We have shown that the release of gelatinase activity t PASMCs obtained is sensitive to cAMP Existing substances, including prostacyclin analogues Gamma Secretase and selective PDE4 inhibitors. Regulation of MMP 2 and MMP 9 Press PASMCs people can represent a different mechanism to the chronic effects of prostacyclin analogs in hypertensive Lungengef The s. This is indicated by reports of increased Gelatinaseaktivit t In PASMCs of patients with PAH and Lungengef S rat models of pulmonary hypertension, and the realization that MMP 2 and MMP 9 gel Deleted and supported Gef Remodeling in animals with inhibitors and iloprost cAMP-PDE activity of t treated. Additionally Tzlich selective inhibitors of PDE4, but not or PDE3 PDE5 inhibitors have been found to reduce the release of MMP 2 and MMP 9, stimulated by PMA and cytokines such as TNF, other cells and tissues of humans.
In accordance with studies of fibroblast cell lines, we also observed that dexamethasone ged fights Release of gelatinase activity t PASMCs, which can be important in light of recent findings indicating that prednisolone selectively inhibits the proliferation of PASMCs of patients with AT7519 IPAH . In summary, this study demonstrated that PDE4 genes are expressed in the human distal PASMCs. In addition to the relief of the DNA synthesis and cell proliferation, the stimulation of cAMP signaling by one obtains Hte apoptosis and a decrease in the production of MMP was associated. The effect of cAMP-stimulating agents dependent Ngig, was at least partially, on the activity of t of PDE4, supports the hypothesis that PDE4 enzymes play an r In the regulation of DNA synthesis, cellular proliferation Ren and gelatinase activity of t In human PASMCs.
PDE4 inhibition may therefore be useful as adjunctive therapy in the treatment of pulmonary Vaskul Ren proliferative disease. Pulmonary fibrosis, a group of devastating and largely irreversible human interstitial lung disease with limited Behandlungsm Opportunities. The disease is characterized by chronic inflammation, abnormal function of the interstitial interstitial fibroblasts and lodgment of berm Strength amounts of collagen, w During the severe tissue remodeling. Pathological Ver Changes are accompanied by high levels of expression of cytokines TNF, IL-1, IL-6, growth factors, and matrix metalloproteinases. The h Most frequent model of experimental human PF by bleomycin in M Usen induced PF.
It is caused by inflammation and remodeling phases, erm to examine the different aspects of the disease Marked glicht. Phosphodiesterases a superfamily of enzymes that cAMP and / or cGMP are hydrolyzed and thus regulate the intracellular Re secondary Re messengers. The PDE4 family are composed cAMP specific PDE isoforms of several heavily represented in the lungs. As part of the cAMP / protein kinase A pathway plays an PDE4 Align the proliferation, differentiation and migration by regulating cAMP levels. After all, the enzyme of the PDE-4 gr Th cAMP hydrolysis in monocytes, lymphocytes and neutrophils, and its activation is required for the inflammatory reaction. For these reasons, PDE4 inhibitors for the treatment of various lung diseases have been proposed as a new anti-inflammatory and anti-remodeling.