A Novel CD147 Inhibitor, SP-8356, Attenuates Pathological Fibrosis in Alkali-Burned Rat Cornea

• Published in: International journal of molecular sciences 2020-04, Vol.21 (8), p.2990
• Main Authors: Joung, Chanmin, Noh, Hyojin, Jung, Jeein, Song, Hwa Young, Bae, Hwanse, Pahk, Kisoo, Kim, Won-Ki
• Format: Article
• Language: English
• Subjects: Acetic acid; Actin; Alkalies - adverse effects; alpha-smooth muscle actin; Animals; Basigin - antagonists & inhibitors; Bicyclic Monoterpenes - pharmacology; Biopsy; Blindness; CD147 antigen; Collagen; Collagen (type III); Collagen - metabolism; Cornea; corneal alkali burn; corneal haze; Corneal Injuries - drug therapy; Corneal Injuries - etiology; Corneal Injuries - pathology; Corticosteroids; Cytokines - metabolism; Differentiation; Disease Models, Animal; Extracellular matrix; Eye Burns - drug therapy; Eye Burns - etiology; Eye Burns - pathology; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Immunohistochemistry; Inflammation Mediators - metabolism; Ligands; Male; Matrix metalloproteinase; Matrix metalloproteinases; Metalloproteinase; Muscles; myofibroblast; Population; Prednisolone; Rats; Smooth muscle; Verbenone
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21082990

The corneal fibrotic responses to corneal damage often lead to severe corneal opacification thereby resulting in severe visual impairment or even blindness. The persistence of corneal opacity depends heavily on the activity of corneal myofibroblast. Myofibroblasts are opaque and synthesize a disorganized extracellular matrix (ECM) and thus promoting opacification. Cluster of differentiation 147 (CD147), a member of the immunoglobulin superfamily, is known to play important roles in the differentiation process from fibroblast to myofibroblast in damaged cornea and may therefore be an effective target for treatment of corneal opacity. Here, we examined the therapeutic efficacy of novel CD147 inhibiting verbenone derivative SP-8356 ((1S,5R)-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one) on corneal fibrosis. Topical SP-8356 significantly reduced corneal haze and fibrosis in the alkali-burned cornea. In detail, SP-8356 inhibited both alpha-smooth muscle actin (α-SMA) expressing myofibroblast and its ECM-related products, such as matrix-metalloproteinase-9 and collagen type III and IV. Similar to SP-8356, topical corticosteroid (prednisolone acetate, PA) also reduced the ECM-related products and opacification. However, prednisolone acetate failed to decrease the population of α-SMA-positive corneal myofibroblast. In conclusion, SP-8356 is capable enough to prevent corneal haze by preventing pathological fibrosis after severe corneal damage. Therefore, SP-8356 could be a potentially promising therapeutic drug for corneal fibrosis.