The major theme of this research is to identify novel factors regulating leukocyte trafficking during inflammatory responses. The main regulators of leukocyte trafficking are chemokines, a family of chemoattracting cytokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Extracellular cyclophilins have been shown to induce chemotaxis in vitro for several different leukocytes, including neutrophils, eosinophils, and T lymphocytes, by a mechanism that is dependent on the presence of CD147 receptors. Indirect evidence that cyclophilins might contribute to inflammation-mediated pathology is provided by several human diseases, including rheumatoid arthritis, sepsis and vascular smooth muscle disease, in which elevated levels of extracellular cyclophilins are observed in inflamed tissues. Such findings suggest that extracellular cyclophilins might contribute directly to the influx of leukocytes during inflammatory responses. In preliminary studies, we set out to establish the potential contribution of extracellular cyclophilins to leukocyte recruitment in vivo using two different mouse models of lung inflammation. The first was a model of acute lung inflammation, characterized by a rapid and predominant neutrophilia in airways and tissues. The second was a mouse model of allergic asthma, characterized by eosinophilia and Th2 T cell recruitment. While the inflammatory phenotype is very different in these two models of inflammation, both were associated with elevated levels of extracellular cyclophilins. Strikingly, we found that blocking the activity of these cyclophilins (using anti-GDI 47 treatment or non-immunosuppressive cyclosporine A) reduced subsequent neutrophil or eosinophil accumulation in inflamed tissues and airways by 40-50%. We also observed a significant reduction in airway mucus secretion and hyperreactivity in the asthma model. These findings provide evidence that cyclophilins contribute significantly to the onset of two very different types of lung tissue inflammation. In the current proposal, we plan to establish how extracellular cyclophilins contribute to different parameters of lung inflammation and examine how cyclophilins interact with other chemokines present in tissues. In addition, we plan to establish whether blocking the activity of extracellular cyclophilins can also reduce inflammatory responses that are ongoing. ? ? ?
| Stemmy, Erik J; Balsley, Molly A; Jurjus, Rosalyn A et al. (2011) Blocking cyclophilins in the chronic phase of asthma reduces the persistence of leukocytes and disease reactivation. Am J Respir Cell Mol Biol 45:991-8 |
| Balsley, Molly A; Malesevic, Miroslav; Stemmy, Erik J et al. (2010) A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation. J Immunol 185:7663-70 |
| Yurchenko, V; Constant, S; Eisenmesser, E et al. (2010) Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol 160:305-17 |
| Malesevi?, Miroslav; Kühling, Jan; Erdmann, Frank et al. (2010) A cyclosporin derivative discriminates between extracellular and intracellular cyclophilins. Angew Chem Int Ed Engl 49:213-5 |
| Beaver, Laura M; Stemmy, Erik J; Constant, Stephanie L et al. (2009) Lung injury, inflammation and Akt signaling following inhalation of particulate hexavalent chromium. Toxicol Appl Pharmacol 235:47-56 |
| Beaver, Laura M; Stemmy, Erik J; Schwartz, Arnold M et al. (2009) Lung inflammation, injury, and proliferative response after repetitive particulate hexavalent chromium exposure. Environ Health Perspect 117:1896-902 |
| Daum, Sebastian; Schumann, Michael; Mathea, Sebastian et al. (2009) Isoform-specific inhibition of cyclophilins. Biochemistry 48:6268-77 |
| Choi, Eun Young; Chavakis, Emmanouil; Czabanka, Marcus A et al. (2008) Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322:1101-4 |
| Damsker, Jesse M; Bukrinsky, Michael I; Constant, Stephanie L (2007) Preferential chemotaxis of activated human CD4+ T cells by extracellular cyclophilin A. J Leukoc Biol 82:613-8 |
| Wolnicka-Glubisz, Agnieszka; Damsker, Jesse; Constant, Stephanie et al. (2007) Deficient inflammatory response to UV radiation in neonatal mice. J Leukoc Biol 81:1352-61 |
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