62 Chapter 3 INTRODUCTION Alveolar macrophages are self-renewing tissue-resident macrophages that derive from fetal liver progenitors without contribution from circulating monocytes under steady-state conditions (1). They are part of the first line of defense in the lungs and need to respond to dangers without impairing lung function. Depending on which environmental factors alveolar macrophages are exposed to, even in healthy individuals, these cells can change their phenotype swiftly to deal with a threat as efficiently as possible (2). Alveolar macrophages, therefore, play a dual role in the lung: initiating lung inflammation to neutralize threats and resolving inflammation to prevent lung function loss (3,4). These two seemingly opposite functions appear to be regulated by changes in metabolism, called metabolic reprogramming. Many studies have shown that induction of macrophage glycolysis favors inflammation while induction of macrophage oxidative phosphorylation favors tissue repair (5). However, Woods and colleagues recently showed that alveolar macrophages do not rely on glycolysis as their main source of energy during inflammatory responses, challenging this view for tissue-resident macrophages in the lung (6). Most chronic respiratory diseases are characterized by an imbalance between pro and anti-inflammatory responses (7), with alveolar macrophages showing phenotypical and functional changes (8). Chronic obstructive pulmonary disease (COPD) is one of these diseases affecting more than 300 million patients worldwide (9). COPD is characterized by chronic inflammation which leads to small airway inflammation and obstruction (chronic bronchitis) together with parenchymal destruction (emphysema) (10). Alveolar macrophages are important contributors to chronic inflammation through the secretion of a number of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, and interleukin (IL)-1 β (7). Moreover, previous work has shown an increase in pro-inflammatory macrophages in bronchoalveolar lavage fluid and sputum of patients with COPD compared to healthy individuals (11,12). Furthermore, resolution of inflammation and initiation of tissue repair through the production of IL-10 and transforming growth factor (TGF)-β (7) seems to be deficient in lung tissue of patients with COPD (13). To overcome this deficit, patients are often treated with corticosteroids, which can induce an anti-inflammatory phenotype in macrophages (14–16). However, corticosteroids are not effective in many COPD patients as some patients develop resistance and others have a nonresponsive phenotype (17–19). Therefore, there is a pressing need to find alternative therapeutics that can be used to treat COPD patients and to rebalance macrophage-driven inflammation with macrophage-driven tissue repair. An interesting approach was recently postulated by Leus et al., showing that inhibitors of lysine deacetylases (KDACs also known as histone deacetylases or HDACs) have anti-inflammatory effects. They found that KDAC inhibitors reduced
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