The targeted overexpres sion of PDGF ligands within the lungs of transgenic mice produces a lethal phenotype related with hyperplasia of mesenchymal cells. Collectively, these trans genic research indicate that PDGF and its receptors are vital to lung mesenchymal cell survival throughout pul monary fibrogenesis. PDGF and its receptors are potentially significant ther apeutic targets in pulmonary fibrosis. For the reason that PDGF can be a important mitogen and chemoattractant for mesenchymal cells, targeting PDGF or its receptors might be useful in limiting the replication of those cells and minimizing col lagen deposition and matrix formation. Inhibition of PDGF activity with kinase inhibitors has been demon strated to significantly minimize lung fibrosis in animal models. Imatinib mesylate, an inhibi tor of PDGFR tyrosine kinase and c Abl, has been evalu ated in a clinical trial for the therapy of IPF.
Nevertheless, a recent study showed no considerable useful effect of imatinib on IPF. Agents that downregulate PDGFR expression at the cell surface of mesenchymal cells could also be of prospective therapeutic worth. For example, PGE2, an arachidonic acid metabolite gener ated selleck inhibitor by the cyclooxygenase 2 enzyme, is pro tective in lung fibrosis partly since it downregulates the PDGF Ra and suppresses fibroblast growth. Unlike TGF b1, which also downregulates PDGF Ra, PGE2 does not stimulate collagen secretion by fibro blasts. Reduced PGE2 final results in enhanced epithelial cell apoptosis and but increases mesenchymal cell resistance to apoptosis. Although COX 2 is actually a therapeutic tar get for arthritis, there is considerable proof that COX 2 serves a protective function in pulmonary fibrosis. One example is, COX 2 deficient mice are susceptible to pulmonary fibrosis induced by V2O5 or bleomycin and produce lesser quantities of PGE2.
Also, COX two deficiency in mice final results within a loss with the anti proliferative buy inhibitor response to TGF b1. That is additional evidence that suggests COX two is protective through lim iting mesenchymal cell survival. The EGF Family members, The Duality of Guarding Epithelial and Mesenchymal Cells The EGF loved ones of ligands mediate various cellular activities, like proliferation, adhesion, migration, apoptosis and differentiation. EGF ligands bind to a complicated system of cell surface receptors, termed the ErbB method, composed of four membrane linked proteins, ErbB1, ErbB2, ErbB3 and ErbB4. Like PDGF receptors, each and every on the ErbB receptors con sists of an extracellular ligand binding domain, a short membrane spanning area and also a cytoplasmic area possessing tyrosine kinase enzymatic activity. EGF ligands include EGF, transforming development issue a, heparin binding EGF like development aspect, amphiregulin, neuregulin, beta cellulin, epiregulin and epigen.