Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia
Received date: February 29, 2012; Accepted date: March 03, 2012; Published date: March 05, 2012
Citation: Hodge S (2012) Pulmonary Macrophage-Targeted Therapies-The Way Forward in Chronic Inflammatory Lung Diseases?. J Pulmonar Respirat Med 2:e105. doi:10.4172/2161-105X.1000e105
Copyright: © 2012 Hodge S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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It is becoming increasingly evident that pulmonary macrophage dysfunction contributes to disease pathogenesis in a variety of chronic lung diseases including chronic obstructive pulmonary disease (COPD) , bronchiolitis obliterans syndrome (BOS) following lung transplantation , cystic fibrosis (CF)  and severe asthma (NEA) . An abnormal accumulation of apoptotic bronchial epithelial cells with an associated defect in the phagocytic ability of neighboring macrophages (efferocytosis) can lead to secondary necrosis of the uncleared apoptotic material with pro-inflammatory effects [5,6]. Specific therapeutic targeting of the macrophage dysfunction is being increasingly studied. The actual progression of this strategy to clinical use is however still very much in the early stages and much of our knowledge of the potential impact of macrophage-targeted therapies has evolved in retrospect rather than from a direct developmental approach.
The emerging body of evidence suggests that that the use of longterm macrolide therapy is both feasible and may offer useful clinical outcomes in chronic lung diseases, including COPD, BOS and NEA [6-8], while results in CF have been inconclusive [9,10]. The mechanism of action of macrolides in this regard may be through their effects on macrophage function [6-8]. In a small uncontrolled study using lowdose azithromycin in COPD subjects the principal findings were a significant increase in the efferocytosis capacity of alveolar macrophages and a reduction in the percentage of apoptotic airway epithelial cells obtained by airway brushing . A role for phosphatidyserine (PS) in these effects was shown .
Pulmonary macrophages may contribute to the relative insensitivity to cortocosteroids in chronic lung diseases [11,12]. Dexamethasone has been shown to improve efferocytosis  while in patients with severe asthma, defective efferocytosis was improved after a course of high dose steroids . In COPD, lung macrophages have reduced expression of the epigenetic modifying enzyme histone deacetylase 2 (HDAC2) and this is associated with increased expression of inflammatory genes and also resistance to corticosteroids .
Statins also have been shown to improve macrophage phagocytic function mediated in part by their inhibitory effects on RhoA . In COPD, there is evidence of an improved mortality rate following treatment with statins ; however, whether the effects of statins on macrophage function will translate to human clinical benefit is uncertain, as the doses used to achieve the in vitro effects were higher than those typically used clinically.
The process of efferocytosis involves signaling through macrophage surface receptors that include MER tyrosine kinase (MERTK), GAS6, milk fat globule epidermal growth factor 8 (MFG-E8) and several putative PS receptors including a G protein-coupled receptor, BAI1 (brain-specific angiogenes 1), TIM-1 and TIM-4. Activation of protein kinase C βII is required for efferocytosis. Scavenger receptors (mannose receptor, SRA11 (type AII), MARCO (class A) CD36 (class B)) facilitate the phagocytosis of modified protein on apoptotic cells. Dysregulated expression of macrophage receptors in COPD has been reported [6,7,17-19] and these may provide suitable targets for macrophagetargeted therapies. Whether epigenetic regulation of the various receptors alters their ligand-binding properties also remains unclear,and there is a need for characterizing epigenetic signatures of relevant genes in macrophages isolated from the various patient groups.
More recently, strategies are being pursued that are more specifically directed towards macrophage function, such as the use of mannosebinding lectin (MBL). MBL plays a key role in regulating efferocytosis and it is expressed at reduced levels in the airway in COPD or BOS [2,20]. Human and animal studies support the potential role for MBL in improving phagocytosis and reducing inflammation as a therapeutic strategy for airways disease . Further studies using anti-oxidants with a resultant improvement in macrophage function in smoke exposed mice have also been reported .
Compelling evidence is thus emerging for the role of defective pulmonary macrophage function in the pathogenesis of chronic inflammatory airways diseases, and it is also becoming clear that several therapies with established clinical efficacy for various conditions may be exerting some of their beneficial effects via modulation of macrophage function. Greater understanding of the clinical consequences of defective macrophage function and its modulation by therapeutic agents will progress the development of specific macrophage-targeted therapies with complementary or synergistic benefits to established therapies.
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