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• Transcription factors have a key role in the pathogenesis of asthma and COPD. • Transcription factors inhibitors have a potential therapeutic role in asthma and COPD. • Low dose theophylline could have an anti-inflammatory and clinical efficacy in stable COPD. 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 new 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. [ABSTRACT FROM AUTHOR]

Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway, although the drivers and site of the inflammation differ between diseases. Asthmatics with a neutrophilic airway inflammation are associated with a poor response to corticosteroids, whereas asthmatics with eosinophilic inflammation respond better to corticosteroids. Biologicals targeting the Th2-eosinophil nexus such as anti-interleukin (IL)-4, anti-IL-5, and anti-IL-13 are ineffective in asthma as a whole but are more effective if patients are selected using cellular (eg, eosinophils) or molecular (eg, periostin) biomarkers. This highlights the key role of individual inflammatory mediators in driving the inflammatory response and for accurate disease phenotyping to allow greater understanding of disease and development of patient-oriented antiasthma therapies. In contrast to asthmatic patients, corticosteroids are relatively ineffective in COPD patients. Despite stratification of COPD patients, the results of targeted therapy have proved disappointing with the exception of recent studies using CXC chemokine receptor (CXCR)2 antagonists. Currently, several other novel mediator-targeted drugs are undergoing clinical trials. As with asthma specifically targeted treatments may be of most benefit in specific COPD patient endotypes. The use of novel inflammatory mediator-targeted therapeutic agents in selected patients with asthma or COPD and the detection of markers of responsiveness or nonresponsiveness will allow a link between clinical phenotypes and pathophysiological mechanisms to be delineated reaching the goal of endotyping patients. [ABSTRACT FROM AUTHOR]

Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness. [ABSTRACT FROM AUTHOR]

Background: Impaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation. Objective: We sought to investigate airway interferon production in response to rhinovirus infection in children who are asthmatic, atopic, or both and its correlation with the airway inflammatory profile. Methods: Bronchial biopsy specimens and epithelial cells were obtained from 47 children (mean age, 5 ± 0.5 years) undergoing bronchoscopy. The study population included asthmatic children who were either atopic or nonatopic, atopic children without asthma, and children without atopy or asthma. Rhinovirus type 16 induction of IFN-λ and IFN-β mRNA and protein levels was assessed in bronchial epithelial cell cultures. The immunoinflammatory profile was evaluated by means of immunohistochemistry in bronchial biopsy specimens. Results: Rhinovirus type 16–induced interferon production was significantly reduced in atopic asthmatic, nonatopic asthmatic, and atopic nonasthmatic children compared with that seen in nonatopic nonasthmatic children (all P < .05). Increased rhinovirus viral RNA levels paralleled this deficient interferon induction. Additionally, IFN-λ and IFN-β induction correlated inversely with the airway TH2 immunopathologic profile (eosinophilia and IL-4 positivity: P < .05 and r = −0.38 and P < .05 and r = −0.58, respectively) and with epithelial damage (P < .05 and r = −0.55). Furthermore, total serum IgE levels correlated negatively with rhinovirus-induced IFN-λ mRNA levels (P < .05 and r = −0.41) and positively with rhinovirus viral RNA levels (P < .05 and r = 0.44). Conclusions: Deficient interferon responses to rhinovirus infection are present in childhood in asthmatic subjects irrespective of their atopic status and in atopic patients without asthma. These findings suggest that deficient immune responses to viral infections are not limited to patients with atopic asthma but are present in those with other TH2-oriented conditions. [Copyright &y& Elsevier]

Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future. [Copyright &y& Elsevier]

Abstract: Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. COPD is also a major independent risk factor for lung carcinoma, among long-term smokers. Smokers with COPD also have a higher risk of developing a specific histological subtype of non-small cell lung cancer termed squamous cell carcinoma. For these reasons the focus of this review is on the potential pathogenic molecular links between tobacco smoking-related COPD and squamous cell carcinoma. We believe that we need to promote more studies on the molecular and cellular pathobiology of smokers with premalignant bronchial lesions of the squamous cell lung carcinoma compared with a control group of smokers with and without COPD to unravel the complex molecular interactions between COPD and early squamous cell lung carcinoma. These studies should also look at younger healthy smokers in combination with risk models of lung cancer and COPD. Overall these studies may allow the discovery of new molecular targets of the early carcinogenesis process that in the foreseeable future may render the early diagnosis and treatment, and may be even the prevention, of invasive squamous cell lung carcinoma a reality. [Copyright &y& Elsevier]

Background: Glucocorticoid function is markedly impaired in the lungs of patients with chronic obstructive pulmonary disease (COPD). This reduction in glucocorticoid sensitivity might be due to an oxidant-mediated increase in phosphoinositol 3–kinase (PI3K) δ signaling. Objective: We sought to determine the role of PI3Kδ in the reduced glucocorticoid responsiveness in patients with COPD. Methods: Peripheral lung tissue was obtained from 24 patients with COPD, 20 age-matched smokers with normal lung function, and 13 nonsmokers. Peripheral blood monocytes were isolated from 9 patients with COPD and 7 age-matched smokers with normal lung function and from healthy volunteers. Results: The expressions of PI3Kδ and Akt phosphorylation were increased in macrophages from patients with COPD compared with those from control groups of age-matched smokers and nonsmokers. In vitro oxidative stress induced phosphorylation of Akt in monocytes and macrophages, which was abolished by means of selective inhibition of PI3Kδ but not PI3Kγ. Dexamethasone was less effective at repressing LPS-induced GM-CSF and CXC motif chemokine 8 release in blood monocytes from patients with COPD compared with age-matched smokers. This reduced sensitivity was reversed by inhibition of PI3Kδ but not PI3Kγ. Conclusion: PI3Kδ expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kδ might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target. [Copyright &y& Elsevier]

Background: Both smokers and patients with asthma can experience fixed airflow obstruction, which is associated with distinctive patterns of airway pathology. The influence of fixed airflow obstruction on the prognosis of these patients is unknown. Objective: We sought to investigate lung function decline and exacerbations in a 5-year prospective study of subjects with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease (COPD). We also sought to explore correlations between functional, pathological, and clinical features. Methods: Patients with fixed airflow obstruction due to asthma (n = 16) or COPD (n = 21) and a control group of asthmatic patients with fully reversible airflow obstruction (n = 15) were followed for 5 years. Results: The rates of decline in FEV1 were similar in patients with fixed airflow obstruction caused by asthma (−49.7 ± 10.6 mL/y) or COPD (−51.4 ± 9.8 mL/y) and were higher than in asthmatic patients with reversible airflow obstruction (−18.1 ± 10.1 mL/y, P < .01). Exacerbation rates were also higher in patients with fixed airflow obstruction caused by asthma (1.41 ± 0.26 per patient-year) or COPD (1.98 ± 0.3 per patient-year) compared with those seen in asthmatic patients with reversible airflow obstruction (0.53 ± 0.11 per patient-year, P < .01). Baseline exhaled nitric oxide levels and sputum eosinophil counts correlated with the FEV1 decline in asthmatic patients with fixed airflow obstruction. By contrast, baseline sputum neutrophil counts, emphysema scores, comorbidities, and exacerbation frequency correlated directly and pulmonary diffusion capacity correlated inversely with the FEV1 decline in patients with COPD. Conclusion: In both patients with asthma and those with COPD, fixed airflow obstruction is associated with increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function entails the specific pathological and clinical features of the underlying diseases. [Copyright &y& Elsevier]

Long acting β2-agonists and glucocorticoids together control asthma in ∼95% of affected individuals, although symptoms return after treatment is stopped. Treatment of chronic obstructive pulmonary disease (COPD) scarcely influences the natural course of the disease. Neither long-acting β2-agonists (LABAs) nor glucocorticoids alone significantly influence the course of COPD. Recent evidence suggests that a combination of the two therapies is more promising: It can decrease the exacerbation rates in severe COPD and may also decrease mortality. [Copyright &y& Elsevier]

Background: Reactive nitrogen species, formed via the reaction of nitric oxide (NO) with superoxide anion and via (myelo)peroxidase-dependent oxidation of NO2 −, have potent proinflammatory and oxidizing actions. Reactive nitrogen species formation and nitrosative stress are potentially involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Objectives: To investigate the expression of markers of nitrosative stress, including nitrotyrosine (NT), inducible NO synthase (iNOS), endothelial NO synthase (eNOS), myeloperoxidase (MPO), and xanthine oxidase (XO) in bronchial biopsies and bronchoalveolar lavage from patients with mild to severe stable COPD compared with control groups (smokers with normal lung function and nonsmokers). Methods: The expression of NT, iNOS, eNOS, MPO and XO in the bronchial mucosa and bronchoalveolar lavage of patients was measured by using immunohistochemistry, Western blotting, and ELISA and correlated with the inflammatory cell profile. Results: Patients with severe COPD in stable phase had higher numbers of NT+ and MPO+ cells in their bronchial submucosa compared with mild/moderate COPD, smokers with normal lung function, and nonsmokers (P < .01). iNOS+ and eNOS+ but not XO+ cells were significantly increased in smokers with COPD or normal lung function compared with nonsmokers (P < .05 and P < .01, respectively). In patients with COPD, the number of MPO+ cells was significantly correlated with the number of neutrophils (r = +0.61; P < .0025) in the bronchial submucosa. Furthermore, the number of NT+ and MPO+ cells was negatively correlated with postbronchodilator FEV1. Conclusion: These data suggest that nitrosative stress, mainly mediated by MPO and neutrophilic inflammation, may contribute to the pathogenesis of severe COPD. [Copyright &y& Elsevier]

IL-33 is a multifaceted cytokine, plays a pivotal role in various biological processes, making it a subject of extensive research and intrigue in the field of immunology. This cytokine acts as a key regulator, effectively putting the brakes on proinflammatory nuclear factor-kappa B (NF-κB), thereby modulating chromatin compaction by promoting nucleosome-to-nucleosome interactions. IL-33's influence extends to the realm of innate and acquired immunity through its binding to the membrane-bound ST2 molecule (ST2L) of the IL-33R complex, which is expressed on various immune cells, such as Th2 cells, mast cells, natural killer cells, myeloid cells, and dendritic cells. IL-33's role in inflammation is far from one-dimensional, as it has been found to have a dual role in inflammatory disorders. In the quest to understand the origins of IL-33, immunohistochemical examination of lung tissue samples from patients with adenocarcinoma could shed light on its presence in bronchial epithelial and vascular endothelial cells, in lung tissue cancerous lesions. For this reason, we conducted a pilot study about the immunohistochemical expression of IL-33 in surgical specimens of stage 1 o 2 lung adenocarcinoma received after lung resection surgery.Our results demonstrated that patients had nuclear IL-33 immunopositivity in the alveolar pneumocytes of the normal lung tissue at the periphery of lung adenocarcinoma specimen. Note the evident negativity of the neoplastic adenocarcinoma cells. Other data showed IL-33 nuclear immunoexpression in endothelial cells of intratumoral vascular structures.This finding could indicate that IL-33 might be involved in regulating blood vessel formation and maintenance within the tumor, which is a critical factor in tumor growth and progression.The presence of IL-33 in normal lung tissue and intratumoral vascular structures may be related to its physiological functions in these contexts, while its absence in neoplastic adenocarcinoma cells could indicate a potential loss of regulatory control, which might have implications for the development and progression of the tumor. [ABSTRACT FROM AUTHOR]

Background: 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. Objective: We sought to evaluate whether rhinovirus infection interferes with the mechanisms of action of glucocorticoids. Methods: Cultured primary human bronchial or transformed (A549) respiratory epithelial cells were infected with rhinovirus 16 (RV-16) before dexamethasone exposure. Glucocorticoid receptor (GR) ? 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 I?B kinase (IKK) were used to investigate the involvement of intracellular signaling pathways. Results: RV-16 infection impaired dexamethasone-dependent (1) inhibition of IL-1?–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 GR? 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 ?B activation and GR? 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 GR? nuclear translocation. Conclusion: RV-16 infection of human airway epithelium induces glucocorticoid resistance. Inhibition of RV-16–induced JNK and nuclear factor ?B activation fully reversed rhinovirus impairment of both GR? nuclear translocation and the transactivation/transrepression activities of glucocorticoids. [Copyright &y& Elsevier]

Abstract: Kinases are believed to play a crucial role in the expression and activation of inflammatory mediators in the airway, in T-cell function and airway remodelling. Important kinases such as Inhibitor of κB kinase (IKK)2, mitogen activated protein (MAP) kinases and phsopho-inositol (PI)3 kinase regulate inflammation either through activation of pro-inflammatory transcription factors such as activating protein-1 (AP-1) and nuclear factor κB (NF-κB), which are activated in airway disease, or through regulation of mRNA half-life. Selective kinase inhibitors have been developed which reduce inflammation and some characteristics of disease in animal models. Targeting specific kinases that are overexpressed or over active in disease should allow for selective treatment of respiratory diseases. Interest in this area has intensified due to the success of the specific Abelson murine leukaemia viral oncogene (Abl) kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myelogenous leukaemia. Encouraging data from animal models and primary cells and early Phase I and II studies in other diseases suggest that inhibitors of p38 MAP kinase and IKK2 may prove to be useful novel therapies in the treatment of severe asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and other inflammatory airway diseases. [Copyright &y& Elsevier]

The role of nitric oxide (NO) in allergic inflammation and bronchial hyperresponsiveness is unclear. We studied a selective prodrug nitric oxide synthase (NOS)-2 inhibitor, l-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51). In ovalbumin-sensitized and challenged rats, exhaled NO levels increased by 3 h following challenge (3.73±0.74 ppb; P<0.05), peaking at 9 h (11.0±2.75; P<0.01) compared to saline controls (1.87±0.26; P<0.05 and 2.81±0.18; P<0.01). Immunoreactive lung NOS2 expression was increased in ovalbumin-challenged rats compared with ovalbumin-sensitized, saline-challenged rats at 8 h post-challenge. SC-51 (10 mg/kg; p.o.) inhibited allergen-induced increase in exhaled NO levels to 1.3±0.17 ppb. SC-51 inhibited bronchial hyperresponsiveness in ovalbumin-sensitized and challenged rats (P<0.05). In sensitized non-exposed rats, SC-51 increased bronchial responsiveness (P<0.05). SC-51 reduced the allergen-induced increase in bronchoalveolar lavage neutrophils, but caused a nonsignificant reduction in bronchial mucosal eosinophil numbers. NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed. [Copyright &y& Elsevier]

Rhinoviruses are the major cause of the common cold and acute exacerbations of asthma and chronic obstructive pulmonary disease. We previously reported rapid rhinovirus induction of intracellular superoxide anion, resulting in NF-κB activation and pro-inflammatory molecule production. The mechanisms of rhinovirus superoxide induction are poorly understood. Here we found that the proteolytic activation of the xanthine dehydrogenase/ xanthine oxidase (XD/XO) system was required because pretreatment with serine protease inhibitors abolished rhinovirus-induced superoxide generation in primary bronchial and A549 respiratory epithelial cells. These findings were confirmed by Western blotting analysis and by silencing experiments. Rhinovirus infection induced intracellular depletion of reduced glutathione (GSH) that was abolished by pretreatment with either XO inhibitor oxypurinol or serine protease inhibitors. Increasing intracellular GSH with exogenous H2S or GSH prevented both rhinovirus-mediated intracellular GSH depletion and rhinovirus-induced superoxide production. We propose that rhinovirus infection proteolytically activates XO initiating a pro-inflammatory vicious circle driven by virus-induced depletion of intracellular reducing power. Inhibition of these pathways has therapeutic potential. [ABSTRACT FROM AUTHOR]