As infiltration of inflammatory cells in the interstitial tissue k Nnte Also contribute to a violation of the lung function, we believe that the significant improvement in compliance at day 14 by the efficient removal of interstitial inflammation at this point time relatively late to the step of forming ter on day 24 Treatment with PDE4 inhibitor also tend to reduce lung collagen accumulation, such as by examination total collagen and Masson Trichromf Shown dyeings,Particularly GSK1349572 14 days after bleomycin administration. In contrast, no significant effect in the mRNA level of COL1 that can lead from the contribution of the other types of collagen expression was observed. Similarly, no effect of treatment on cilomilast TGF was observed 1 expression. Based on our observations and the results of other authors, we believe that the inhibition of PDE4 both the general aspects of the PF, n Namely inflammation and tissue remodeling itself is concerned. Anf Accessible PDE4 inhibition suppresses tissue fibrosis shown by partial removal of fibrotic Pro environment, for example by removal of the infiltration of inflammatory cells, the negative regulation of TNF and IL-6 stimulation of the expression in this work.
TNF is secreted AZD8055 by macrophages is a direct mitogen lung fibroblasts and its inhibition may itself be sufficient to fight PF d. Moreover, it has been shown that the PDE4 is a prerequisite for the production of TNF and the development of the inflammatory response in turn. Secondly, there is evidence which suggests that PDE4 inhibitors are also capable of independently Inflammation-dependent process. For example, it has been shown that the increase Erh Of fa Reproducible results. On the level of cAMP in the inhibition of proliferation of fibroblasts, migration, transition to myofibroblasts and collagen production It was also shown that PKA can directly inhibit Raf and therefore influence the Ras / Raf / MEK / ERK. The details of this interaction are not completely Constantly understood, but suggested at least three meters Aligned mechanisms.
Our group has previously shown that cAMP by tolafentrine PDE3 / 4 inhibitor inhibits raised PASMCs increased migration of vessels of rats with pulmonary hypertension. Taken together, these data indicate that the effects observed in this study, a number of mutually independent-Dependent actions of PDE4 inhibitor that could both the inflammatory process and the effector cells are returned to the site of the fibrosis in work. Conclusions PDE4 inhibition by cilomilast bleomycininduced d Fights lung fibrosis usen in M. Haupt Chlich cilomilast has a positive impact by reducing the inflammatory response, even if it does not substantially adversely Chtigt the release of neutrophils. Cilomilast treatment also affects m Ig tissue remodeling in fibrosis stage sp Ter.
This seems to be the result of its anti-inflammatory effect, although the direct effect independent of tissue remodeling through inflammation-Dependent mechanism is quite m Possible. W During the past decade, the inhibition of phosphodiesterase 4 has developed as a new approach for treating a variety of chronic inflammatory diseases of chronic obstructive pulmonary disease and asthma, multiple sclerosis, rheumatoid arthritis to various diseases and inflammatory bowel disease. Roflumilast is an oral, once t Resembled experimental PDE4 inhibitor in advanced clinical development for respiratory diseases such as COPD. Previous in vitro and in vivo reveals the extent the anti-inflammatory potential of roflumilast. Roflumilast reduced antigeninduced influx of inflammatory cells and the accumulation of the protein or lipopolysaccharide-induced neutrophil influx into the bronchoalveolar lavage fluid of the Brown Norway rats in vivo.