RESUMO
BACKGROUND: Asthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor α (IL-4Rα), a critical mediator of Th2 signalling, improved their outcomes. METHODS: Male BALB/c mice were intranasally sensitized with house dust mite antigen (Der p 1) for 2 weeks; the mice were then inoculated intranasally with a single dose of pandemic H1N1 (pH1N1). The mice were administered intraperitoneally anti-IL-4Rα through either a prophylactic or a therapeutic treatment strategy. RESULTS: Infection with pH1N1 of mice sensitized to house dust mite (HDM) led to a 24% loss in weight by day 7 of infection (versus 14% in non-sensitized mice; p < .05). This was accompanied by increased viral load in the airways and a dampened anti-viral host responses to the infection. Treatment of HDM sensitized mice with a monoclonal antibody against IL-4Rα prior to or following pH1N1 infection prevented the excess weight loss, reduced the viral load in the lungs and ameliorated airway eosinophilia and systemic inflammation related to the pH1N1 infection. CONCLUSION: Together, these data implicate allergic asthma as a significant risk factor for H1N1-related morbidity and reveal a potential therapeutic role for IL-4Rα signalling blockade in reducing the severity of influenza infection in those with allergic airway disease.
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Asma/metabolismo , Hipersensibilidade/metabolismo , Influenza Humana/metabolismo , Pyroglyphidae/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Asma/induzido quimicamente , Asma/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Hipersensibilidade/tratamento farmacológico , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/fisiologia , Influenza Humana/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Rationale: Lung dysbiosis promotes airway inflammation and decreased local immunity, potentially playing a role in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Objectives: We sought to determine the relationship between sputum microbiome at the time of AECOPD hospitalization and 1-year mortality in a COPD cohort. Methods: We used sputum samples from 102 patients hospitalized because of AECOPD. All subjects were followed for 1 year after discharge. The microbiome profile was assessed through sequencing of 16S rRNA gene. Microbiome analyses were performed according to 1-year mortality status. To investigate the effect of α-diversity measures and taxon features on time to death, we applied Cox proportional hazards regression models and obtained hazard ratios (HRs) associated with these variables. Measurements and Main Results: We observed significantly lower values of α-diversity (richness, Shannon index, evenness, and Faith's Phylogenetic Diversity) among nonsurvivors (n = 19, 18.6%) than survivors (n = 83, 81.4%). ß-Diversity analysis also demonstrated significant differences between both groups (adjusted permutational multivariate ANOVA, P = 0.010). The survivors had a higher relative abundance of Veillonella; in contrast, nonsurvivors had a higher abundance of Staphylococcus. The adjusted HRs for 1-year mortality increased significantly with decreasing α-diversity. We also observed lower survival among patients in whom sputum samples were negative for Veillonella (HR, 13.5; 95% confidence interval, 4.2-43.9; P < 0.001) or positive for Staphylococcus (HR, 7.3; 95% confidence interval, 1.6-33.2; P = 0.01). Conclusions: The microbiome profile of sputum in AECOPD is associated with 1-year mortality and may be used to identify subjects with a poor prognosis at the time of hospitalization.
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Disbiose/mortalidade , Microbiota , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/microbiologia , Doença Pulmonar Obstrutiva Crônica/mortalidade , Escarro/microbiologia , Idoso , Colúmbia Britânica , Estudos de Coortes , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
Epidemiological studies have implicated lung inflammation as a risk factor for acute cardiovascular events, but the underlying mechanisms linking lung injury with cardiovascular events are largely unknown.Our objective was to develop a novel murine model of acute atheromatous plaque rupture related to lung inflammation and to investigate the role of neutrophils in this process.Lipopolysaccharide (LPS; 3â mg·kg(-1)) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8â weeks of a Western-type diet. 24â h later, atheromas in the right brachiocephalic trunk were assessed for stability ex vivo using high-resolution optical projection tomography and histology. 68% of LPS-exposed mice developed vulnerable plaques, characterised by intraplaque haemorrhage and thrombus, versus 12% of saline-exposed mice (p=0.0004). Plaque instability was detectable as early as 8â h post-intratracheal LPS instillation, but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque rupture.We have established a novel plaque rupture model related to lung injury induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque rupture. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.
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Apolipoproteínas E/genética , Citocinas/metabolismo , Neutrófilos/citologia , Placa Aterosclerótica/patologia , Animais , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tomografia ÓpticaAssuntos
COVID-19/diagnóstico por imagem , Procedimentos Clínicos , Infecções Assintomáticas , COVID-19/complicações , Diagnóstico Diferencial , Serviço Hospitalar de Emergência , Humanos , Achados Incidentais , Pulmão/diagnóstico por imagem , Pandemias , Radiografia Torácica , SARS-CoV-2 , Austrália do Sul , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
BACKGROUND AND OBJECTIVE: CD8(+) cell infiltration and apoptosis of airway epithelial cells are increased in chronic obstructive pulmonary disease (COPD). CD8(+) T cells induce apoptosis by releasing granzymes, which can also cause extracellular matrix degradation and remodelling. Granzyme B levels and T cells expressing granzyme B are increased in bronchoalveolar lavage fluid of COPD patients, which suggests that granzyme B may contribute to the pathogenesis of COPD. This study provides quantitation of granzyme B-positive cells in relation to CD8(+) cells in the small airway walls of emphysema. METHODS: Antibodies against CD8 and granzyme B were used to identify CD8(+) and granzyme B(+) cells. Volume fraction (Vv) of CD8(+) and granzyme B(+) cells were quantitated by the point counting method in the small airways of 13 non-smoker control subjects and 46 emphysema patients (14 panlobular emphysema (PLE) and 32 centrilobular emphysema (CLE) lungs). Immunohistochemical detection of macrophage scavenger receptor was also performed in randomly selected cases. RESULTS: The Vv of CD8(+) and granzyme B(+) cells in CLE was greater than those in control and PLE (both P < 0.001) subjects. The Vv of granzyme B(+) cells was greater than that of CD8(+) cells (P = 0.006), and not all CD8(+) cells were positive for granzyme B in CLE subjects. Monocytes expressing both granzyme B and macrophage scavenger receptor and granulocytes expressing granzyme B were identified. CONCLUSIONS: Upregulation of granzyme B in CD8(+) and non-CD8(+) cells is an early phenomenon of small airway wall remodelling in centrilobular emphysema and suggests its possible role in the pathogenesis of COPD.
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Remodelação das Vias Aéreas/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Granzimas/metabolismo , Enfisema Pulmonar/fisiopatologia , Linfócitos T/metabolismo , Adulto , Idoso , Apoptose/fisiologia , Linfócitos T CD8-Positivos/patologia , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/metabolismo , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Linfócitos T/patologiaAssuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Material Particulado , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/fisiopatologia , Idoso , Progressão da Doença , Feminino , Humanos , Inflamação , Pulmão/patologia , Pulmão/fisiopatologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Fagocitose , Remodelação VascularRESUMO
BACKGROUND: In cystic fibrosis (CF) patients, it has been suggested that systemic inflammation may be an important risk factor for poor health outcomes. The relationship of plasma inflammatory biomarkers to lung function and hospitalization history remains largely unexplored. METHODS: This cross-sectional study included 58 consecutive, clinically stable adults from the CF Clinic at St. Paul's Hospital (Vancouver, Canada). Blood levels of interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), interleukin (IL)-6, IL-1ß, granzyme B (GzmB), chemokine C-C motif ligand 18 (CCL18/PARC), surfactant protein D (SP-D), lipopolysaccharide (LPS)-binding protein, and soluble cluster of differentiation 14 (sCD14) were measured using enzyme-linked immunosorbent assays, and LPS levels were measured using a Limulus amebocyte lysate assay. Spirometry was also performed. Multivariable linear regression analysis was used to assess relationships of the blood biomarkers to lung function. RESULTS: Lung function impairment was independently associated with elevated plasma levels of CRP (P < 0.01), IL-6 (P = 0.04), IL-1ß (P < 0.01), and LBP (P < 0.01). Increasing age (P < 0.01), reduced body mass index (P = 0.02), prior hospitalizations (P = 0.03), and presence of Pseudomonas aeruginosa in sputum cultures (P < 0.01) were also associated with reduced lung function. Elevated concentrations of LPS in plasma were associated with a previous history of hospitalization (P < 0.05). There was a trend towards an increase in plasma IL-6 (P = 0.07) and IL-1ß (P = 0.06) levels in patients who were previously hospitalized. CONCLUSIONS: IL-6 and IL-1ß are promising systemic biomarkers for lung function impairment and history of hospitalization in adult patients with CF.
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Fibrose Cística/sangue , Hospitalização/estatística & dados numéricos , Inflamação/sangue , Proteínas de Fase Aguda , Adolescente , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Proteínas de Transporte/sangue , Quimiocinas CC/sangue , Estudos Transversais , Feminino , Granzimas/sangue , Humanos , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Infecções por Pseudomonas/sangue , Proteína D Associada a Surfactante Pulmonar/sangue , Fatores de Risco , Espirometria , Escarro/microbiologiaRESUMO
Acute lung injury (ALI) is associated with systemic inflammation and cardiovascular dysfunction. IL-6 is a biomarker of this systemic response and a predictor of cardiovascular events, but its possible causal role is uncertain. Inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) down-regulate the systemic expression of IL-6, but whether they can ameliorate the cardiovascular dysfunction related to ALI is uncertain. We sought to determine whether IL-6 contributes to the cardiovascular dysfunction related to ALI, and whether budesonide/formoterol ameliorates this process. Wild-type mice were pretreated for 3 hours with intratracheal budesonide, formoterol, or both, before LPS was sprayed into their tracheas. IL-6-deficient mice were similarly exposed to LPS. Four hours later, bronchoalveolar lavage fluid (BALF) and serum were collected, and endothelial and cardiac functions were measured, using wire myography of the aortic tissue and echocardiography, respectively. LPS significantly impaired vasodilatory responses to acetylcholine (P < 0.001) and cardiac output (P = 0.002) in wild-type but not IL-6-deficient mice. Intratracheal instillations of exogenous IL-6 into IL-6-deficient mice restored these impairments (vasodilatory responses to acetylcholine, P = 0.005; cardiac output, P = 0.025). Pretreatment with the combination of budesonide and formoterol, but not either alone, ameliorated the vasodilatory responses to acetylcholine (P = 0.018) and cardiac output (P < 0.001). These drugs also attenuated the rise in the systemic expression of IL-6 (P < 0.05) related to LPS. IL-6 contributes to the cardiovascular dysfunction related to LPS, and pretreatment with budesonide/formoterol reduces the systemic expression of IL-6 and improves cardiovascular dysfunction. ICS/LABA may reduce acute cardiovascular events related to ALI.
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Lesão Pulmonar Aguda/patologia , Budesonida/farmacologia , Doenças Cardiovasculares/metabolismo , Etanolaminas/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/metabolismo , Acetilcolina/metabolismo , Corticosteroides/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Broncodilatadores/farmacologia , Fumarato de Formoterol , Inflamação , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , VasodilataçãoRESUMO
PURPOSE: Mitomycin C (MMC) plus standard 5-fluorouracil (FU) infusion in weeks 1 and 5 often contributes to radiotherapy interruptions and possibly less-than-ideal outcomes in anal cancer. This study was to evaluate alternative strategies for chemotherapy delivery that might be less toxic or more efficacious, and outcomes of patient-initiated treatment interruption for severe acute toxicity. MATERIALS AND METHODS: This was a prospective, nonrandomized study for patients with T1-4N0-3M0 anal squamous carcinoma. Radiotherapy of 54 Gy in 30 fractions over 6 weeks was given with infusion FU 300 mg/m2 /day for 96 hours/week for 6 weeks plus bolus MMC at 10 mg/m2 on D1. RESULTS: Fifty patients were recruited (72% female). Median age was 60.5 years (35-84). Forty-seven patients (94%) received 54 Gy. Median duration of chemoradiation was 39 days (37-105). Grade 3 and 4 acute toxicity were observed in 66%. Thirty-one percent with severe acute toxicity developed severe late toxicity. Of those who experienced severe late skin toxicity, 29% did not have severe acute toxicity. Disease-free survival at 5 years was 74% (95% confidence interval [CI], 60-84), and at 9 years 61% (95% CI, 46-74). Overall survival at 5 years was 84% (95% CI, 71-92), and at 9 years 67% (95% CI, 50-81). Colostomy-free survival at 5 years was 70% (95% CI, 56-81), and at 9 years 57% (95% CI, 40-72). CONCLUSION: It is feasible to deliver chemoradiation with bolus MMC and protracted infusion FU for anal cancer. Efficacy and toxicity of this regimen seem similar to conventional chemoradiation with FU/MMC. Acute skin toxicity is not a reliable predictor of severe late skin toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Canal Anal , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
STUDY OBJECTIVES: Untreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA. METHODS: We measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms. RESULTS: The most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction). CONCLUSIONS: These genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care.
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Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/genética , Apneia Obstrutiva do Sono/sangue , Apneia Obstrutiva do Sono/genética , Molécula 1 de Adesão de Célula Vascular/sangue , Molécula 1 de Adesão de Célula Vascular/genética , Adulto , Proteínas Sanguíneas/análise , Selectina E/sangue , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polissonografia , Análise de RegressãoRESUMO
INTRODUCTION: The use of beta-blockers in chronic obstructive pulmonary disease (COPD) is controversial, primarily due to concerns that they may worsen lung function and attenuate bronchodilator response. Areas covered: This review summarizes the reasons for and against the use of beta-blockers in COPD by evaluating the literature on the effects of these drugs on lung function, exacerbation rate, and mortality. The safety of beta-blockers in COPD patients with concomitant heart failure, an entity that is not always distinguishable from COPD exacerbations, is also explored. Expert commentary: The use of cardioselective beta-blockers appears safe in the management of cardiac comorbidities associated with COPD and may lower exacerbation and mortality risk. There is a growing body of evidence demonstrating the safety of beta-blockers in patients with acute heart failure, acute respiratory failure or sepsis, entities that could occur simultaneously with COPD exacerbations. However, randomized controlled trials are still lacking to confirm these results.
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Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência Cardíaca/epidemiologia , Doença Pulmonar Obstrutiva Crônica , Comorbidade , Saúde Global , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Resultado do TratamentoRESUMO
AIMS: Although surfactant protein-D (SP-D) is a pneumoprotein that is predominantly synthesized by type II epithelial cells in the lung, individuals with increased circulating levels of SP-D are at an elevated risk of mortality from ischemic heart disease. Whether SP-D contributes directly to atherosclerosis is unknown. We determined the effects of SP-D gene deletion in a mouse model of atherosclerosis. METHODS AND RESULTS: SP-D knockout (KO) mice were crossed with hyperlipidemic and atherosclerosis-prone apolipoprotein E (ApoE) KO mice to generate SP-D/ApoE double knockout (DKO) mice. Mice were placed on a high-fat diet for 12 weeks beginning at 8 weeks of age. Compared with ApoE KO mice, SP-D/ApoE DKO mice had significantly less atherosclerosis with reduced macrophage accumulation, decreased local macrophage proliferation, and increased smooth muscle cell coverage in plaques. Interestingly, SP-D deficiency worsened hypercholesterolemia and induced obesity and insulin resistance but suppressed plasma interleukin-6 (IL-6) levels. SP-D deficiency also reduced blood monocytes and neutrophils counts in ApoE KO mice. CONCLUSION: SP-D deficiency reduces atherosclerosis in part by decreasing the accumulation and proliferation of macrophages and by reducing IL-6 levels systemically. SP-D is a promising therapeutic target for cachectic COPD patients with elevated circulating SP-D levels who are at increased risk of cardiovascular morbidity and mortality.
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Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Inflamação/prevenção & controle , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica , Proteína D Associada a Surfactante Pulmonar/deficiência , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células , Modelos Animais de Doenças , Predisposição Genética para Doença , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina/genética , Interleucina-6/sangue , Ativação de Macrófagos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Obesidade/genética , Obesidade/metabolismo , Fenótipo , Proteína D Associada a Surfactante Pulmonar/genéticaRESUMO
The small airways are characterized by an internal diameter < 2 mm and absence of cartilage. Approximately 10-25% of total airway resistance in healthy lungs is due to the small airways, with their contribution to total airway resistance increasing substantially in chronic obstructive pulmonary disease (COPD). As the small airways are located in the lung periphery, they are not easily evaluable, which can potentially interfere with the diagnosis (especially at early stages), monitoring, detection of responses to clinical interventions, and prognostic evaluation in COPD. Here, we will discuss the currently available methods in clinical practice to evaluate small airway disease in COPD, focusing on the concept, advantages, and disadvantages of each method.
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Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in peripheral leukocytes from 231 HIV-infected adults. Comparisons were made to 691 HIV-uninfected individuals from a population-based sample. Subject quartiles of aTL were assessed for relationships with measures of HIV disease severity, airflow obstruction, and emphysema severity on computed tomographic (CT) imaging. Multivariable regression models identified factors associated with shortened aTL. Compared to HIV-uninfected subjects, the mean aTL in HIV-infected patients was markedly shorter by 27 kbp/genome (p<0.001); however, the slopes of aTL vs. age were not different (p=0.469). Patients with longer known durations of HIV infection (p=0.019) and lower nadir CD4 cell counts (p=0.023) had shorter aTL. Shorter aTL were also associated with older age (p=0.026), smoking (p=0.005), reduced forced expiratory volume in one second (p=0.030), and worse CT emphysema severity score (p=0.049). HIV-infected subjects demonstrate advanced cellular aging, yet in a cART-treated cohort, the relationship between aTL and age appears no different from that of HIV-uninfected subjects.
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Senescência Celular/genética , Infecções por HIV/genética , Leucócitos/ultraestrutura , Doença Pulmonar Obstrutiva Crônica/complicações , Telômero , Adulto , Estudos de Coortes , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologiaRESUMO
BACKGROUND: One in four cystic fibrosis (CF) patients diagnosed with a pulmonary exacerbation will not recover their baseline lung function despite standard treatment. This highlights the importance of preventing such events. Clinical decision-making can be improved through a simple blood test that predicts individuals at elevated short-term risk of an exacerbation. METHODS: We obtained plasma samples from 30 stable CF patients from the St. Paul's Hospital Adult CF Clinic (Vancouver, Canada). For 15 patients, an additional plasma sample was obtained during an exacerbation. Soluble CD14 (sCD14) and C-reactive protein (CRP) were quantified using ELISA kits. Myeloperoxidase (MPO), interleukin(IL)-6, IL-1ß, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor (G-CSF) were quantified using Luminex™ immunoassays. Stable state biomarker levels were examined in their ability to predict individuals that would experience a pulmonary exacerbation requiring intravenous (IV) antibiotics within 4 months. Paired stable and exacerbation plasma biomarker levels were also compared. RESULTS: sCD14 levels were significantly higher in patients that experienced a pulmonary exacerbation requiring IV antibiotics within 4 months (p = 0.001). sCD14 cut-off value of 1450 ng/mL was associated with an area under the curve of 0.91 (95% CI 0.83-0.99) for predicting an exacerbation within 4 months of a stable visit, with a sensitivity of 100% and specificity of 82%. Plasma sCD14 levels were significantly higher during exacerbations than during periods of clinical stability (p = 0.03). CONCLUSIONS: Plasma sCD14 is a promising biomarker for identifying CF patients who will exacerbate within 4 months of a stable visit but requires further study in larger, independent cohorts.
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Biomarcadores/sangue , Fibrose Cística/sangue , Fibrose Cística/diagnóstico , Receptores de Lipopolissacarídeos/sangue , Adulto , Progressão da Doença , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Masculino , Prognóstico , Testes de Função Respiratória , Adulto JovemRESUMO
The increased longevity afforded by combination antiretroviral therapy in developed countries has led to an increased concern regarding senescence-related diseases in patients with human immunodeficiency virus (HIV) infection. Previous epidemiologic analyses have demonstrated an increased risk of chronic obstructive pulmonary disease, as well as a significant burden of respiratory symptoms in HIV-infected patients. We performed the St. George's Respiratory Questionnaire (SGRQ) in 199 HIV-positive men, and determined the predominant factors contributing to poor respiratory-related health status. In univariate analyses, worse SGRQ scores were associated with respiratory-related variables such as greater smoking pack-year history (p=0.028), lower forced expiratory volume in 1 second (FEV1) (p<0.001), and worse emphysema severity as quantified by computed tomographic imaging (p=0.017). In addition, HIV-specific variables, such as a history of plasma viral load >100,000 copies/mL (p=0.043), lower nadir CD4 cell count (p=0.040), and current CD4 cell count ≤350 cells/µL (p=0.005), as well as elevated levels of inflammatory markers, specifically plasma interleukin (IL)-6 (p=0.002) and alpha-1 antitrypsin (p=0.005) were also associated with worse SGRQ scores. In a multiple regression model, FEV1, current CD4 count ≤350 cells/µL, and IL-6 levels remained significant contributors to reduced respiratory-related health status. HIV disease activity as measured by HIV-related immunosuppression in conjunction with the triggering of key inflammatory pathways may be important determinants of worse respiratory health status among HIV-infected individuals. Limitations of this analysis include the absence of available echocardiograms, diffusion capacity and lung volume testing, and an all-male cohort due to the demographics of the clinic population.
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Infecções por HIV/fisiopatologia , Nível de Saúde , Pneumopatias Obstrutivas/fisiopatologia , Pulmão/fisiopatologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Índice de Massa Corporal , Colúmbia Britânica , Contagem de Linfócito CD4 , Volume Expiratório Forçado , Indicadores Básicos de Saúde , Humanos , Modelos Lineares , Masculino , Análise de Regressão , Fumar/efeitos adversos , Fatores Socioeconômicos , Espirometria , Inquéritos e Questionários , Carga ViralRESUMO
Lung infections are associated with acute lung injury (ALI), systemic inflammation, and vascular events. Clinical studies suggest that statins improve health outcomes of patients with pneumonia and ALI. The mechanisms by which this occurs are unknown. The aim of this study was to determine whether statins attenuate systemic inflammation and cardiovascular dysfunction related to ALI in mice. Simvastatin (SS; 20 mg/kg) or vehicle solution was instilled intraperitoneally into mice 24 h before and again just prior to intratracheal LPS instillation (1 µg/g). These mice were then anesthetized with 2.0% isoflurane and underwent a short surgical procedure to instill LPS. Four hours later, IL-6 levels in bronchoalveolar lavage fluid and in arterial and venous serum were measured. Cardiac function was evaluated using 2-D echocardiography, and endothelial function was determined using wire myography on aortic sections. LPS induced a significant increase in serum IL-6 levels. SS reduced venous (P = 0.040) but not arterial concentrations of IL-6 (P = 0.112). SS improved the maximal vasodilatory response of the aorta to ACh (P = 0.004) but not to sodium nitroprusside (P = 1.000). SS also improved cardiac output (P = 0.023). Vasodilatory response to ACh was impaired when aorta from untreated mice was incubated with ex vivo IL-6 (P = 0.004), whereas in the aorta from mice pretreated with SS, the vasodilatory response did not change with IL-6 incubation (P = 0.387). SS significantly improved LPS-induced cardiovascular dysfunction possibly by reducing systemic expression of IL-6 and its downstream signaling pathways. These findings may explain how statins improve health outcomes in patients with ALI.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Sinvastatina/farmacologia , Acetilcolina/farmacologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Coração/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitroprussiato/farmacologia , Permeabilidade/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/imunologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologia , Veias/efeitos dos fármacos , Veias/imunologia , Veias/metabolismoRESUMO
Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory lung condition characterized by airways disease and emphysema, and the precise mechanism of pathogenesis is poorly understood. The consistent features of COPD include protease-antiprotease imbalance, inflammation and accelerated aging caused by apoptosis or senescence. One family of molecules involved in all of these processes is the granzymes, serine proteases with the best-known member being granzyme B (GzmB). The majority of GzmB is released unidirectionally towards target cells, but GzmB can also be released nonspecifically and escape into the extracellular environment. GzmB is capable of cleaving extracellular matrix (ECM) proteins in vitro, and the accumulation of GzmB in the extracellular milieu during chronic inflammation in COPD could contribute to ECM degradation and remodelling and, consequently, the emphysematous phenotype in the lung. Preliminary studies suggest that increased GzmB expression is associated with increased COPD severity, and this may represent a promising new target for drug and biomarker discovery in COPD. In this paper, we review the potential pathogenic contributions of GzmB to the pathogenesis of COPD.