AB0089 SILDENAFIL COUNTERACTS THE ACTIVATION OF CXCR3/CXCL10, -11 AXIS IN SCLERODERMA FIBROBLASTS EXPOSED TO REACTIVE OXYGEN SPECIES

Background: Oxidative stress associated with vascular damage represents one the major contributor in pathogenesis of systemic sclerosis (SSc) [1]. Indeed, different studies demonstrated that excessive free radicals production can contribute to activation fibrotic process skin and visceral organs CXCL10 CXCL11, together their receptor CXCR3, are involved fibrosis [2]. Furthermore, these chemokines have been proposed as biomarkers progression severe SSc prognosis [3]. Emerging evidences highlight beneficial effects phosphodiesterase type 5 (PDE5) inhibitor, sildenafil, protect cell types from reactive oxygen species (ROS)-induced DNA damage, vitro This effect has linked modulation concentration pathological conditions [4,5]. Objectives: Here we set out investigate modulating CXCR3/CXCL10, -11 inflammatory axis dermal fibroblasts exposed oxidative stress, . Methods: Human isolated by biopsies were treated for 24h 100µM hydrogen peroxide (H 2 O ), presence or not sildenafil (1µM). Dermal fibrobalsts healthy used controls. CXCL11 evaluated medium luminex technology assay; expression chemokine (CXCR)3 peroxisome proliferator-activated (PPARγ) (a regulator CXCL10,-11 mRNA) was western blot assay. Results: As showed figure 1, (grey bar) similar basal levels (A) (B) controls (black bar). H induced a significant increase both only (by 4.6 fold 4.2 CXCL11) (*P<0.05 **P<0.01 vs. c; # P<0.05 vs controls). Sildenal pre-incubation reduced approximatively 50% on release (Figure 1A B) ( § CXCR3 PPARγ peroxyde exposure (data shown). Conclusion: In study support clinical determine efficacy preventing tissue SSc, reducing pro-inflammatory stress. References: [1]Di Luigi L, Sgrò P, Duranti G, Sabatini S, Caporossi D, Del Galdo F, Dimauro I, Antinozzi C. Sildenafil Reduces Expression Release IL-6 IL-8 Induced Reactive Oxygen Species Systemic Sclerosis Fibroblasts. Int J Mol Sci. 2020 Apr 30;21(9):3161. doi: 10.3390/ijms21093161. PMID: 32365773; PMCID: PMC7246497. [2]Koper OM, Kamińska J, Sawicki K, Kemona H. CXCL9, CXCL10, (CXCR3) neuroinflammation neurodegeneration. Adv Clin Exp Med. 2018 Jun;27(6):849-856. 10.17219/acem/68846. 29893515. [3]Crescioli C, Corinaldesi Riccieri V, Raparelli Vasile M, Valesini Lenzi A, Basili Association circulating sclerosis. Ann Rheum Dis. Dec;77(12):1845-1846. 10.1136/annrheumdis-2018-213257. Epub May 14. 29760155; PMC6241615. [4]Giannattasio Colletti Di Filardi T, Scolletta Morano Crescioli The inhibitor decreases proinflammatory diabetic cardiomyopathy: vivo evidence. Endocrinol Invest. 2019 Jun;42(6):715-725. 10.1007/s40618-018-0977-y. Nov 10. 30415310; PMC6531405. [5]You N, Li Huang X, Wu Tang Y, Wang H, Mi Zheng L. COMMD7 activates regulating NF-κB species. Med Rep. May;17(5):6784-6788. 10.3892/mmr.2018.8706. Mar 8. 29532873. Disclosure Interests: None declared