Background/Purpose:

PDE4 catalyses the breakdown of the second messengers cAMP and cGMP to modulate intracellular effects. PDE4 is mainly expressed in inflammatory cells, and its inhibition leads to reduced inflammatory cell activity. In this study, we examined the role of PDE4 inhibition in skin fibrosis and evaluated its potential as an anti-fibrotic target in systemic sclerosis (SSc).

Methods:

We studied the anti-fibrotic effects of the PDE4-specific inhibitor rolipram in the models of bleomycin-induced skin fibrosis and sclerodermatous chronic graft versus host disease (sclGvHD), reflecting local and systemic inflammatory fibrotic disease. To better understand the anti-fibrotic activity of PDE4 blockade, we treated fibroblasts and macrophages obtained from healthy individuals and patients suffering from diffuse cutaneous SSc with rolipram and investigated its effects on fibrosis relevant cytokines.

Results:

PDE4 inhibition had potent dose-dependent anti-fibrotic effects in bleomycin-induced skin fibrosis and sclGvHD. In bleomycin-induced skin fibrosis, the treatment with the higher dosis (5 mg/kg once daily) of rolipram reduced skin thickness by 36% (p < 0.001), hydroxyproline content by 42% (p = 0.004) and the number of α-SMA-positive myofibroblasts by 24% (p < 0.001). The anti-fibrotic activity of PDE4 inhibition was also prominent in sclGvHD in which we observed reductions of skin thickness by 95% (p = 0.002) and of activated myofibroblasts by 24% (p = 0.002). The hydroxyproline content showed an almost significant decrease upon PDE4 inhibition. In line with the mode of action of PDE4 blockade, we observed reduced leukocytes counts in bleomycin-induced skin fibrosis (by 37%; p = 0,012) and in sclGvHD (by 78%; p = 0.005).

Consistent with our in vivo findings and the fact that PDE4 is mainly expressed in inflammatory cells, we showed that fibroblasts were not the direct targets of the anti-fibrotic effects of PDE4 blockage. By contrast, PDE4 inhibition decreased the release of pro-fibrotic cytokines IL-6 and 13, TGF-β1 and β2, and fibronectin-1 from activated M2 macrophages obtained from healthy volunteers and SSc patients, resulting in reduced fibroblast activation and collagen release.  

Conclusion:

PDE4 inhibition reduces the release of pro-fibrotic cytokines from M2 macrophages, which leads to decreased fibroblast activation and collagen release. Importantly, rolipram is a lead compound of the PDE4 inhibitor apremilast, which is approved for the treatment of psoriatic arthritis. Therefore, our preclinical findings might prompt the use of PDE4 inhibitors in clinical studies with patients suffering from SSc, in particular those with inflammation-driven fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-phosphodiesterase-4-pde4-reduces-dermal-fibrosis-by-interfering-with-the-release-of-pro-fibrotic-cytokines-from-m2-macrophages/