Modulation of Fibrosis in Systemic Sclerosis by Nitric Oxide and Antioxidants
Figure 1
Schematic diagram depicting the possible pathways in which NO modulates collagen type I gene expression to affect fibrosis. In the first hypothesis (1), the rapid reaction between NO and leads to decreased NO bioavailability. NO regulation by ADMA may also occur. NO normally can directly activate transcription factors such as NFκB, SP-1, and AP-1 to inhibit collagen gene expression. The second possibility (2) is that NO normally by activating the protective stress enzyme HO-1 can negatively modulate the NADPH oxidase pathway. In fibrosis, activation of the NADPH oxidase pathway has been shown to increase collagen synthesis and myofibroblast differentiation. The third plausible pathway (3) is that there is signalling crosstalk following TGF-β binding to a receptor. Signal pathways potentially important here include the MAP kinase JNK. This would synergise with the Smad signalling pathway and decrease the activation of downstream TGF-β-dependent genes. Alternatively, NO could enhance the proteasomal degradation of SMAD. In the fourth pathway (4), NO indirectly exerts its effects by modulating oxidative stress through upregulation of antioxidant/redox defence genes such as Nrf2 leading to regulation of the extracellular matrix.
