Abstract
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.
Highlights
Corneal opacity is a common clinical finding that interferes with the cornea’s light transmission thereby impairing visual function, and it is a leading cause of blindness globally [1,2]
There is a need to develop a therapy against corneal fibrosis, which can prevent the process of corneal opacity or reverse the pre-existing fibrotic tissue to the transparent cornea
SP-8356 Improves Corneal Haze after Alkali Burn. Both SP-8356 dissolved in hyaluronic acid (SP-8356/HA) and prednisolone acetate (PA) significantly attenuated2.1t.hSeP-s8e3v56erImitpyroovefscCoorrnneealaHl aozpe aafcteirtyAlckaolimBupranred to the saline-treated control group in Corneal Alkali Injury B(CothAIS)P-r8a3t56mdoisdseollvsed(Fiinguhryeal1uAron,Bic).aFciudrt(ShPe-r8m356o/rHeA, )thaendarperaedonifsoolopnaeqauceetarteegi(PoAn) in cornea was dsineigcCnrioefriacnaseneatldlyAbalkyttaelSni PuIna-jt8ue3rdy5t6(hCe/HAseIA)vrearatintmydoofdPceAolsr,n(wFeiaghluoerpreae1caAitsy,BHc)o.AmFuparatlhroeednrmetoocrtohe,eutshladeliannreoe-attroeimaf toeppdarcqoouvneetrroetlhggieornocuoipnrneal haze (SupplemecnortnaeraywFaisgaulsroedSe1cr)e.ased by SP-8356/HA and PA, whereas HA alone could not improve the corneal haze (Supplementary Figure S1)
Summary
Corneal opacity is a common clinical finding that interferes with the cornea’s light transmission thereby impairing visual function, and it is a leading cause of blindness globally [1,2]. Corneal fibrosis following corneal injury has been closely associated with persistent corneal myofibroblast activation in damaged cornea [3,4,5,6]. Corneal fibroblast becomes activated and differentiates to myofibroblast [5]. Myofibroblast can generate a disorganized fibrotic extracellular matrix (ECM), which contributes to decreasing in refractory index with increasing light scattering significantly [7,8,9]. Cluster of differentiation 147 (CD147), known as extracellular matrix-metalloproteinase (MMP). 2e0n20c, 2e1, sxuFOgRgPeEsEtRsREthVIaEWt CD147 promotes tumor growth factor-β (TGF2-oβf 1) mediated myofibroblast differentiation [11]. DIrnugtheSPp-8r3e5s6ent study, we studied(b(i1tnShd,e5sRit)on-4hC-(iD3b,1i4t4-od7rihtyhyedprrehobaxyyrm-i5n-hamicbeoitthlinooggxyincsetayolrinyetlffi)m-e6ac,6lt-dhoiyfmpSeePtrhp-yl8al3bsii5ac6yaconlodn[3sc.t1oa.1br]inliezaihnlegfipptb-l3ra-oqeusnie-s2v-kounnlneo)ewranbdiiltrioteycbtilnye mediated by CD147/aMnimMaPl -m9o.dels through the inhibition of MMP-9 activity [14,15]. 2. Resultspresent study, we studied the inhibitory pharmacological effect of SP-8356 on corneal fibrosis known to be mediated by CD147/MMP-9
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