herbimycin and Asthma

There is increasing interest in testing surfactant preparations for asthma therapy. Previously, Curosurf was demonstrated to increase inflammation in allergic asthmatics. So far, little is known about the immunomodulatory effects of therapeutic surfactants, in particular concerning the interaction of surfactant components with eosinophils as key effector cells of the allergic airway inflammation. The aim of the present study was to determine the effect of different therapeutic surfactants on cellular functions of eosinophils.. Eosinophils were isolated from peripheral blood of atopic volunteers and incubated with the natural animal-derived surfactants Curosurf or Alveofact or the synthetic recombinant human surfactant Venticute at different concentrations for up to 42 h.. Curosurf and Venticute modulated the viability of eosinophils. While incubation with Curosurf increased the number of necrotic eosinophils after 1, 20 and 42 h, Venticute increased the number of apoptotic and necrotic cells after 1 h, but there were no differences compared with control cells at later time points. All surfactant preparations increased the levels of eosinophil cationic protein after 20 h and, in addition, Curosurf enhanced eosinophil cationic protein release after 42 h. The supernatant of eosinophils induced chemotaxis against autologous eosinophils, and the presence of Curosurf, but not Alveofact or Venticute, augmented the chemotactic effect. Chemotaxis was partly blocked by inhibition of eotaxin but not by inhibition of leukotrienes or platelet-activating factor.. Therapeutic surfactants differ in their effects on eosinophil viability and the accompanying release of inflammatory mediators and chemotactic signals. Proinflammatory effects were most pronounced for the natural surfactant Curosurf.

Topics: Apoptosis; Asthma; Benzoquinones; Biological Products; Cell Degranulation; Cell Survival; Chemokine CCL11; Chemotaxis; Eosinophil Cationic Protein; Eosinophils; Humans; Immunologic Factors; Inflammation Mediators; Lactams, Macrocyclic; Macrophages, Alveolar; Phospholipids; Pulmonary Surfactants; Recombinant Proteins; Rifabutin

Eosinophils are known to play an important role in the pathogenesis of asthma and other allergic diseases. This study demonstrated the effects of various drugs on eosinophil viability in vitro, which might help clinicians and researchers in treating and studying eosinophilic diseases. Staurosporine, a protein kinase C inhibitor, and herbimycin A, a tyrosine kinase inhibitor, at 10(-6) M and 10(-7) M significantly lowered eosinophil viability in a dose-dependent fashion (p < 0.002, p < 0.02 and p < 0.001, p < 0.002, respectively). Both staurosporine and herbimycin A reduced eosinophil survival in a time-dependent fashion at 10(-6) M and 10(-7) M. Ketotifen at 10(-4) M and theophylline at 10(-3) M, significantly decreased eosinophil viability (p < 0.001 and p < 0.001, respectively) in the presence of 100 pg/ml of recombinant human interleukin-5 (rhIL-5). Both FK506 and cyclosporin A at 10(-4) M significantly reduced eosinophil viability (p < 0.001 and p < 0.005, respectively) in the presence of 100 pg/ml of rhIL-5. Our data show that ketotifen, theophylline, FK506, cyclosporin A reduced eosinophil viability at a high concentration. Furthermore, it is suggested that protein kinase C and tyrosine kinase are involved in eosinophil survival.

Topics: Alkaloids; Asthma; Benzoquinones; Cell Survival; Cyclosporine; Eosinophils; Humans; Ketotifen; Lactams, Macrocyclic; Protein Kinase C; Protein-Tyrosine Kinases; Quinones; Rifabutin; Staurosporine; Tacrolimus; Theophylline