Pirfenidone Nanoparticles Improve Corneal Wound Healing and Prevent Scarring Following Alkali Burn

Chowdhury, Sushovan; Guha, Rajdeep; Trivedi, Ruchit; Kompella, Uday B.; Konar, Aditya; Hazra, Sarbani

doi:10.1371/journal.pone.0070528

Cited by 60 publications

(40 citation statements)

References 21 publications

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“…Inorganically-coated all-trans retinoic acid NPs have shown promise in enhancing corneal epithelial wound healing in cultured cells and a rabbit wound model (Hattori et al, 2012). Popular poly (lactide-co-glycolide) NPs loaded with antifibrotic drug pirfenidone also increased corneal re-epithelialization, as well as reduced collagen synthesis and prevented myofibroblast formation in a rabbit alkaline burn model (Chowdhury et al, 2013). Elastin-like polypeptide-based NPs bearing a mitogenic protein lacritin promoted corneal epithelial wound healing in non-obese diabetic mice (Wang et al, 2014).…”

Section: Corneal Epithelial Wound Healingmentioning

confidence: 99%

“…Similar data on haze inhibition were obtained with cationic NPs encapsulating a triple combination of siRNAs targeting TGF-β1, TGF-β receptor 2 and CTGF (Sriram et al, 2014). Poly (lactide-co-glycolide) NPs with encapsulated antifibrotic pirfenidone reduced stromal collagen production and myofibroblast formation (Chowdhury et al, 2013), and those with shRNA to VEGF-A inhibited neovascularization (Qazi et al, 2012) upon corneal alkaline burns in vivo. These data show great promise of gene therapy using either viral vectors or NPs to counteract excessive wound healing and ensuing haze or fibrosis in refractive surgery.…”

Section: Corneal Stromal Wound Healingmentioning

confidence: 99%

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Progress in corneal wound healing

Ljubimov

Saghizadeh

2015

Progress in Retinal and Eye Research

637

554

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Corneal wound healing is a complex process involving cell death, migration, proliferation, differentiation, and extracellular matrix remodeling. Many similarities are observed in the healing processes of corneal epithelial, stromal and endothelial cells, as well as cell-specific differences. Corneal epithelial healing largely depends on limbal stem cells and remodeling of the basement membrane. During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of transforming growth factor-β system. Endothelial cells heal mostly by migration and spreading, with cell proliferation playing a secondary role. In the last decade, many aspects of wound healing process in different parts of the cornea have been elucidated, and some new therapeutic approaches have emerged. The concept of limbal stem cells received rigorous experimental corroboration, with new markers uncovered and new treatment options including gene and microRNA therapy tested in experimental systems. Transplantation of limbal stem cell-enriched cultures for efficient re-epithelialization in stem cell deficiency and corneal injuries has become reality in clinical setting. Mediators and course of events during stromal healing have been detailed, and new treatment regimens including gene (decorin) and stem cell therapy for excessive healing have been designed. This is a very important advance given the popularity of various refractive surgeries entailing stromal wound healing. Successful surgical ways of replacing the diseased endothelium have been clinically tested, and new approaches to accelerate endothelial healing and suppress endothelial-mesenchymal transformation have been proposed including Rho kinase (ROCK) inhibitor eye drops and gene therapy to activate TGF-β inhibitor SMAD7. Promising new technologies with potential for corneal wound healing manipulation including microRNA, induced pluripotent stem cells to generate corneal epithelium, and nanocarriers for corneal drug delivery are discussed. Attention is also paid to problems in wound healing understanding and treatment, such as lack of specific epithelial stem cell markers, reliable identification of stem cells, efficient prevention of haze and stromal scar formation, lack of data on wound regulating microRNAs in keratocytes and endothelial cells, as well as virtual lack of targeted systems for drug and gene delivery to select corneal cells.

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Section: Corneal Epithelial Wound Healingmentioning

confidence: 99%

Section: Corneal Stromal Wound Healingmentioning

confidence: 99%

Progress in corneal wound healing

Ljubimov

Saghizadeh

2015

Progress in Retinal and Eye Research

637

554

View full text Add to dashboard Cite

show abstract

“…More recently, treatment with cationic nanoparticles encapsulating a combination of silencing RNAs (siRNAs) targeting TGFβ1, type II TGFβ receptor and connective tissue growth factor (CTGF) significantly reduced the levels of α-SMA expression and scar formation in an organ culture model of excimer ablated rabbit corneas (Sriram et al, 2014). Similarly, pirfenidone-loaded nanoparticles also inhibited TGFβ-induced upregulation of α-SMA, collagen type I expression and subsequent corneal haze using an in vivo rat cornea alkali burn model (Chowdhury et al, 2013). Further research is required to better understand the role of TGFβ in corneal fibrosis to enable promising new translational areas in the development of anti-fibrotic and accelerated healing agents as well as combination gene therapy approaches.…”

Section: Corneal Fibrotic Diseasementioning

confidence: 99%

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Shu

Lovicu

2017

Progress in Retinal and Eye Research

284

239

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Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFβ) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring.

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“…Kim et al (40) found that non-toxic concentrations of PFD exert significant anti-fibrotic effects on orbital fibroblasts from patients with thyroid-associated ophthalmopathy. Chowdhury et al (41) indicated that PFD decreased collagen synthesis, prevented myofibroblast formation and improved corneal wound healing. After trabeculectomy surgery, Zhong et al (42) used 0.5% PFD eye drops to improve postoperative bleb survival.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone ameliorates the formation of choroidal neovascularization in mice

Bao

Huang

et al. 2020

Mol Med Report

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The formation and development of choroidal neovascularization (cnV) is accompanied by inflammation and fibrosis. Existing treatments are expensive and can cause irreversible complications. Pirfenidone (PFD) exerts anti-inflammatory and anti-fibrotic effects; however, its applications in the eye remain unclear. Male C57BL/6J mice (aged 6-8 weeks) were used to explore whether PFD can inhibit the formation of laser-induced CNV. The localization of transforming growth factor β 2 (TGFβ 2 ) was determined through immunofluorescent staining. After laser photocoagulation, the vehicle and PFD groups were intravitreally injected with 1 µl PBS and 1 µl 0.5% PFD, respectively. At day 7 after intravitreal injection, the expression of TGFβ 2 and vascular endothelial growth factor (VEGF) was assessed. Fundus fluorescein angiography was performed to investigate the extent of fluorescence leakage, and the CNV areas were analyzed using a choroidal flat mount. The results demonstrated that, on day 7 after photocoagulation, the expression of TGFβ 2 and VEGF was reduced in the experimental group. In addition, fluorescein angiography showed that the leakage area of CNV was significantly smaller in the PFD injection group than those observed in the control and vehicle groups. Moreover, the areas of CNV in the PFD injection group were smaller compared with those reported in the other two injection groups. Histopathological and Tunel analyses performed on day 28 revealed that there were no notable abnormalities on the layers of the neural retina of PFD-treated mice. In conclusion, intravitreal injection of PFD inhibited the formation of CNV in mice, likely via the downregulation of VEGF and TGFβ 2 , which did not cause damage to the mouse retina after 28 days of treatment.

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Pirfenidone Nanoparticles Improve Corneal Wound Healing and Prevent Scarring Following Alkali Burn

Cited by 60 publications

References 21 publications

Progress in corneal wound healing

Progress in corneal wound healing

Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis

Pirfenidone ameliorates the formation of choroidal neovascularization in mice

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