[show abstract][hide abstract] ABSTRACT: Tuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (M. Tuberculosis, MTB) and despite ongoing global efforts for its eradication there were still an estimated 8.7 million new cases and 1.4 million deaths worldwide in 2011 (1). Co-infection with HIV caused 13% new actively infected people resulting in a high mortality rate (48.6 %) among these patients (2). TB is therefore considered as one of the leading causes of death due to infectious diseases worldwide despite the availability of effective and extensive therapeutic approaches (3, 4). Two TB-related conditions have been reported, namely, active TB and a latent form of TB infection whereby MTB survives in the body without causing overt signs or symptoms of the disease. People with latent TB infection are not infectious and cannot spread the TB bacteria to others. However, if TB bacteria become active in the body and multiply, the person will go from having a latent TB infection to being sick with TB disease and becoming infective. This unmasking of the latent disease may be idiopathic or the result of immunosuppression either from disease directly or from the use of drugs for treatment of other diseases (5). The first line of defense against MTB is provided by alveolar macrophages, which ingest and sequester the bacilli within granulomatous structures. The control and resolution of the infection also require activated T lymphocytes (6) and Th 1 cytokines (7). Interestingly, genetic defects within the IL-12/IFN− pathway have been found in patients with mendelian susceptibility to mycobacterial disease (MSMD) caused by live BCG vaccine or NTM species. This highlights the crucial role of IL-12/IFN− axis in the immune regulation of TB (8). Sarcoidosis is considered an autoimmune disease characterized by multisystem disorder of unclear etiology that involves any organ, but most commonly the lungs and the intrathoracic lymph nodes although the heart, skin and central nervous system are frequently affected (9). Despite the first clinical description of sarcoidosis over 120 years ago, little is known about the pathogenesis of this disease (10). A genetic predisposition to sarcoidosis is evident from epidemiological studies of familial aggregation, differences in disease susceptibility and severity between racial groups and the significantly increased incidence of sarcoidosis in monozygotic twins of affected individuals compared to other siblings (11, 12). More recent results have provided further insights into the genetic risks for TANAFFOS
[show abstract][hide abstract] ABSTRACT: To the Editor:Hydrogen sulfide (H2S) has emerged as a new and important endogenous regulator of inflammation in recent years (1) and may also protect from emphysema induced by cigarette smoke exposure (2). We have also recently shown that H2S can inhibit airway smooth muscle cell proliferation and inflammatory mediator release in vitro (3). Serum levels of H2S positively correlate with the decline in lung function in chronic obstructive pulmonary disease (COPD) and were significantly lower in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III patients compared with those in GOLD I (4). Existing therapies for COPD, such as corticosteroids or long-acting anticholinergic agents, may reduce the exacerbation rate but do not significantly slow disease progression. A previous study has shown that theophylline alone had no impact on serum H2S levels and is of limited value in the management of stable COPD (5). Interestingly, sputum H2S measured in patients with asthma correlated with sputum neutrophil counts and the degree of airflow obstruction measured by forced expiratory volume in 1 s (FEV1) % predicted (6). Moreover, combination therapy of an inhaled glucocorticoid with low-dose theophylline has been shown to attenuate airway inflammation in patients with COPD and reverse glucocorticoid resistance (7). We.
European Respiratory Journal 02/2014; · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: The immunopathology of sarcoidosis remains elusive despite years of research into this multiorgan disease.However, recent studies have provided new insights into the genetics and immune components involved in the clinical manifestation of the disease. Granulomatous inflammation is due to the host immune response to a persistent poorly degradable unknown antigen.Mycobacterium tuberculosis (MTB) is the major disease driver in many patients. The immune mechanisms that cause this disease start with the antigenic stimulus, followed by T-cell, macrophage and dendritic cell activation via a classic MHC II–mediated pathway. In addition, the profile of immune mediators reported in sarcoidosis indicates that the inflammasome pathway plays a critical role in disease pathogenesis. Increased understanding of the signal transductions pathways involved in the induction of inflammatory processes in sarcoidosis could give rise to new therapeutic approaches in future.
[show abstract][hide abstract] ABSTRACT: In models of COPD, environmental stressors induce innate immune responses, inflammasome activation and inflammation. However, the interaction between these responses and their role in driving pulmonary inflammation in stable COPD is unknown.
To investigate the activation of innate immunity and inflammasome pathways in the bronchial mucosa and bronchoalveolar lavage (BAL) of patients with stable COPD of different severity and control healthy smokers and non-smokers.
Innate immune mediators (interleukin (IL)-6, IL-7, IL-10, IL-27, IL-37, thymic stromal lymphopoietin (TSLP), interferon γ and their receptors, STAT1 and pSTAT1) and inflammasome components (NLRP3, NALP7, caspase 1, IL-1β and its receptors, IL-18, IL-33, ST2) were measured in the bronchial mucosa using immunohistochemistry. IL-6, soluble IL-6R, sgp130, IL-7, IL-27, HMGB1, IL-33, IL-37 and soluble ST2 were measured in BAL using ELISA.
In bronchial biopsies IL-27+ and pSTAT1+ cells are increased in patients with severe COPD compared with control healthy smokers. IL-7+ cells are increased in patients with COPD and control smokers compared with control non-smokers. In severe stable COPD IL-7R+, IL-27R+ and TSLPR+ cells are increased in comparison with both control groups. The NALP3 inflammasome is not activated in patients with stable COPD compared with control subjects. The inflammasome inhibitory molecules NALP7 and IL-37 are increased in patients with COPD compared with control smokers. IL-6 levels are increased in BAL from patients with stable COPD compared with control smokers with normal lung function whereas IL-1β and IL-18 were similar across all groups.
Increased expression of IL-27, IL-37 and NALP7 in the bronchial mucosa may be involved in progression of stable COPD.
[show abstract][hide abstract] ABSTRACT: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need.Supported by the American Thoracic Society (ATS) and European Respiratory Society (ERS), a Task Force reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.We performed a literature review followed by discussion by an expert committee according to the GRADE approach to develop specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
European Respiratory Journal 12/2013; · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: Combination inhaled therapy with long-acting β2 agonists (LABAs) and corticosteroids is beneficial in treating asthma and chronic obstructive pulmonary disease (COPD).
In asthma, LABAs enhance glucocorticoid receptor (GR) nuclear translocation in the presence of corticosteroids. Whether this biological mechanism occurs in COPD, a relatively corticosteroid-resistant disease, is uncertain.
Eight patients with mild/moderate COPD participated in a double-blind, placebo-controlled, crossover study and inhaled single doses of fluticasone propionate (FP) 100 μg, FP 500 μg, salmeterol xinafoate (SLM) 50 μg, and combination FP 100 μg + SLM 50 μg. One hour postinhalation, sputum was induced, nuclear proteins isolated from purified macrophages, and levels of activated nuclear GR quantified by using a GR-glucocorticoid response element ELISA-based assay.
Nuclear GR significantly increased after the inhalation of FP 500 μg (P < .01), but not after the inhalation of FP 100 μg or SLM 50 μg, compared with placebo. Interestingly, SLM in combination with FP 100 μg increased nuclear GR levels equivalent to those of FP 500 μg alone. This was significantly greater than either FP 100 μg (P < .05) or SLM 50 μg (P < .01) alone. In vitro in a human macrophage cell line, SLM (10(-8) mol/L) enhanced FP (10(-9) mol/L)-induced mitogen-activated protein kinase phosphatase-1 mRNA (5.8 ± 0.6 vs 8.4 ± 1.1 × 10(-6) copies, P < .05) and 2 × glucocorticoid response element-luciferase reporter gene activity (250.1 ± 15.6 vs 103.1 ± 23.6-fold induction, P < .001). Addition of SLM (10(-9) mol/L) to FP (10(-11) mol/L) significantly enhanced FP-mediated suppression of IL-1β-induced CXCL8 (P < .05).
Addition of SLM 50 μg to FP 100 μg enhanced GR nuclear translocation equivalent to that seen with a 5-fold higher dose of FP in sputum macrophages from patients with COPD. This may account for the superior clinical effects of combination LABA/corticosteroid treatment compared with either as monotherapy observed in COPD.
The Journal of allergy and clinical immunology 09/2013; · 9.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ozone is an oxidizing environmental pollutant that contributes significantly to respiratory health. Exposure to increased levels of ozone has been associated to worsening of symptoms of patients with asthma and COPD. In this study we investigated the acute and chronic effects of ozone exposure-induced oxidative stress related inflammation mechanics in mouse lung. In particular we investigated the oxidative stress-induced effects on HDAC2 modification and activation of the Nrf2 and HIF-1α signalling pathways. Male C57BL/6 mice were exposed to ozone (3 ppm) for 3 hours a day, 2 times a week for a period 1, 3 and 6 weeks. Control mice were exposed to normal air. After the last exposure mice were sacrificed for bronchoalveolar lavage (BAL) fluid and lung tissue collection. BAL total cell counts were elevated at all time points studied. This was associated with increased levels of chemokines and cytokines in all ozone exposed groups indicating the presence of a persistent inflammatory environment in the lung. Increased inflammation and Lm scores were observed in chronic exposed mice indicating emphysematous changes were present in lungs of chronic exposed mice. The anti-oxidative stress response was active (indicated by increased Nrf2 activity and protein) after 1 week of ozone exposure but this ability was lost after 3 and 6 weeks of ozone exposure. The transcription factor HIF-1α was elevated in 3 and 6 week ozone exposed mice and this was associated with increased gene expression levels of several of HIF-1α target genes including hdac2, vegf, keap1, and mif. HDAC2 protein was found to be phosphorylated and carbonylated in nuclear and cytoplasm fractions, respectively, and was associated with a decrease in DNA binding activity and protein expression of HDAC2. Decreased HDAC2 activity, most likely a direct result from protein modification, in combination with the loss of the anti-oxidative stress response and activation of the HIF-1α pathway contribute to the inflammatory response and emphysema observed in ozone-exposed mice.
[show abstract][hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response of the lung to noxious particles or gases. The cellular inflammatory response in COPD is characterised by an increased number of inflammatory cells in the lungs. Although the molecular and cellular mechanisms responsible for the development of COPD are not well understood; several mediators are assumed to regulate the activation and recruitment of these inflammatory cells into the lung of COPD patients particularly those belonging to the chemokine family. Inhibitors or blockers of chemokine and chemokine receptors are therefore of great interest as potential novel therapies for COPD and many are now in clinical development. A high degree of redundancy exists in the chemokine network and inhibition of a single chemokine or receptor may not be sufficient to block the inflammatory response. Despite this, animal studies suggest a strong rationale for inhibiting the chemokine network in COPD. As such, every leading pharmaceutical company maintains a significant interest in developing agents that regulate leukocyte navigation as potential anti-inflammatory drugs. Drugs and antibodies targeting chemokines and their receptors are generally still in early stages of development and the results of clinical trial are awaited with great interest. These agents may not only provide improved management of COPD but also, importantly, indicate proof-of-concept to further clarify the role of chemokines in the pathophysiology of COPD.
Current Medicinal Chemistry 09/2013; · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Increased airway smooth muscle (ASM) mass is a feature of asthmatic airways and could result from augmented proliferation. We determined whether proliferation and IL-6 release are abnormal in ASM cells from severe asthma patients, and whether these could be mediated by microRNA-221 and microRNA-222, through modulation of the cyclin-dependent kinase inhibitors, p21WAF1 and p27kip1. ASM cells cultured from bronchial biopsies of healthy subjects and patients with non-severe or severe asthma were studied. Proliferation was measured by incorporation of bromodeoxyuridine and IL-6 by ELISA. Foetal calf serum (FCS) and TGF-β caused greater proliferation and IL-6 release in severe compared to non-severe asthma patients and to normal subjects. FCS+TGF-β inhibited p21WAF1 and p27kip1 expression and increased miR-221 expression in severe ASM cells. miR-221, not miR-222, mimics increased proliferation and IL-6 release induced by FCS+TGF in healthy ASM, while in severe asthmatics, inhibition of miR-221, but not miR-222, inhibited proliferation and IL-6 release. miR-221 inhibition led to increased expression of FCS+TGF-β induced p21WAF1 and p27kip1. Dexamethasone suppressed proliferation in healthy subjects but not in asthmatic subjects. IL-6 was less suppressible by dexamethasone in non-severe and severe asthmatics compared to healthy subjects. miR-221 did not affect the effects of dexamethasone. ASM from severe asthma patients shows greater proliferation and IL-6 release than non-severe asthma patients, but both groups show corticosteroid insensitivity. miR-221 regulates p21WAF1 and p27kip1 expression levels. Furthermore, miR-221 regulates the hyper-proliferation and IL-6 release of ASM cells from severe asthma patients, but not the corticosteroid insensitivity.
American Journal of Respiratory Cell and Molecular Biology 08/2013; · 4.15 Impact Factor
[show abstract][hide abstract] ABSTRACT: Some patients with severe inflammatory disease fail to respond to glucocorticoids, and oxidative stress contributes to this insensitivity. Importin receptors are associated with nuclear translocation of the glucocorticoid receptor (GR), which is essential for glucocorticoid function. We hypothesized that importin-7 is central to GR nuclear translocation and glucocorticoid sensitivity. We investigated the effects of importin-7 siRNA on fluticasone propionate (FP)-induced GR nuclear localization and suppression of IL-1β-induced CXCL8 and the effects of hydrogen peroxide (H2O2) plus IL-1β costimulation on importin-7 expression, function, and glucocorticoid responsiveness in a human macrophagecell line (U937). H2O2 significantly reduced FP-induced GR nuclear localization (3.4±0.51- vs. 5.7±0.85-fold increase, P<0.05) and suppression of IL-1β-induced CXCL8 (62.3±2.3 vs. 85.1±7.0%, P<0.05). Knockdown of importin-7 by 38.4 ± 11.5% (compared with control siRNA) significantly reduced FP-mediated GR nuclear localization (3.5±0.5- vs. 5.7±0.85-fold increase, P<0.05) and suppression of IL-1β-induced CXCL8 expression (40.2±16.1 vs. 68.4±3.0%, P<0.05). H2O2 plus IL-1β had no direct effect on importin-7 but caused a significant loss (61.2±12.6% compared with baseline) of nuclear RanGTP, an essential cofactor for importin-7-mediated nuclear import of cargo proteins. The importin-7 complex is essential for glucocorticoid function, and the expression of its cofactor RanGTP is reduced during oxidative stress-induced glucocorticoid insensitivity.-Hakim, A., Barnes, P. J., Adcock, I. M., Usmani, O. S. Importin-7 mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity.
[show abstract][hide abstract] ABSTRACT: Although inhaled glucocorticoids are the mainstays of asthma treatment, they are poorly effective at treating and preventing virus-induced asthma exacerbations. The major viruses precipitating asthma exacerbations are rhinoviruses.
We sought to evaluate whether rhinovirus infection interferes with the mechanisms of action of glucocorticoids.
Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) α nuclear translocation, glucocorticoid response element (GRE) binding, and transactivation/transrepression functional readouts were evaluated by using immunocytochemistry, Western blotting, DNA binding assays, real-time quantitative PCR, coimmunoprecipitation, and ELISA techniques. Specific inhibitors of c-Jun N-terminal kinase (JNK) and of IκB kinase (IKK) were used to investigate the involvement of intracellular signaling pathways.
RV-16 infection impaired dexamethasone-dependent (1) inhibition of IL-1β-induced CXCL8 release, (2) induction of mitogen-activated protein kinase phosphatase 1 gene expression, and (3) binding of GR to GREs in airway epithelial cells. This was associated with impaired GRα nuclear translocation, as assessed by means of both immunochemistry (54.0% ± 6.8% vs 24.7% ± 3.8% GR-positive nuclei after 10 nmol/L dexamethasone treatment in sham- or RV-16-infected cells, respectively; P < .01) and Western blotting. RV-16 infection induced nuclear factor κB activation and GRα phosphorylation, which were prevented by inhibitors of IKK2 and JNK, respectively. In rhinovirus-infected cells the combination of JNK and IKK2 inhibitors totally restored dexamethasone suppression of CXCL8 release, induction of mitogen-activated protein kinase phosphatase 1 gene expression, and GRα nuclear translocation.
RV-16 infection of human airway epithelium induces glucocorticoid resistance. Inhibition of RV-16-induced JNK and nuclear factor κB activation fully reversed rhinovirus impairment of both GRα nuclear translocation and the transactivation/transrepression activities of glucocorticoids.
The Journal of allergy and clinical immunology 07/2013; · 9.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide. It is characterised by chronic inflammation in the lungs that leads to progressive chronic airflow obstruction. The main strategy for treating COPD is control of the chronic inflammation. However, current anti-inflammatory treatments fail to prevent disease progression. New long-acting bronchodilators and their combinations are currently under development. Research has been focused on identifying the key inflammatory regulators. CXCR2 antagonists inhibit neutrophilic inflammation; inhibitors of phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (p38), Janus kinases and IL-6 have also shown some promising effects. There is an emerging need for identification of key modulators of the oxidative stress-regulated corticosteroid function aiming the development of monotherapies which will resolve any side effects issues currently faced.
Current Opinion in Pharmacology 04/2013; · 5.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD). Despite recent advances in the knowledge of the pathogenesis of asthma and COPD, much more research on the molecular mechanisms of asthma and COPD are needed to aid the logical development of new therapies for these common and important diseases, particularly in COPD where no effective treatments currently exist. In the future the role of the activation/repression of different transcription factors and the genetic regulation of their expression in asthma and COPD may be an increasingly important aspect of research, as this may be one of the critical mechanisms regulating the expression of different clinical phenotypes and their responsiveness to therapy, particularly to anti-inflammatory drugs.
Cell Communication & Adhesion 03/2013; · 1.05 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is associated with persistent inflammation and oxidative stress in susceptible individuals. Using microarray analysis of bronchial biopsy samples from patients with COPD and controls, we identified Wnt4 as being up-regulated in COPD. Analysis of bronchial biopsy samples showed a very strong correlation between Wnt4 and IL8 gene expression, suggesting that Wnt4 plays a role in chronic lung inflammation. In vitro, Wnt4 induced proliferation and inflammation in human epithelial cells (BEAS-2B) and normal primary human bronchial epithelial cells in a concentration-dependent manner. This effect was enhanced in the presence of interleukin-1β (IL-1β) as a result of activation of the p38 and c-Jun NH2-terminal kinase mitogen-activated protein kinase pathways. Hydrogen peroxide, but not proinflammatory stimuli, up-regulated Wnt4 expression in epithelial cells. In monocytic THP-1 and primary airway smooth muscle cells, Wnt4 induced inflammation and enhanced the inflammatory response to lipopolysaccharide and IL-1β but did not induce proliferation. In addition, these other cell types did not have enhanced Wnt4 expression in response to hydrogen peroxide. Our results indicate that airway epithelial activation, due to oxidative stress, may lead to Wnt4 induction. Wnt4, in turn, acts through the noncanonical pathway to activate epithelial cell remodeling and IL8 gene expression, leading to neutrophil infiltration and inflammation.-Durham, A. L., McLaren, A., Hayes, B. P., Caramori, G., Clayton, C. L., Barnes, P. J., Chung, K. F., Adcock, I. M. Regulation of Wnt4 in chronic obstructive pulmonary disease.
[show abstract][hide abstract] ABSTRACT: Inflammatory lung diseases are highly complex in respect of pathogenesis and relationships between inflammation, clinical disease and response to treatment. Sophisticated large-scale analytical methods to quantify gene expression (transcriptomics), proteins (proteomics), lipids (lipidomics) and metabolites (metabolomics) in the lungs, blood and urine are now available to identify biomarkers that define disease in terms of combined clinical, physiological and patho-biological abnormalities. The aspiration is that these approaches will improve diagnosis, i.e., define pathological phenotypes, and facilitate the monitoring of disease and therapy and, also, unravel underlying molecular pathways. Biomarker studies can either select pre-defined biomarker(s) measured by specific methods or apply an "unbiased" approach involving detection platforms that are indiscriminate in focus. This article reviews the technologies presently available to study biomarkers of lung disease within the 'omics field. The contributions of the individual 'omics analytical platforms to the field of respiratory diseases are summarised, with the goal of providing background on their respective abilities to contribute to systems medicine-based studies of lung disease.
European Respiratory Journal 02/2013; · 6.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess activation of the inflammatory transcription factor NF-kappa B (NF-κB) in human idiopathic pulmonary arterial hypertension (PAH).
Idiopathic PAH is a severe progressive disease characterized by pulmonary vascular remodeling and excessive proliferation of vascular cells. Increasing evidence indicates that inflammation is important in disease pathophysiology.
NF-κB-p65 and CD68, CD20 and CD45 were measured by immunohistochemistry and confocal microscopy on lung specimens from patients with idiopathic PAH (n = 12) and controls undergoing lung surgery (n = 14). Clinical data were recorded for all patients including invasive pulmonary hemodynamics for the PAH patients. Immunohistochemical images were analyzed by blinded observers to include standard pulmonary vascular morphometry; absolute macrophage counts/mm(2) and p65-positivity (p65+) using composite images and image-analysis software; and cytoplasmic:nuclear p65+ of individual pulmonary arterial endothelial and smooth muscle cells (PASMC) in 10-20 pulmonary arteries or arterioles per subject. The expression of ET-1 and CCL5 (RANTES) in whole lung was determined by RT-qPCR.
Macrophage numbers were increased in idiopathic PAH versus controls (49.0±4.5 vs. 7.95±1.9 macrophages/100 mm(2), p<0.0001): these macrophages demonstrated more nuclear p65+ than in macrophages from controls (16.9±2.49 vs. 3.5±1.25%, p<0.001). An increase in p65+ was also seen in perivascular lymphocytes in patients with PAH. Furthermore, NF-κB activation was increased in pulmonary arterial endothelial cells (62.3±2.9 vs. 14.4±3.8, p<0.0001) and PASMC (22.6±2.3 vs. 11.2±2.0, p<0.001) in patients with PAH versus controls, with similar findings in arterioles. Gene expression of both ET-1 mRNA ((0.213±0.069 vs. 1.06±0.23, p<0.01) and CCL5 (RANTES) (0.16±0.045 vs. 0.26±0.039, p<0.05) was increased in whole lung homogenates from patients with PAH.
NF-κB is activated in pulmonary macrophages, lymphocytes, endothelial and PASMC in patients with end-stage idiopathic PAH. Future research should determine whether NF-κB activation is a driver or bystander of pulmonary vascular inflammation and if the former, its potential role as a therapeutic target.
PLoS ONE 01/2013; 8(10):e75415. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For example, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohn's disease. Probiotics have been defined as "live microorganisms which, when administered in adequate amounts, confer health benefits on the host." In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus, Bifidobacterium, and Saccharomyces, and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases.
Mediators of Inflammation 01/2013; 2013:751068. · 3.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. COPD is mostly associated with cigarette smoking. Cigarette smoke contains over 4,700 chemical compounds, including free radicals and LPS (a Toll-Like Receptor 4 agonist) at concentrations which may contribute to the pathogenesis of diseases like COPD. We have previously shown that short-term exposure to cigarette smoke medium (CSM) can stimulate several inflammatory cells via TLR4 and that CSM reduces the degranulation of bone-marrow-derived mast cells (BMMCs). In the current study, the effect of CSM on mast cells maturation and function was investigated. Coculturing of BMMC with CSM during the development of bone marrow progenitor cells suppressed the granularity and the surface expression of and Fc RI receptors. Stimulation with IgE/antigen resulted in decreased degranulation and release of Th1 and Th2 cytokines. The effects of CSM exposure could not be mimicked by the addition of LPS to the culture medium. In conclusion, this study shows that CSM may affect mast cell development and subsequent response to allergic activation in a TLR4-independent manner.
Mediators of Inflammation 01/2013; 2013:813091. · 3.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: COPD is an inflammatory lung disease largely associated with exposure to cigarette smoke (CS). The mechanism by which CS leads to the pathogenesis of COPD is currently unclear; it is known however that many of the inflammatory mediators present in the COPD lung can be produced via the actions of the transcription factor Nuclear Factor-kappaB (NF-κB) and its upstream signalling kinase, Inhibitor of κB kinase-2 (IKK-2). Therefore the NF-κB/IKK-2 signalling pathway may represent a therapeutic target to attenuate the inflammation associated with COPD.
To use a range of assays, genetically modified animals and pharmacological tools to determine the role of NF-κB in CS-induced airway inflammation.
NF-κB pathway activation was measured in pre-clinical models of CS-induced airway inflammation and in human lung tissue from COPD patients. This data was complemented by employing mice missing a functional NF-κB pathway in specific cell types (epithelial and myeloid cells) and with systemic inhibitors of IKK-2.
We showed in an airway inflammation model known to be NF-κB-dependent that the NF-κB pathway activity assays and modulators were functional in the mouse lung. Then, using the same methods, we demonstrated that the NF-κB pathway appears not to play an important role in the inflammation observed after exposure to CS. Furthermore, assaying human lung tissue revealed that in the clinical samples there was also no increase in NF-κB pathway activation in the COPD lung, suggesting that our pre-clinical data is translational to human disease.
In this study we present compelling evidence that the IKK-2/NF-κB signalling pathway does not play a prominent role in the inflammatory response to CS exposure and that this pathway may not be important in COPD pathogenesis.
PLoS ONE 01/2013; 8(1):e54128. · 3.73 Impact Factor