Redox Signaling as a Therapeutic Target to Inhibit Myofibroblast Activation in Degenerative Fibrotic Disease
Figure 1
Feed-forward loop of TGFβ activation and myofibroblast differentiation in fibrosis. Upon injury activated platelets, infiltrating inflammatory and vascular cells secrete TGFβ, which acts on local fibroblasts and other precursor cells (e.g., hepatic stellate cells, fibrocytes) inducing their production of NOX4-derived H2O2. Consequently, downstream MAPK signaling cascades are activated resulting in differentiation into myofibroblasts, whose production of ECM components facilitates wound closure. Prolonged injury or inflammation leads to persistent myofibroblast activation via a feed-forward loop driven by several different factors. For example, myofibroblasts themselves secrete and produce large amounts of active TGFβ and thereby generate an autocrine feed-forward loop that is characteristic of persisting myofibroblast activity (1) [27]. Activation of latent TGFβ in ECM deposits via dissociation of latency associated peptide (LAP) is promoted by various mechanisms, including direct oxidative modification (2) [29–31]. Thus, NOX4-derived H2O2 may drive myofibroblast differentiation not only by oxidative modulation of MAPK signaling cascades that culminate in downstream transcriptional programs of differentiation [26], but also via its ability to freely diffuse across biological membranes and oxidatively modulate components in the extracellular space. Myofibroblasts also secrete high levels of ECM components. The resulting increase in mechanical tension and tissue stiffness can activate ECM-bound latent TGFβ due to mechanical pulling of LAP by specific integrins at the myofibroblast cell surface (3) [32]. Thereby, TGFβ is released and activated from the latent complex, which in turn drives further myofibroblast contraction and differentiation as well as ECM deposition [25]. In addition to this physical mechanism of TGFβ activation by the remodeled ECM, components of the remodeled ECM can modulate TGFβ signaling in a biochemical manner (4), for example, latent TGFβ binding proteins, fibrillins, fibulins, fibronectin, and proteoglycans (reviewed [33]). Moreover, a number of targets downstream of TGFβ signaling provide feedback modulation of the ECM either directly or indirectly, for example, thrombospondin-1 (TSP-1), collagens/ECM components themselves, and ECM remodeling components such as matrix metalloproteinases (5) (MMP2, -9), plasminogen activator inhibitor (PAI-1), and tissue inhibitors of metalloproteinases (TIMPs) [26]. Thus, the stiffened/remodeled ECM together with autocrine production of TGFβ and NOX4-derived H2O2 actively perpetuate TGFβ signaling and myofibroblast differentiation leading to fibrosis.
