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1.
Respir Res ; 23(1): 131, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610699

RESUMO

BACKGROUND: Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. METHODS: Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. RESULTS: Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. CONCLUSIONS: In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.


Assuntos
Asma , Hipersensibilidade , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Alérgenos , Animais , Asma/metabolismo , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Hipersensibilidade/metabolismo , Leptina , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fibrose Pulmonar/metabolismo , Pyroglyphidae , RNA Mensageiro/metabolismo
2.
Toxicol Appl Pharmacol ; 426: 115645, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34271066

RESUMO

Elevated ambient temperatures and extreme weather events have increased the incidence of wildfires world-wide resulting in increased wood smoke particle (WSP). Epidemiologic data suggests that WSP exposure associates with exacerbations of respiratory diseases, and with increased respiratory viral infections. To assess the impact of WSP exposure on host response to viral pneumonia, we performed WSP exposures in rodents followed by infection with mouse adapted influenza (HINI-PR8). C57BL/6 male mice aged 6-8 weeks were challenged with WSP or PBS by oropharyngeal aspiration in acute (single dose) or sub-acute exposures (day 1, 3, 5, 7 and 10). Additional groups underwent sub-acute exposure followed by infection by influenza or heat-inactivated (HI) virus. Following exposures/infection, bronchoalveolar lavage (BAL) was performed to assess for total cell counts/differentials, total protein, protein carbonyls and hyaluronan. Lung tissue was assessed for viral counts by real time PCR. When compared to PBS, acute WSP exposure associated with an increase in airspace macrophages. Alternatively, sub-acute exposure resulted in a dose dependent increase in airspace neutrophils. Sub-acute WSP exposure followed by influenza infection was associated with improved respiratory viral outcomes including reduced weight loss and increased blood oxygen saturation, and decreased protein carbonyls and viral titers. Flow cytometry demonstrated dynamic changes in pulmonary macrophage and T cell subsets based on challenge with WSP and influenza. This data suggests that sub-acute WSP exposure can improve host response to acute influenza infection.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae , Pneumonia Viral , Fumaça , Incêndios Florestais , Administração por Inalação , Animais , Vírus da Influenza A Subtipo H1N1/fisiologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Transcriptoma , Replicação Viral , Madeira
3.
J Transl Med ; 18(1): 427, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176790

RESUMO

BACKGROUND: Foxp3+ regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4+ T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples. METHODS: We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48-96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4+ T cells that were Tregs. RESULTS: The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood. CONCLUSION: Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4+ cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.


Assuntos
Síndrome do Desconforto Respiratório , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar , Humanos , Respiração Artificial , Síndrome do Desconforto Respiratório/terapia , Linfócitos T Reguladores
6.
BMJ Open Respir Res ; 11(1)2024 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-39097412

RESUMO

BACKGROUND: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection. METHODS: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae, Mycoplasma pneumoniae, influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust. RESULTS: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96. DISCUSSION: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes.


Assuntos
Modelos Animais de Doenças , Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Streptococcus pneumoniae , Animais , Humanos , Camundongos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/diagnóstico , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/isolamento & purificação , Feminino , Pneumonia Pneumocócica/microbiologia , Infecções por Orthomyxoviridae/imunologia , Curva ROC , Perfilação da Expressão Gênica , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/diagnóstico , Interações Hospedeiro-Patógeno
7.
Front Endocrinol (Lausanne) ; 14: 1092277, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36926031

RESUMO

Introduction: Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization. Bariatric surgery improves asthma control and airway hyperresponsiveness in patients with asthma and comorbid obesity, however, the underlying mechanisms for these improvements remain to be elucidated. We hypothesized that vertical sleeve gastrectomy (VSG), a model of metabolic surgery in mice, would improve glucose tolerance and airway inflammation, resistance, and fibrosis induced by chronic allergen challenge and obesity. Methods: Male C57BL/6J mice were fed a high fat diet (HFD) for 13 weeks with intermittent house dust mite (HDM) allergen administration to induce allergic asthma, or saline as control. At week 11, a subset of mice underwent VSG or Sham surgery with one week recovery. A separate group of mice did not undergo surgery. Mice were then challenged with HDM or saline along with concurrent HFD feeding for 1-1.5 weeks before measurement of lung mechanics and harvesting of tissues, both of which occurred 24 hours after the final HDM challenge. Systemic and pulmonary cytokine profiles, lung histology and gene expression were analyzed. Results: High fat diet contributed to increased body weight, serum leptin levels and development of glucose intolerance for both HDM and saline treatment groups. When compared to saline-treated mice, HDM-challenged mice exhibited greater weight gain. VSG improved glucose tolerance in both saline and HDM-challenged mice. HDM-challenged VSG mice exhibited an increase in airway hyperresponsiveness to methacholine when compared to the non-surgery group. Discussion: The data presented here indicate increased airway hyperresponsiveness in allergic mice undergoing bariatric surgery.


Assuntos
Asma , Masculino , Animais , Camundongos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Asma/etiologia , Pulmão/metabolismo , Inflamação/metabolismo , Alérgenos/metabolismo , Obesidade/complicações , Obesidade/cirurgia , Obesidade/metabolismo , Glucose/metabolismo
8.
J Spec Oper Med ; 22(4): 111-116, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36525023

RESUMO

BACKGROUND: The purpose of our study was to assess risks/ outcomes of acute respiratory distress syndrome (ARDS) in US combat casualties. We hypothesized that combat trauma patients with ARDS would have worse outcomes based on mechanism of injury (MOI) and labs/vital signs aberrancies. MATERIALS AND METHODS: We reviewed data on military Servicemembers serving in Iraq and Afghanistan from 1 January 2003 to 31 December 2015 diagnosed with ARDS by ICD-9 code. We extracted patient demographics, injury specifics, and mortality from the Department of Defense Trauma Registry (DoDTR). RESULTS: The most common MOI was an explosion, accounting for 67.6% of all injuries. Nonsurvivors were more likely to have explosion-related injuries, have higher injury severity score (ISS), higher international normalized ratio (INR), lower platelet count, greater base deficit, lower temperature, lower Glasgow Coma Scale (GCS) score, and lower pH. There was no significant difference in deaths across time. CONCLUSION: By identifying characteristics of patients with higher mortality in trauma ARDS, we can develop treatment guidelines to improve outcomes. Given the high mortality associated with trauma ARDS and relative paucity of clinical data available, we need to improve battlefield data capture to better guide practice and ultimately improve care. The management of ARDS will be increasingly relevant in prolonged casualty care (PCC; formerly prolonged field care) on the modern battlefield.


Assuntos
Militares , Síndrome do Desconforto Respiratório , Ferimentos e Lesões , Humanos , Estudos Retrospectivos , Escala de Gravidade do Ferimento , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Sistema de Registros , Ferimentos e Lesões/complicações , Ferimentos e Lesões/epidemiologia , Ferimentos e Lesões/terapia , Guerra do Iraque 2003-2011 , Campanha Afegã de 2001-
9.
J Asthma Allergy ; 14: 179-186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692628

RESUMO

Asthma is an obstructive airway disease that is characterized by reversible airway obstruction and is classically associated with atopic, TH2 driven inflammation. Landmark studies in the second half of the twentieth century identified eosinophils as a key mediator of inflammation and steroids, both inhaled and systemic, as a cornerstone of therapy. However, more recently other phenotypes of asthma have emerged that do not respond as well to traditional therapies. In particular, obese patients who develop asthma as adults are less likely to have eosinophilic airway inflammation and do not respond to traditional therapies. Obese patients often have metabolic comorbidities such as impaired glucose tolerance and dyslipidemias, also known as metabolic syndrome (MetS). The unified pathophysiology of metabolic syndrome is not known, however, several signaling pathways, such as the neuropeptide glucagon-like peptide-1 (GLP-1) and nitric oxide (NO) signaling have been shown to be dysregulated in MetS. These pathways are targeted by commercially available medications. This review discusses the potential roles that dysregulation of the GLP-1 and NO signaling pathways, along with arginine metabolism, play in the development of asthma in obese patients. GLP-1 receptors are found in high density in the lung and are also detectable in bronchoalveolar lavage fluid. NO has long been associated with asthma. We hypothesize that these derangements in metabolic signaling pathways underpin the asthmatic phenotype seen in obese patients with non-eosinophilic airway inflammation and poor response to established therapies. While still an active area of research, novel interventions are needed for this subset of patient who respond poorly to available asthma therapies.

10.
Oncotarget ; 7(18): 26331-45, 2016 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-27028866

RESUMO

Melanoma risk is increased in patients with mutations of melanocortin 1 receptor (MC1R) yet the basis for the increased risk remains unknown. Here we report in vivo evidence supporting a critical role for MC1R in regulating melanoma tumor growth and determining overall survival time. Inhibition of MC1R by its physiologically relevant competitive inhibitor, agouti signaling protein (ASIP), reduced melanin synthesis and morphological heterogeneity in murine B16-F10 melanoma cells. In the lungs of syngeneic C57BL/6 mice, mCherry-marked, ASIP-secreting lung tumors inhibited MC1R on neighboring tumors lacking ASIP in a dose dependent manner as evidenced by a proportional loss of pigment in tumors from mice injected with 1:1, 3:1 and 4:1 mixtures of parental B16-F10 to ASIP-expressing tumor cells. ASIP-expressing B16-F10 cells formed poorly pigmented tumors in vivo that correlated with a 20% longer median survival than those bearing parental B16-F10 tumors (p=0.0005). Mice injected with 1:1 mixtures also showed survival benefit (p=0.0054), whereas injection of a 4:1 mixture showed no significant difference in survival. The longer survival time of mice bearing ASIP-expressing tumors correlated with a significantly slower growth rate than parental B16-F10 tumors as judged by quantification of numbers of tumors and total tumor load (p=0.0325), as well as a more homogeneous size and morphology of ASIP-expressing lung tumors. We conclude that MC1R plays an important role in regulating melanoma growth and morphology. Persistent inhibition of MC1R provided a significant survival advantage resulting in part from slower tumor growth, establishing MC1R as a compelling new molecular target for metastatic melanoma.


Assuntos
Proteína Agouti Sinalizadora/metabolismo , Melanoma Experimental/patologia , Receptor Tipo 1 de Melanocortina/antagonistas & inibidores , Proteína Agouti Sinalizadora/genética , Animais , Linhagem Celular Tumoral , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
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