IL-4Rα blockade reduces influenza-associated morbidity in a murine model of allergic asthma.

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.

Adhesion molecule gene variants and plasma protein levels in patients with suspected obstructive sleep apnea.

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.

The role of beta-blockers in the management of chronic obstructive pulmonary disease.

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.

Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation.

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; 3 mg·kg(-1)) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8 weeks of a Western-type diet. 24 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 8 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.

Current methods to diagnose small airway disease in patients with COPD.

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.

Absolute leukocyte telomere length in HIV-infected and uninfected individuals: evidence of accelerated cell senescence in HIV-associated chronic obstructive pulmonary disease.

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.

Plasma sCD14 as a biomarker to predict pulmonary exacerbations in cystic fibrosis.

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.

A possible role for CD8+ and non-CD8+ cell granzyme B in early small airway wall remodelling in centrilobular emphysema.

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.

The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis.

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.

The possible role of granzyme B in the pathogenesis of chronic obstructive pulmonary disease.

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.