Translating Basic Research Into Clinical Practice CHEST CHEST / 141 / 4 / APRIL, 2012 1055 www.chestpubs.org C learance of inhaled particles and bacteria is of utmost importance in maintaining the sterility of the lung. This is achieved through a number of mech- anisms, including mucociliary clearance and secretion of antimicrobial proteins from epithelial cells and leukocytes in the airways. 1-3 Other essential mech- anisms include phagocytosis of particulate matter and invading organisms, with the macrophage being the most prominent phagocyte in the lung, 4 although, during a specific insult or infection, neutrophils are also recruited rapidly and contribute to this clear- ance process. 5 Neutrophils are released by the bone marrow into the circulation and are relatively short lived but will respond to specific signals that recruit them to sites of invasion or damage. Macrophages are longer-lived cells derived from circulating mono- cytes that migrate into lung tissue from the blood- stream and subsequently differentiate with little, if any, local proliferation. 6 Together, these phagocytic cells act with soluble proteins that bind microbial products to maintain the sterility of the airway tract and remove detrimental invading pathogens and particles. Bacterial infections contribute to the pathophysi- ology of a number of pulmonary conditions, including COPD, asthma, and cystic fibrosis (CF). There is now accumulating evidence that defects in the ability of the innate immune system to counteract bacterial pathogens in these conditions appear to be associated Defective Phagocytosis in Airways Disease Louise E. Donnelly, PhD; and Peter J. Barnes, DM, FCCP Manuscript received September 13, 2011; revision accepted November 1, 2011. Affiliations: From Airway Disease, National Heart and Lung Institute, Imperial College London, London, England. Correspondence to: Louise Donnelly, PhD, Airway Disease, National Heart and Lung Institute, Imperial College London, Dovehouse St, London, SW3 6LY, England; e-mail: l.donnelly@ imperial.ac.uk © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2348 Maintaining an airway clear of inhaled particles, pathogens, and cellular debris is paramount for lung homeostasis. In healthy individuals, the phagocytes of the innate immune system act as sentinels to patrol the airway and ensure sterility. However, in airways diseases, including asthma, COPD, and cystic fibrosis, there is a propensity for bacterial colonization that may contribute to disease worsening. Evidence suggests that this may be due to dysfunctional phagocytosis. In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations; however, the literature is currently contradictory and requires further clarification. In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strat- egies. The identification of this and other mechanisms underlying phagocyte dysfunction may present novel therapeutic opportunities for the treatment of many of these intractable diseases and improve patient morbidity and mortality. CHEST 2012; 141(4):1055–1062 Abbreviations: CD 5 cluster of differentiation; CF 5 cystic fibrosis; CR 5 complement receptor; HLA-DR 5 human leukocyte antigen-DR; MARCO 5 macrophage receptor with collagenous structure; SR 5 scavenger receptor; TLR 5 toll- like receptor Downloaded From: http://journal.publications.chestnet.org/ on 02/02/2014