DAMPs implicated in lung diseases. A) DAMPs have been associated with the pathogenesis of several lung diseases, including ALI/ARDS,4–11 COPD,12–16 pneumonia,17 asthma,18–21 and pulmonary fibrosis.7,22–26 In these diseases, DAMPs may be released into the extracellular space either passively (from damaged or necrotic cells) or actively (from activated inflammatory cells). B) Extracellular DAMPs activate pattern receptors located on the cell surface or within the cytoplasm of target cells, including dendritic cells.15 Note the considerable redundancy in danger signaling: individual DAMPs are often capable of activating a variety of pattern receptors, and pattern receptors are often capable of being activated by a variety of DAMPs. C) Pattern receptor activation generally leads to upregulation of pro-inflammatory mediators, resulting in alveolar injury and airspace destruction.15–16,26–30 This inflammatory response is often mediated through nuclear factor-kappa B (NF-κB) signaling or activation of the cytosolic interleukin-1β (IL-1β)-producing “inflammasome”. In certain cases (e.g. purines), pattern receptor activation may be cell-protective; this protection is dependent upon the receptor subtype activated and the duration of activation.6,12 (ALI/ARDS: acute lung injury/acute respiratory distress syndrome; COPD: chronic obstructive pulmonary disease; ATP: adenosine triphosphate; P1, P2: purinergic 1 and 2 receptors; TLR: toll-like receptor; RAGE: receptor for advanced glycosylation end products; NKG2D: natural killer cell group 2D receptor).