Optimising experimental research in respiratory diseases: an ERS statement.

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.

Increased levels of enzymes involved in local estradiol synthesis in chronic obstructive pulmonary disease.

Introduction: Steroid hormones are involved in lung development, pulmonary inflammation, and lung cancer. Estrogen signaling and exposure may play a role in pulmonary disorders, including COPD. In both genders, estrogens can be generated locally in the lungs and this contributes importantly to the tissue exposure to these steroids.

Hyperleptinemia is associated with impaired pulmonary host defense.

We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia.

Granzyme A impairs host defense during Streptococcus pneumoniae pneumonia.

Streptococcus pneumoniae is the most common causative pathogen in community-acquired pneumonia (CAP). Granzyme A (GzmA) is a serine protease produced by a variety of cell types involved in the immune response. We sought to determine the role of GzmA on the host response during pneumococcal pneumonia.

A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α.

Remodeling in chronic obstructive pulmonary disease (COPD) has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recently we showed comparable alterations of the extracellular matrix (ECM) compounds collagen, hyaluoran, and elastin in alveolar and small airway walls of COPD patients. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models.

The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury.

Objectives: One of the hallmarks of severe pneumonia and associated acute lung injury is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and acute lung injury.

Leptin as regulator of pulmonary immune responses: involvement in respiratory diseases.

Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases.

Interferon-β induces a long-lasting antiviral state in human respiratory epithelial cells.

Objectives: Interferon-β (IFNβ) induces strong antiviral effects and is therefore an attractive agent to prevent or reduce the incidence of virus-mediated exacerbations in asthmatic or chronic obstructive pulmonary disease (COPD) patients. We therefore investigated the effects of prophylactic IFNβ on respiratory epithelial cells infected with rhinovirus (RV).

Methods: A549 cells and primary bronchial epithelial cells (PBECs) were exposed for 18 h to IFNβ.

NF-κB activation is required for the transition of pulmonary inflammation to muscle atrophy.

Disease exacerbations and muscle wasting comprise negative prognostic factors of chronic obstructive pulmonary disease (COPD). Transient systemic inflammation and malnutrition have been implicated in skeletal muscle wasting after acute exacerbations of COPD. However, the interactions between systemic inflammation and malnutrition in their contributions to muscle atrophy, as well as the molecular basis underlying the transition of systemic inflammation to muscle atrophy, remain unresolved.

Obesity is associated with neutrophil dysfunction and attenuation of murine acute lung injury.

Although obesity is implicated in numerous health complications leading to increased mortality, the relationship between obesity and outcomes for critically ill patients appears paradoxical. Recent studies have reported better outcomes and lower levels of inflammatory cytokines in obese patients with acute lung injury (ALI)/acute respiratory distress syndrome, suggesting that obesity may ameliorate the effects of this disease. We investigated the effects of obesity in leptin-resistant db/db obese and diet-induced obese mice using an inhaled LPS model of ALI.

Gender differences in the adipose secretome system in chronic obstructive pulmonary disease (COPD): a pivotal role of leptin.

Background: COPD is characterized by a multi-component character involving a state of low-grade systemic inflammation and an increased prevalence of cardiovascular co-morbidity. The role of circulating leptin and other adipokines in the involvement of the systemic inflammation in COPD is only studied scarcely.

Objective: To investigate gender related differences in the adipokine metabolism in relation to systemic inflammatory biomarkers in clinically stable subjects with COPD.

Leptin modulates innate and adaptive immune cell recruitment after cigarette smoke exposure in mice.

Leptin, a pleiotropic type I cytokine, was recently demonstrated to be expressed by resident lung cells in chronic obstructive pulmonary disease patients and asymptomatic smokers. To elucidate the functional role of leptin in the onset of chronic obstructive pulmonary disease, we tested leptin-deficient ob/ob mice (C57BL/6), leptin receptor-deficient db/db mice (C57BKS), and littermates in a model of cigarette smoke (CS)-induced pulmonary inflammation. Wild-type (WT) C57BL/6 mice were exposed for 4 or 24 wk to control air or CS.

Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection?

Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) and probably asthma are associated with low-grade systemic inflammatory changes. In patients with COPD, systemic inflammation is considered a key factor in the pathogenesis of the multicomponent disease manifestations. Spillover of inflammatory mediators into the circulation is generally considered to be the source of this systemic inflammation.

Inhibition of acute pulmonary and systemic inflammation by 1,7-dimethylxanthine.

The nuclear enzyme poly(ADP-ribose) polymerse-1 (PARP-1) has previously been reported to play an important role in lipopolysaccharide (LPS)-induced pulmonary inflammation and is highly activated in COPD patients. In the present study, the anti-inflammatory efficacy of a previously identified poly(ADP-ribose) polymerase-1 (PARP-1) inhibiting caffeine metabolite, 1,7-dimethylxanthine, was both in vivo as well as ex vivo evaluated. Orally administered 1,7-dimethylxanthine significantly attenuated lung myeloperoxidase-levels, transcription of IL-6, TNF-alpha, MIP1alpha and MIP2 genes as well as PAR-polymer formation in a mouse model of intratracheally LPS-induced acute pulmonary inflammation.

Enhanced deposition of low-molecular-weight hyaluronan in lungs of cigarette smoke-exposed mice.

Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of inflammatory cells, destruction of lung parenchyma, and airway wall remodeling. Hyaluronan (HA) is a component of the extracellular matrix, and low-molecular-weight (LMW) HA fragments have proinflammatory capacities. We evaluated the presence of HA in alveolar and airway walls of C57BL/6 mice that were exposed to air or cigarette smoke (CS) for 4 weeks (subacute) or 24 weeks (chronic).

Myeloperoxidase deficiency attenuates lipopolysaccharide-induced acute lung inflammation and subsequent cytokine and chemokine production.

Lung neutrophilia is common to a variety of lung diseases. The production of reactive oxygen and nitrogen species during neutrophil oxidative burst has been associated with protein and DNA damage. Myeloperoxidase (MPO) is an enzyme stored in the azurophilic granula of neutrophils.

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids.

In the present study, the anti-inflammatory effects of the flavonoids flavone, fisetin and tricetin were evaluated in a mouse model of LPS-induced acute pulmonary inflammation. The flavonoid fisetin significantly reduced lung myeloperoxidase-levels and gene-expression of inflammatory mediators such as IL-6, TNF-alpha, IL-1beta, MIP-1alpha and MIP-2. The LPS-induced gene transcription of HO-1 and SOD2 was also significantly reduced by fisetin.

Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers.

Background: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory reaction of the lungs involving activation of epithelial cells. Leptin is a pleiotropic cytokine important in the regulation of immune responses via its functional receptor Ob-Rb. This study was undertaken to test the hypothesis that severe COPD is associated with increased leptin expression in epithelial cells.

Systemic inflammation in chronic obstructive pulmonary disease: the role of exacerbations.

The systemic manifestations of chronic obstructive pulmonary disease (COPD) exacerbations are recognized, but our understanding of their etiology and importance is lacking largely due to the small number of systematic and longitudinal studies. Most of the systemic manifestations are likely the result of inflammatory processes. Serum biomarkers, such as various cytokines, adipokines, C-reactive protein, and coagulation factors, are elevated during exacerbations.

Myeloperoxidase modulates lung epithelial responses to pro-inflammatory agents.

During extensive inflammation, neutrophils undergo secondary necrosis causing myeloperoxidase (MPO) release that may damage resident lung cells. Recent observations suggest that MPO has pro-inflammatory properties, independent of its enzymatic activity. The aims of the present study were to characterise MPO internalisation by lung epithelial cells and to investigate the effect of MPO on oxidative stress, DNA damage and cytokine production by lung epithelial cells.

Control of lymphocyte infiltration of lung tumors in mice by host's genes: mapping of four Lynf (lymphocyte infiltration) loci.

Tumor infiltration by lymphocytes is essential for cell-mediated immune elimination of tumors in experimental systems and in immunotherapy of cancer. Presence of lymphocytes in several human cancers has been associated with a better prognosis. We present evidence that individual propensity to tumor infiltration is genetically controlled.

Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased numbers of CD8(+) cytotoxic T lymphocytes (CTLs) in the lung, but the functional activity of CTLs remains unknown. Granzyme A (GrA) and B (GrB) are serine proteases considered to be important effector molecules of CTLs and natural killer cells.

Objective: To investigate protein and mRNA expression of GrA and GrB in peripheral lung tissue from patients with COPD and control subjects with normal lung function.

Breath condenser coatings affect measurement of biomarkers in exhaled breath condensate.

Exhaled breath condensate collection is not yet standardised and biomarker measurements are often close to lower detection limits. In the current study, it was hypothesised that adhesive properties of different condenser coatings interfere with measurements of eicosanoids and proteins in breath condensate. In vitro, condensate was derived from a collection model using two test solutions (8-isoprostane and albumin) and five condenser coatings (silicone, glass, aluminium, polypropylene and Teflon).

Patterns of inflammation and the use of reversibility testing in smokers with airway complaints.

Background: Although both smoking and respiratory complaints are very common, tools to improve diagnostic accuracy are scarce in primary care. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, and what factors are associated with eosinophilia.

Method: Induced sputum and blood plasma of 59 primary care patients with COPD (n = 17), asthma (n = 11), chronic bronchitis (CB, n = 14) and smokers with no respiratory complaints ('healthy smokers', n = 17) were collected, as well as lung function, smoking history and clinical work-up.

Rapid pulmonary expression of acute-phase reactants after local lipopolysaccharide exposure in mice is followed by an interleukin-6 mediated systemic acute-phase response.

This study investigated local and systemic innate immune responses in lipopolysaccharide (LPS)-induced lung inflammation in mice. Intratracheal LPS exposure resulted in increased pulmonary mRNA expression for acute-phase reactants (APRs) alpha(1)-antitrypsin (alpha(1)-AT), alpha(1)-acid glycoprotein (AGP), and LPS-binding protein (LBP) from 4 hours post exposure. Although pulmonary serum amyloid P component (SAP) mRNA was not increased, systemic levels of SAP, AGP, and LBP were elevated from 24 hours post exposure.