Fpr1 Blockade And Smoking-Induced Lung Emphysema In Mice

INTRODUCTION: Current dogma supports the concept that airway inflammation is central to the development and progression of chronic obstructive pulmonary disease (COPD) leading to destruction of lung parenchyma as well as alveolar and bronchial tissue remodeling. Formyl peptide receptors (FPRs) present on neutrophils and macrophages have been reported to modulate various cellular responses associated with inflammation (i.e. chemotaxis, adhesion, release of superoxide anions and granule contents). FPRs were also found to be increased in the bronchoalveolar lavage (BAL) fluids and peripheral neutrophils from cigarette smokers and subjects with emphysema. We recently found that genetic ablation of the Fpr1 gene confers protection from cigarette smoke (CS) induced lung emphysema in mice. METHODS & RESULTS: We explored the basis of the possible mechanism(s) of protection from the development of emphysema and whether the modulation of FPR1 signal by synthetic inhibitors may limit inflammation induced by CS. Upon transgenic approach, we observed a significant decrease of BAL neutrophils and macrophages and a marked variation of the expression of some factors involved in the inflammatory and oxidative stress responses (i.e. heme oxygenase 1, melanocortin receptor type 3, IL-b etc.). The selective Fpr1 antagonist cyclosporine H (CsH) and the non-selective FPR antagonist N-t-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were tested using an acute 3-day protocol of exposure to CS in C57 Bl/6 mice. Administration of the FPR1 antagonist CsH significantly attenuated the inflammatory response evoked by CS, whereas administration of Boc2 (that inhibits both FPR1 and FPR2) led to a complete block of inflammatory cell migration in both WT and Fpr1-/- mice after CS. CONCLUSIONS: These results demonstrate the involvement of FPR1, and at a minor extent of FPR2, in the inflammatory response induced by CS. Modulating FPR signals should be explored as a potential new therapy for COPD.