Genetic ablation of the fpr1 gene confers protection from smoking-induced lung emphysema in mice

Am J Respir Cell Mol Biol. 2012 Sep;47(3):332-9. doi: 10.1165/rcmb.2012-0036OC. Epub 2012 Mar 29.

Abstract

Cigarette smoke (CS) is the main causative factor of chronic obstructive pulmonary disease (COPD). Current research supports the concept that airway inflammation is central to the development and progression of the disease. Studies have demonstrated that neutrophils are increased in COPD lungs and that neutrophil-associated products correlate with the development and severity of COPD. The peptide FMLP is an active component of CS. FMLP interacts on the neutrophil and macrophage membranes with a high-affinity receptor subtype (FPR1) and with a low-affinity subtype FPRL1, promoting a chemotactic response, superoxide anion production, and degranulation. Bacterial colonization of the lower respiratory tract and lung cell damage may represent further sources of formyl peptides in patients with COPD. We investigated the role of FPR in a mouse model on lung inflammation and emphysema induced by CS. Here, we report the novel observation that genetic ablation of the FPR1 gene (Fpr1) confers protection from smoking-induced lung emphysema in mice. Compared with wild-type mice, Fpr1 knockout mice displayed marked decreases in the lung migration of neutrophils and macrophages after CS exposure. Upon transgenic approach, the changes in cell numbers were accompanied by marked modulation of the expression of genes implicated in the inflammatory response. Administration of the FPR1 antagonist cyclosporine H to wild-type mice attenuated the acute inflammatory response evoked by CS. These findings may have clinical significance because current smokers and subjects with emphysema showed increased FPR expression in bronchoalveolar fluids and on peripheral neutrophils. Modulating the FPR1 signal should be explored as a potential new therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid
  • Emphysema / etiology
  • Emphysema / genetics
  • Emphysema / prevention & control*
  • Male
  • Mice
  • Mice, Knockout
  • Real-Time Polymerase Chain Reaction
  • Receptors, Formyl Peptide / antagonists & inhibitors
  • Receptors, Formyl Peptide / genetics*
  • Smoking / adverse effects*

Substances

  • Fpr1 protein, mouse
  • Receptors, Formyl Peptide