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

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-(3,4dihydroxy-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.

Potential of Ocular Transmission of SARS-CoV-2: A Review

“…For example, a clinically approved CD147-monoclonal antibody, Meplazumab could potentially block viral entry. A recent small molecule CD147 inhibitor was reported that reduces corneal fibrosis in a rat model of alkali burn [ 17 ]. Azithromycin, approved use in the US and global markets as AzaSite may act to block CD147 [ 6 ].…”

“…In regards to direct ocular infection, CD147 has been critically shown to be expressed in the retina as well as the ocular surface [ 15 ]. CD147 has been shown to be upregulated in ocular surface disease [ 16 , 17 ]. For this reason, the use of silicone punctal plugs or intracanalicular plugs may dually block transport of virus from the ocular surface to the highly susceptible nasal epithelium, but could also act to optimize the ocular surface thereby reducing relative expression of CD147.…”

CD147 mediates the CD44s-dependent differentiation of myofibroblasts driven by transforming growth factor-β1

“…CD147 is well established as an MMP inducer (57-59) and has been shown to have multifunctional roles in many progressive diseases and in animal models of disease (28)(29)(30)(31), including, cardiovascular disease, Alzheimer's and more recently as an entry route into cells for SARs-CoV-2 (COVID 19) (60-62). Its involvement in CKD has been well described (32,33) and in the supplementary data (Fig.…”

“…Using SP-8356 an inhibitor of CD147, topically on rat corneas that had undergone alkali burns, inhibited αSMA expressing myofibroblasts and other fibrotic associated ECM components such as collagen and MMP9 (29). Basigin (bsg)+/mice had less cardiac interstitial fibrosis following transverse aortic constriction compared to control mice.…”

Cell-Free Biological Approach for Corneal Stromal Wound Healing

“…Topical administration of EMMPRIN inhibitor, SP-8356, suppressed the myofibroblast population and the deposition of abnormal ECM products (e.g. MMP9, Col3, and Col5) in a rat model of corneal alkali injury, hence reducing corneal haze and fibrosis (Joung et al, 2020). Moreover, green tea polyphenol epigallocatechin-3-gallate (EGCG), was reported to restrain EMMPRIN and MMP-9 expression via 67-kD laminin receptor pathway in a PMA-induced macrophage system (Wang et al, 2016).…”