Anti-Inflammatory Role of the cAMP Effectors Epac and PKA: Implications in Chronic Obstructive Pulmonary Disease

Cigarette smoke-induced release of pro-inflammatory cytokines including interleukin-8 (IL-8) from inflammatory as well as structural cells in the airways, including airway smooth muscle (ASM) cells, may contribute to the development of chronic obstructive pulmonary disease (COPD). Despite the wide use of pharmacological treatment aimed at increasing intracellular levels of the endogenous suppressor cyclic AMP (cAMP), little is known about its exact mechanism of action. We report here that next to the β2-agonist fenoterol, direct and specific activation of either exchange protein directly activated by cAMP (Epac) or protein kinase A (PKA) reduced cigarette smoke extract (CSE)-induced IL-8 mRNA expression and protein release by human ASM cells. CSE-induced IκBα-degradation and p65 nuclear translocation, processes that were primarily reversed by Epac activation. Further, CSE increased extracellular signal-regulated kinase (ERK) phosphorylation, which was selectively reduced by PKA activation. CSE decreased Epac1 expression, but did not affect Epac2 and PKA expression. Importantly, Epac1 expression was also reduced in lung tissue from COPD patients. In conclusion, Epac and PKA decrease CSE-induced IL-8 release by human ASM cells via inhibition of NF-κB and ERK, respectively, pointing at these cAMP effectors as potential targets for anti-inflammatory therapy in COPD. However, cigarette smoke exposure may reduce anti-inflammatory effects of cAMP elevating agents via down-regulation of Epac1

Design of the Dutch Obesity Intervention in Teenagers (NRG-DOiT): systematic development, implementation and evaluation of a school-based intervention aimed at the prevention of excessive weight gain in adolescents

BACKGROUND: Only limited data are available on the development, implementation, and evaluation processes of weight gain prevention programs in adolescents. To be able to learn from successes and failures of such interventions, integral written and published reports are needed. METHODS: Applying the Intervention Mapping (IM) protocol, this paper describes the development, implementation, and evaluation of the Dutch Obesity Intervention in Teenagers (DOiT), a school-based intervention program aimed at the prevention of excessive weight gain. The intervention focussed on the following health behaviours: (1) reduction of the consumption of sugar-sweetened beverages, (2) reduction of energy intake derived from snacks, (3) decrease of levels of sedentary behaviour, and (4) increase of levels of physical activity (i.e. active transport behaviour and sports participation). The intervention program consisted of an individual classroom-based component (i.e. an educational program, covering 11 lessons of both biology and physical education classes), and an environmental component (i.e. encouraging and supporting changes at the school canteens, as well as offering additional physical education classes). We evaluated the effectiveness of the intervention program using a randomised controlled trial design. We assessed the effects of the intervention on body composition (primary outcome measure), as well as on behaviour, behavioural determinants, and aerobic fitness (secondary outcome measures). Furthermore, we conducted a process evaluation. DISCUSSION: The development of the DOiT-intervention resulted in a comprehensive school-based weight gain prevention program, tailored to the needs of Dutch adolescents from low socio-economic background

A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms

Bronchoconstriction Induces TGF-beta Release and Airway Remodelling in Guinea Pig Lung Slices

<p>Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-beta, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-beta release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-beta(1) augmented the expression of contractile proteins (sm-alpha-actin, sm-myosin, calponin) after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-beta, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A) or TGF-beta receptor kinase (SB431542) prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl) mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-beta, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.</p>