2320 Current Pharmaceutical Design, 2012, 18, 2320-2328 1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers Inflammasome Signaling in Pathogenesis of Lung Diseases Esmaeil Mortaz 1,2 , Mohammad Reza Masjedi 2 *, Abdolamir Allameh 3 and Ian M. Adcock 4 1 Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands; 2 Chronic Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3 Department of Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; and 4 Cell and Molecular Biol- ogy Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK Abstract: Asthma and Chronic Obstructive Pulmonary Disease (COPD) are two important lung and airways diseases which affect the lives of ~500 million people worldwide. Asthma is a heterogeneous disease that is broadly defined as a clinical syndrome characterized by altered lung function, mucus hypersecretion, peribronchial inflammation and hyperresponsiveness In contrast, the effect of inhalation of toxic particles and gases on the innate and adaptive inflammatory immune systems underlie the pathogenesis of COPD. In the last dec- ade, knowledge concerning the pathophysiologic mechanisms underlying asthma and COPD has risen tremendously and current dogma suggests that the pathogenesis of both diseases is driven by the chronic inflammation present in the airways of these patients. Thus, un- derstanding the mechanisms for the persistence of inflammation may lead to new therapeutic approaches. In this review, we provide an overview of the main signal transduction pathways implicated in asthma and COPD pathophysiology focusing on inflammasome signal- ing in various cells types which result in altered inflammatory mediator expression. Keywords: Airways, COPD, asthma, inflammasome, NLRP3, caspase-1. INTRODUCTION The characteristics and functional relationship of lung immune cells and their ability to govern selective aspects of adaptive and acquired immunity through the production of inflammatory and anti-inflammatory mediators which display specific functions in pathogenesis of lungs disorders is not well described. Understand- ing the signal transduction pathways underpinning the expression of these mediators may help us to find new therapeutic targets in lung disorders. Two important lung and airway diseases, asthma and COPD, are increasing in incidence particularly in developing countries. Worldwide, asthma and COPD affect the lives of ~300 and 200 million people respectively [1]. Allergic asthma is characterized by chronic airway inflammation, dominated by allergen-specific CD4+ T cells, which produce Th2-type cytokines (IL-4, IL-5, IL-9, IL-13 and GM-CSF) [2-5]. Asthma is one of the commonest chronic diseases in the world and its prevalence is rising, particularly in developing coun- tries [1]. The majority of deaths attributed to asthma occur in pa- tients suffering from the severe form of the disease (5-10% of pa- tients), and these are generally not managed effectively with the current Gold Standard therapies i.e. combination of  2 -adrenoceptor agonists and inhaled corticosteroids [6]. COPD is a chronic inflammatory disease for which smoking is the major risk factor in the developed world and is currently the fourth leading cause of death worldwide and is predicted to be the third ranked disease by the year 2030 [7,8]. The inflammatory mediators involved in COPD have not been clearly delineated but are thought to include many lipid mediators, inflammatory peptides, reactive oxygen specious (ROS) and nitrogen species, chemokines, cytokines and growth factors are involved in orchestrating the com- plex inflammatory process that results in small airway fibrosis and alveolar destruction that occur in COPD [9-11]. A similar list of *Address correspondence to this author at the Chronic Respiratory Disease Research Center, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Fax: +9821 2610 9484; E-mail: Mrmasjedi@gmail.com mediators has been implicated in severe asthma particularly in the subset of asthmatics who smoke [12]. Exposure to cigarette smoke activates an inflammatory cascade in the airways, resulting in the production of a number of potent cytokines and chemokines with accompanying damage to the lung epithelium leading to increased permeability and the recruitment of macrophages and neutrophils [13]. Understanding the pathways and mechanisms leading to mediator release may lead to better thera- peutic approaches for these diseases. A growing body of evidence implicates the inflammasome and its products in the inflammation seen in lung diseases [14-16]. In this paper, we review the literature relating to the NLRP3 Inflam- masome and its associated inflammatory mediators (IL-1, IL-18 and IL-33) and discuss cross talk with Toll like receptors (TLRs) in the pathogenesis of asthma and COPD. CELL SIGNAL TRANSDUCTION IN LUNGS DISORDERS For any physiological system to maintain a healthy homeody- namic state, cell signaling routes must have adequate regulatory feedback and controlling steps. With the complexity of inflamma- tory signaling networks and the cross talk that occurs between them, it is important to develop a greater understanding of these networks in the pathogenesis of disease [15]. The determination and modeling of the spatial and temporal organisation of signal trans- duction networks will be greatly helped by the use of new tech- niques, which can detect specific protein-protein interactions and post-translational modifications that define signaling pathways in live cells [16]. In terms of lung disease, it is still debatable as to whether these diseases occur as a result of excessive inflammatory drive or a lack of inhibitory feedback loops. However, it is clear that many of these pathways/networks are abnormally activated in severe asthma and COPD and that interference with these signaling pathways could shed light on disease processes and provide novel therapeutic ap- proaches. The lung is a unique organ in that it is exposed to different irri- tants derived from breathing and from tissue/blood throughout life. Over the past decade, significant progress has been made at the cellular and molecular level regarding the mechanisms by which