| Although the main regulators of leukocyte trafficking are chemokines, another class of chemotactic agents is cyclophilins, proteins traditionally known as peptidyl-protyl cis-trans isomerases and the targets for the immunosuppressive drug, cyclosporine A (CsA). Elevated levels of extracellular cyclophilins have been observed in several inflammatory diseases, including rheumatoid arthritis, vascular smooth muscle cell disease, and sepsis. Previous studies in our laboratory have shown that extracellular cyclophilins might contribute to asthma-mediated lung inflammation, although the mechanism of contribution remains unknown. Based on these findings, the objectives of the current study were to determine the impact of specifically blocking extracellular cyclophilin activity during lung inflammation, and to investigate the potential mechanism(s) by which extracellular cyclophilins might contribute to asthma-mediated lung inflammation. Using a mouse model of acute allergic asthma we show that: (1) extracellular cyclophilins are present at high levels in the airways and lung tissue upon allergen challenge, (2) mice treated with cyclosporine A derivatives have reduced asthma pathology, and (3) cyclosporine A derivatives completely block the in vitro migration of activated CD4+ T cells to cyclophilins A and B. Both our in vivo and in vitro findings suggest that cyclophilins function extracellularly during asthmatic lung inflammation by promoting leukocyte recruitment into lung tissues and airways. Specifically blocking the extracellular function(s) of cyclophilins through drug intervention may provide a novel approach for reducing the pathology associated with acute allergic asthma. |
