Introduction 1 2 3 4 5 6 7 8 50 50 9 10 1 2A 2B 3 11 4 12 1 3 13 14 15 Nucleotide-mediated bacterial clearance 16 1 17 18 19 16 + Fig. 1 Impact of chronic obstructive lung diseases on mucociliary clearance. The polarized epithelium is composed of columnar (ciliated or mucin-secreting) cells facing the lumen and basal cells facing the serosal compartment. Bacterial clearance in healthy lungs is maintained by coordinated cilia beating activity within the PCL layer, moving upward the overlying mucus and pathogens. In chronic obstructive lung diseases, cilia are collapsed under a thick layer of mucus containing bacteria and leukocytes.  20 2B 5 − 2+ − 2 2+ 2 + 2+ 21 − − − 22 2 4 5 2+ 2+ − 7 22 23 7 2 24 26 27 28 2 29 16 30 31 32 33 2 6 34 35 36 37 38 10 29 39 40 41 2 42 P2 receptors and airway inflammation In vivo 43 43 44 2B 7 2B 7 1 2 45 P. aeruginosa 45 2 46 7 47 1 3 14 7 48 Too much of a good thing.. 49 51 6 2 42 1 3 52 53 7 23 7 54 7 7 2 39 7 22 E-NTPDases regulate airway ATP 9 10 55 58 2a 2b 9 59 9 10 15 60 2+ 2+ 61 62 63 64 65 66 67 3 2b 3 67 m 68 Fig. 2 a 10 b N P  Fig. 3 89 N P  in vitro 6 in vivo in vitro 69 2 2 70 67 71 Chronic lung diseases shorten the signals 10 72 4 9 Fig. 4 N 10 N P  Pseudomonas aeruginosa 51 P. aeruginosa P. aeruginosa 73 5A 5B Fig. 5 P. aeruginisa A 10 B N P  74 P aeruginosa 75 76 77 78 79 80 80 5B 79 81 82 83 73 84 P. aeruginosa 85 86 87 P. aeruginosa 88 P. aeruginosa LPS Adaptation of purine signaling to airway diseases 6 P. aeruginosa P. aeruginosa Fig. 6 2B 2 4, 5, 7  The information provided in this review also exposes the complexity of the signaling interactions taking place between different classes of mediators, including bacterial products, cytokines and extracellular nucleotides, as combinations of mediators may induce different responses than when tested individually. Furthermore, communication networks in the airways may evolve with time during the establishment of a chronic infection, as new target cells (bacteria, leukocytes, lymphocytes) agglomerate on either side of the epithelial barrier. It is proposed that nucleotide-mediated airway functions defined in normal tissues or aseptic culture conditions may require reassessment under conditions mimicking chronic lung diseases before their therapeutic potential may be clearly established.