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Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Cell+Mol+Med 2015 ; 19 (12): 2780-92 Nephropedia Template TP
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The I?B kinase inhibitor ACHP strongly attenuates TGF?1?induced myofibroblast formation and collagen synthesis #MMPMID26337045
Mia MM; Bank RA
J Cell Mol Med 2015[Dec]; 19 (12): 2780-92 PMID26337045show ga
Excessive accumulation of a collagen?rich extracellular matrix (ECM) by myofibroblasts is a characteristic feature of fibrosis, a pathological state leading to serious organ dysfunction. Transforming growth factor beta1 (TGF?1) is a strong inducer of myofibroblast formation and subsequent collagen production. Currently, there are no remedies for the treatment of fibrosis. Activation of the nuclear factor kappa B (NF??B) pathway by phosphorylating I?B with the enzyme I?B kinase (IKK) plays a major role in the induction of fibrosis. ACHP {2?Amino?6?[2?(cyclopropylmethoxy)?6?hydroxyphenyl]?4?(4?piperidinyl)?3 pyridinecarbonitrile}, a selective inhibitor of IKK, prohibits the activation of the NF??B pathway. It is not known whether ACHP has potential anti?fibrotic properties. Using adult human dermal and lung fibroblasts we have investigated whether ACHP has the ability to inhibit the TGF?1?induced transition of fibroblasts into myofibroblasts and its excessive synthesis of ECM. The presence of ACHP strongly suppressed the induction of the myofibroblast markers alpha?smooth muscle actin (?SMA) and SM22?, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post?treatment with ACHP partly reversed the expression of ?SMA and collagen type I production. Finally, ACHP suppressed the expression of the three collagen?modifying enzymes lysyl hydroxylase (PLOD1,PLOD2 and PLOD3) in dermal fibroblasts, but did not do so in lung fibroblasts. We conclude that the IKK inhibitor ACHP has potent antifibrotic properties, and that the NF??B pathway plays an important role in myofibroblast biology.