics. The disproportionate distribution of hog facilities and resulting pollutant exposures among communities may have adverse environmental and human health impacts, raising environmental justice concerns. https://doi.org/10.1289/EHP11344.


Assuntos
Poluição do Ar , Poluentes Ambientais , Adulto , Animais , Criança , Humanos , Suínos , Amônia , Justiça Ambiental , North Carolina
5.
Int J Mol Sci ; 24(13)2023 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-37445635

RESUMO

Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. Lung macrophages are important in recruitment of immune cells such as eosinophils, neutrophils, and monocytes that enhance allergic inflammation and initiate T helper cell responses. Persistent lung remodeling including mucus hypersecretion, increased airway smooth muscle mass, and airway fibrosis contributes to progressive lung function decline that is insensitive to current asthma treatments. Macrophages secrete inflammatory mediators that induce airway inflammation and remodeling. Additionally, lung macrophages are instrumental in protecting against pathogens and play a critical role in resolution of inflammation and return to homeostasis. This review summarizes current literature detailing the roles and existing knowledge gaps for macrophages as key inflammatory orchestrators in asthma pathogenesis. We also raise the idea that modulating inflammatory responses in lung macrophages is important for alleviating asthma.


Assuntos
Asma , Humanos , Pulmão/patologia , Inflamação/patologia , Macrófagos , Citocinas , Remodelação das Vias Aéreas
6.
Int J Mol Sci ; 24(7)2023 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-37047327

RESUMO

Asthma in elderly populations is an increasing health problem that is accompanied by diminished lung function and frequent exacerbations. As potent anti-inflammatory drugs, corticosteroids are commonly used to reduce lung inflammation, improve lung function, and manage disease symptoms in asthma. Although effective for most individuals, older patients are more insensitive to corticosteroids, making it difficult to manage asthma in this population. With the number of individuals older than 65 continuing to increase, it is important to understand the distinct mechanisms that promote corticosteroid insensitivity in the aging lung. In this review, we discuss corticosteroid insensitivity in asthma with an emphasis on mechanisms that contribute to persistent inflammation and diminished lung function in older individuals.


Assuntos
Asma , Humanos , Idoso , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Pulmão , Envelhecimento
7.
Pediatr Pulmonol ; 58(3): 825-833, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36444736

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). METHODS: Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls. RESULTS: Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils, interleukin (IL)-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition. CONCLUSIONS: In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.


Assuntos
Fibrose Cística , Masculino , Humanos , Adolescente , Adulto Jovem , Adulto , Feminino , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Interleucina-17/metabolismo , Interleucina-17/uso terapêutico , Interleucina-8/metabolismo , Interleucina-8/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Citocinas/metabolismo , Mutação
8.
Methods Protoc ; 5(5)2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36136814

RESUMO

Macrophage activation refers to the enhanced functionality of macrophages in response to endogenous or exogenous stimuli. Due to the existence of limitless stimuli and a multitude of receptors on macrophage surfaces, the nature of activation (or acquired functioning) can be specific to the encountering stimulus. This article describes a macrophage-activation screening platform in a 96-well format. The methodology involves the generation of bone marrow-derived macrophages, their activation into two extreme activation states, and screening of activated macrophages for expression of bonafide protein biomarkers. A high-throughput and stringent assay to determine macrophage activation markers developed in this article can be adapted for biomarker determination in pathological conditions and toxicant/drug safety screening.

9.
Respir Res ; 23(1): 126, 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35578269

RESUMO

BACKGROUND: Corticosteroids remain a key therapy for treating children with asthma. Patients with severe asthma are insensitive, resistant, or refractory to corticosteroids and have poorly controlled symptoms that involve airway inflammation, airflow obstruction, and frequent exacerbations. While the pathways that mediate corticosteroid insensitivity in asthma remain poorly defined, recent studies suggest that enhanced Th1 pathways, mediated by TNFα and IFNγ, may play a role. We previously reported that the combined effects of TNFα and IFNγ promote corticosteroid insensitivity in developing human airway smooth muscle (ASM). METHODS: To further understand the effects of TNFα and IFNγ on corticosteroid sensitivity in the context of neonatal and pediatric asthma, we performed RNA sequencing (RNA-seq) on human pediatric ASM treated with fluticasone propionate (FP), TNFα, and/or IFNγ. RESULTS: We found that TNFα had a greater effect on gene expression (~ 1000 differentially expressed genes) than IFNγ (~ 500 differentially expressed genes). Pathway and transcription factor analyses revealed enrichment of several pro-inflammatory responses and signaling pathways. Interestingly, treatment with TNFα and IFNγ augmented gene expression with more than 4000 differentially expressed genes. Effects of TNFα and IFNγ enhanced several pro-inflammatory genes and pathways related to ASM and its contributions to asthma pathogenesis, which persisted in the presence of corticosteroids. Co-expression analysis revealed several gene networks related to TNFα- and IFNγ-mediated signaling, pro-inflammatory mediator production, and smooth muscle contractility. Many of the co-expression network hubs were associated with genes that are insensitive to corticosteroids. CONCLUSIONS: Together, these novel studies show the combined effects of TNFα and IFNγ on pediatric ASM and implicate Th1-associated cytokines in promoting ASM inflammation and hypercontractility in severe asthma.


Assuntos
Asma , Interferon gama , Fator de Necrose Tumoral alfa , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Asma/metabolismo , Criança , Expressão Gênica , Humanos , Recém-Nascido , Inflamação/metabolismo , Interferon gama/metabolismo , Pulmão/metabolismo , Músculo Liso , Miócitos de Músculo Liso/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Front Pharmacol ; 13: 855247, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479312

RESUMO

Type 2-high severe asthma is described as a distinct endotype with Th2 inflammation, high eosinophil lung infiltration, impaired lung function, and reduced corticosteroid sensitivity. While the inflammatory milieu is similar to mild asthma, patients with type 2-high severe asthma likely have underlying mechanisms that sustain asthma pathophysiology despite corticosteroid treatments. Acute and chronic allergen models induce robust type 2 inflammatory responses, however differences in corticosteroid sensitivity remains poorly understood. In the present study, we sensitized and challenged mice with ovalbumin (OVA; acute model) or mixed allergens (MA; chronic model). Corticosteroid sensitivity was assessed by administering vehicle, 1, or 3 mg/kg fluticasone propionate (FP) and examining key asthmatic features such as airway inflammation, remodeling, hyperresponsiveness, and antioxidant capacity. Both acute and chronic allergen exposure exhibited enhanced AHR, immune cell infiltration, airway inflammation, and remodeling, but corticosteroids were unable to fully alleviate inflammation, AHR, and airway smooth muscle mass in MA-challenged mice. While there were no differences in antioxidant capacity, persistent IL-4+ Th2 cell population suggests the MA model induces type 2 inflammation that is insensitive to corticosteroids. Our data indicate that chronic allergen exposure is associated with more persistent type 2 immune responses and corticosteroid insensitivity. Understanding differences between acute and chronic allergen models could unlock underlying mechanisms related to type 2-high severe asthma.

12.
J Immunol ; 208(7): 1525-1533, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35288471

RESUMO

Severe asthma is characterized by steroid insensitivity and poor symptom control and is responsible for most asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding of mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in human asthmatic lungs. In this study, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling, and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, retinoic acid-related orphan receptor γt (RORγt), and Th17 responses, with PRMT5-dependent increases in RORγt's agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.


Assuntos
Asma , Hipersensibilidade , Animais , Asma/metabolismo , Granulócitos/metabolismo , Hipersensibilidade/metabolismo , Inflamação/metabolismo , Camundongos , Células Th17/metabolismo
13.
Am J Physiol Lung Cell Mol Physiol ; 321(6): L1194-L1205, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34755542

RESUMO

Corticosteroid insensitivity in asthma limits the ability to effectively manage severe asthma, which is characterized by persistent airway inflammation, airway hyperresponsiveness (AHR), and airflow obstruction despite corticosteroid treatment. Recent reports indicate that corticosteroid insensitivity is associated with increased interferon-γ (IFN-γ) levels and T-helper (Th) 1 lymphocyte infiltration in severe asthma. Signal transducer and activator of transcription 1 (STAT1) activation by IFN-γ is a key signaling pathway in Th1 inflammation; however, its role in the context of severe allergic airway inflammation and corticosteroid sensitivity remains unclear. In this study, we challenged wild-type (WT) and Stat1-/- mice with mixed allergens (MA) augmented with c-di-GMP [bis-(3'-5')-cyclic dimeric guanosine monophosphate], an inducer of Th1 cell infiltration with increased eosinophils, neutrophils, Th1, Th2, and Th17 cells. Compared with WT mice, Stat1-/- had reduced neutrophils, Th1, and Th17 cell infiltration. To evaluate corticosteroid sensitivity, mice were treated with either vehicle, 1 or 3 mg/kg fluticasone propionate (FP). Corticosteroids significantly reduced eosinophil infiltration and cytokine levels in both c-di-GMP + MA-challenged WT and Stat1-/- mice. However, histological and functional analyses show that corticosteroids did not reduce airway inflammation, epithelial mucous cell abundance, airway smooth muscle mass, and AHR in c-di-GMP + MA-challenged WT or Stat1-/- mice. Collectively, our data suggest that increased Th1 inflammation is associated with a decrease in corticosteroid sensitivity. However, increased airway pathology and AHR persist in the absence of STAT1 indicate corticosteroid insensitivity in structural airway cells is a STAT1 independent process.


Assuntos
Corticosteroides/metabolismo , Inflamação/metabolismo , Fator de Transcrição STAT1/metabolismo , Alérgenos/metabolismo , Animais , Asma/metabolismo , Eosinófilos/metabolismo , Feminino , Hipersensibilidade/metabolismo , Interferon gama/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Hipersensibilidade Respiratória/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
14.
Antioxidants (Basel) ; 10(9)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34572965

RESUMO

Corticosteroid insensitivity is a key characteristic of patients with severe asthma and COPD. These individuals experience greater pulmonary oxidative stress and inflammation, which contribute to diminished lung function and frequent exacerbations despite the often and prolonged use of systemic, high dose corticosteroids. Reactive oxygen and nitrogen species (RONS) promote corticosteroid insensitivity by disrupting glucocorticoid receptor (GR) signaling, leading to the sustained activation of pro-inflammatory pathways in immune and airway structural cells. Studies in asthma and COPD models suggest that corticosteroids need a balanced redox environment to be effective and to reduce airway inflammation. In this review, we discuss how oxidative stress contributes to corticosteroid insensitivity and the importance of optimizing endogenous antioxidant responses to enhance corticosteroid sensitivity. Future studies should aim to identify how antioxidant-based therapies can complement corticosteroids to reduce the need for prolonged high dose regimens in patients with severe asthma and COPD.

15.
Sci Rep ; 11(1): 15465, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326406

RESUMO

Increased eosinophil recruitment is a hallmark feature of eosinophilic disorders. Here, we delineated the key molecular and cellular players involved in physiological eosinophilic recruitment during normal postnatal lung development in mice. Physiological eosinophilic recruitment was consistently present in 7-, 10-, and 15-day-old neonatal mice, but not in 42-day-old mice. This feature was completely abolished in interleukin 33 (IL-33)-, interleukin 2 receptor gamma chain (IL2rγ)-, and interleukin 4 receptor alpha (IL4Rα)-knockout mice, but not in recombination activating gene 1 (Rag1)-knockout mice demonstrating an indispensable role for IL-33, innate lymphoid cells (ILCs), and IL4Rα in eosinophil recruitment. Interestingly, myeloid-specific IL4Rα-deficient (mye-IL4Rα-/-) mice had significantly reduced eosinophilia in the airspaces that was associated with reduced levels of IL-4 and IL-5 in the bronchoalveolar lavage fluid (BALF). Further, we tested the effect of myeloid-specific IL4Rα deficiency on IL-13-induced eosinophil recruitment into adult lung airspaces. Eosinophil recruitment into the airspaces was elevated in IL-13-treated WT mice but not in IL-13-treated mye-IL4Rα-/- mice. Consistent with the degree of eosinophilia, the BALF levels of eosinophil recruitment-associated cytokines were significantly elevated in IL-13-treated WT but not in IL-13-treated mye-IL4Rα-/- mice. These data establish that myeloid-IL4Rα is an indispensable component of the IL-33-ILCsIL-13-IL4Rα axis of eosinophil recruitment.


Assuntos
Eosinófilos/metabolismo , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Pulmão/metabolismo , Linfócitos/citologia , Células Mieloides/metabolismo , Receptores de Superfície Celular/metabolismo , Alelos , Animais , Líquido da Lavagem Broncoalveolar , Imunidade Inata , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Eosinofilia Pulmonar
16.
Clin Case Rep ; 9(4): 2373-2381, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33936698

RESUMO

Anaplastic large-cell lymphoma (ALCL) is a CD30 + lymphoproliferative disorder that may manifest with skin involvement.1 We present a rare case of Agent Orange-induced ALCL with cutaneous involvement of the hand, surgical excision, and follow-up treatment.

17.
Front Immunol ; 11: 2164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983182

RESUMO

Tristetraprolin (TTP) is a mRNA binding protein that binds to adenylate-uridylate-rich elements within the 3' untranslated regions of certain transcripts, such as tumor necrosis factor (Tnf) mRNA, and increases their rate of decay. Modulation of TTP expression is implicated in inflammation; however, its role in acute lung inflammation remains unknown. Accordingly, we tested the role of TTP in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. LPS-challenged TTP-knockout (TTPKO) mice, as well as myeloid cell-specific TTP-deficient (TTPmyeKO) mice, exhibited significant increases in lung injury, although these responses were more robust in the TTPKO. Mice with systemic overexpression of TTP (TTPΔARE) were protected from ALI, as indicated by significantly reduced neutrophilic infiltration, reduced levels of neutrophil chemoattractants, and histological parameters of ALI. Interestingly, while irradiated wild-type (WT) mice reconstituted with TTPKO hematopoietic progenitor cells (HPCs) showed exaggerated ALI, their reconstitution with the TTPΔARE HPCs mitigated ALI. The reconstitution of irradiated TTPΔARE mice with HPCs from either WT or TTPΔARE donors conferred significant protection against ALI. In contrast, irradiated TTPΔARE mice reconstituted with TTPKO HPCs had exaggerated ALI, but the response was milder as compared to WT recipients that received TTPKO HPCs. Finally, the reconstitution of irradiated TTPKO recipient mice with TTPΔARE HPCs did not confer any protection to the TTPKO mice. These data together suggest that non-HPCs-specific overexpression of TTP within the lungs protects against ALI via downregulation of neutrophil chemoattractants and reduction in neutrophilic infiltration.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Células Epiteliais Alveolares/metabolismo , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Tristetraprolina/fisiologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Transplante de Medula Óssea , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Quimiotaxia de Leucócito , Citocinas/fisiologia , Feminino , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/imunologia , Quimera por Radiação , Tristetraprolina/biossíntese , Tristetraprolina/deficiência , Tristetraprolina/genética , Regulação para Cima
18.
J Immunol ; 205(6): 1695-1708, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32817334

RESUMO

Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. Scnn1b transgenic (Scnn1b-Tg+) mice, which recapitulate cystic fibrosis-like mucoinflammatory airway disease, deficient in innate lymphoid (Il2rg knockout mice [Il2rg KO]), adaptive immune (Rag1 knockout mice [Rag1 KO]), or both systems (Il2rg KO/Rag1 KO), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg+ juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of Th2-associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction. The bacterial burden was increased in Il2rg KO/Tg+ juveniles but returned to significantly lower levels in Il2rg KO/Rag1 KO/Tg+ juveniles. Mechanistically, this improvement reflected reduced production of adaptive immunity-derived IL-10 and, in turn, increased activation of macrophages. Although all the mucoinflammatory features were comparable between the immunocompetent Tg+ and Rag1 KO/Tg+ juveniles, the Il2rg KO/Tg+ and Il2rg KO/Rag1 KO/Tg+ juveniles exhibited suppressed expression levels of Th2 markers, diminished MCM, suppressed MUC5B expression, and reduced mucus obstruction. Collectively, these data indicate that, in the context of airway mucus obstruction, the adaptive immune system suppresses antibacterial macrophage activation, whereas the innate lymphoid system contributes to MCM, mucin production, and mucus obstruction.


Assuntos
Fibrose Cística/imunologia , Células Epiteliais/metabolismo , Inflamação/imunologia , Mucina-5B/metabolismo , Doenças Respiratórias/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/patologia , Canais Epiteliais de Sódio/genética , Proteínas de Homeodomínio/genética , Humanos , Imunidade Inata , Metaplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mucina-5B/genética , Regulação para Cima
19.
Epigenetics Chromatin ; 13(1): 14, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32151278

RESUMO

BACKGROUND: Pharmacologic inhibition of bromodomain and extra-terminal (BET) proteins is currently being explored as a new therapeutic approach in cancer. Some studies have also implicated BET proteins as regulators of cell identity and differentiation through their interactions with lineage-specific factors. However, the role of BET proteins has not yet been investigated in melanocyte differentiation. Melanocyte inducing transcription factor (MITF) is the master regulator of melanocyte differentiation, essential for pigmentation and melanocyte survival. In this study, we tested the hypothesis that BET proteins regulate melanocyte differentiation through interactions with MITF. RESULTS: Here we show that chemical inhibition of BET proteins prevents differentiation of unpigmented melanoblasts into pigmented melanocytes and results in de-pigmentation of differentiated melanocytes. BET inhibition also slowed cell growth, without causing cell death, increasing the number of cells in G1. Transcriptional profiling revealed that BET inhibition resulted in decreased expression of pigment-specific genes, including many MITF targets. The expression of pigment-specific genes was also down-regulated in melanoma cells, but to a lesser extent. We found that RNAi depletion of the BET family members, bromodomain-containing protein 4 (BRD4) and bromodomain-containing protein 2 (BRD2) inhibited expression of two melanin synthesis enzymes, TYR and TYRP1. Both BRD4 and BRD2 were detected on melanocyte promoters surrounding MITF-binding sites, were associated with open chromatin structure, and promoted MITF binding to these sites. Furthermore, BRD4 and BRD2 physically interacted with MITF. CONCLUSION: These findings indicate a requirement for BET proteins in the regulation of pigmentation and melanocyte differentiation. We identified changes in pigmentation specific gene expression that occur upon BET inhibition in melanoblasts, melanocytes, and melanoma cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Melanócitos/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Células Cultivadas , Células HEK293 , Humanos , Melaninas/biossíntese , Melaninas/genética , Melanócitos/citologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/genética , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Fatores de Transcrição/genética
20.
J Immunol ; 204(6): 1650-1660, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060135

RESUMO

Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis-like lung disease model (i.e., Scnn1b-Tg-positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33KO) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33HET) Tg+ mice. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clca1, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33HET/Tg+ mice, although the IL-33KO/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33KO/Tg+ mice compared with IL-33HET/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.


Assuntos
Fibrose Cística/imunologia , Interleucina-33/metabolismo , Pulmão/patologia , Mucina-5AC/metabolismo , Células Th2/imunologia , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/patologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/metabolismo , Canais Epiteliais de Sódio/genética , Humanos , Interleucina-33/genética , Pulmão/citologia , Pulmão/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Muco/imunologia , Muco/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Células Th2/metabolismo
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