Abstract
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 (TGFβ1) 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-κB) pathway by phosphorylating IκB with the enzyme IκB 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-κB 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 TGFβ1-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 (αSMA) and SM22α, as well as the deposition of the ECM components collagen type I and fibronectin. Furthermore, post-treatment with ACHP partly reversed the expression of αSMA 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-κB pathway plays an important role in myofibroblast biology.
Highlights
Fibrosis is a common outcome of an impaired tissue repair process
Eagle’s minimal essential medium (EMEM) and L-glutamine were obtained from Lonza Group (Basel, Switzerland), penicillin/streptomycin was obtained from Gibco Life Technologies (Paisly, UK), foetal bovine serum (FBS) was obtained from Thermo Scientific (Waltham, MA, USA), bovine serum albumin (BSA) was obtained from Sanquin (Sanquin, Netherlands) and culture plates and chamber slides were obtained from Corning (Corning, NY, USA)
The strong pro-fibrotic effects of Transforming growth factor beta1 (TGFb1) towards fibroblasts results in the formation of myofibroblasts, being the critical cell type that plays a central role in fibrosis
Summary
Fibrosis is a common outcome of an impaired tissue repair process. The hallmark of fibrosis is the production and excessive accumulation of a collagen-rich extracellular matrix (ECM). The ECM is deposited by myofibroblasts under the influence of pro-fibrotic cytokines, such as transforming growth factor beta 1 (TGFb1) [1, 2]. TGFb1 is one of the most potent pro-fibrotic cytokines known to be involved in the activation of fibroblasts into myofibroblasts, a key process associated with fibrosis that seems to be dependent, among others, on the activation of the nuclear factor kappa B (NF-jB) pathway [3,4,5,6], especially NF-jB subunit p65 (= RelA). The RelA signalling pathway is associated with the pathogenesis of fibrosis including organs such as kidney, liver and lung [5,6,7,8,9,10,11,12,13]. The cytoplasmic NF-jB is bound to the inhibitory protein IjB; the complex prevents NF-jB activation
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