Essential role for ATP in the pathogenesis of COPD and emphysema

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease often associated with cigarette smoke inhalation. Extracellular ATP induces inflammation by binding to purinergic receptors (P2R), but its role in COPD is unknown. Methods: The influence of cigarette smoke on endobronchial ATP was studied in healthy adults. In addition, endobronchial ATP concentrations were studied in smokers and ex-smokers with COPD of different severity. The expression of P2R on immune cells and its functional implications were studied in patients with COPD and in controls. Finally, the role of ATP was investigated in a mouse model of acute and chronic smoke-induced lung inflammation where neutralisation of ATP or P2R-blockage, as well as P2R deficient animals were studied. Results: Endobronchial ATP-concentrations were elevated in smokers and even further elevated following acute smoke exposure. Endobronchial ATP was also increased in patients with COPD and in ex-smokers. Highest levels were observed in patients with severe COPD, correlating with endobronchial neutrophil numbers and FEV1-reduction. P2R were upregulated on neutrophils and macrophages from patients with COPD, which was shown to have pro-inflammatory effects (such as recruitment and elastase release/MMP-9 secretion). In the mouse model, we showed that the development of smoke-induced lung inflammation and emphysema was markedly reduced by neutralizing ATP or blocking P2R. Finally in P2Y2-/- and P2X7-/- knockout animals ATP failed to induce COPD associated changes. Thus endogenous ATP, via activation of P2Y2R and P2X7R, contributes to the de- velopment of chronic airway inflammation and emphysema. Targeting P2R might be a new therapeutic option for COPD.