Open Access

The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

  • Authors:
    • Hongyan Zhou
    • Wensong Zhang
    • Miaomiao Bi
    • Jie Wu
  • View Affiliations

  • Published online on: August 4, 2016     https://doi.org/10.3892/ijmm.2016.2699
  • Pages: 1003-1011
  • Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists.

1. Introduction

The cornea is the protective ocular surface, and is transparent to enable the transmission of light. Chemical burns can damage this barrier (1), and in addition to corneal injury and eyelid burns, are risk factors for ocular complications, including ulcers, scars and neovascularization (NV) (2,3). Several potential interventional strategies, including limbal stem cells, amniotic membranes and corneal transplantations have been demonstrated to have some success in clinical outcomes. There are numerous risk factors and molecular markers for the progression of ocular chemical burns. Improvements in the knowledge of the novel biomarkers associated with the inflammation, angiogenesis and fibrosis of ocular chemical injuries have contributed to the development of novel therapeutics. Chemical burns can be divided into alkali and acid burns, with corneal alkali burns (CAB) frequently resulting in a greater severity of injury (4). Peroxisome proliferator-activated receptor (PPAR) controls the regulation of genes through the activation of nuclear receptors, and plays a role in the control of a variety of inflammatory, angiogenic and fibrotic physiological processes (5). This reviews covers the key aspects associated with biomarker research into the pathological process of CAB, and analyzes the potential therapeutic role of PPAR agonists in the treatment of CAB. The processes of cytokine production, chemotaxis, inflammatory and immune responses, signal transduction, matrix metalloproteinase (MMP) production and vascular factors in CAB are summarized, and the potential application of PPAR agonists as treatments to control lesion severity in CAB are also discussed.

2. Conventional CAB treatment

Stem cells potentiate regeneration due to their ability to differentiate into multiple cell lineages. The most common sources of stem cells for clinical use are embryonic, adult and induced (6). Surface transplantation and subsequent keratoplasty can result in good visual function following ocular injury (7). Limbal stem cell grafts with amniotic membrane transplantation or simple limbal epithelial transplantation may additionally be used to restore vision and reduce symptoms in cases with limbal stem cell deficiency following chemical burns (812). Cultivated oral mucosal epithelial transplantation has been indicated to enable the complete epithelialization of persistent corneal epithelial defects, and stabilize the ocular surface in patients with severe ocular surface disease (13). The Boston keratoprosthesis type I is an effective artificial cornea and aids in the recovery from advanced ocular surface disease, and has been shown to result in a significant increase in eyesight (14). Additionally, Boston keratoprosthesis implantation may reduce the risk of post-keratoplasty complications by the wearing of contact lenses (15). Alternatively, a large tectonic corneoscleral lamellar graft represents a good treatment method (16). These methods can treat a selection of clinical applications and present some benefits; however, they require further study.

3. Limitations of traditional therapeutic strategies

Scarring has been attributed to the proliferation of inflammatory cells and fibroblasts during burn wound healing. The irregular remodeling of matrix structures may lead to scar formation. Stem cell immunomodulation has been indicated to address pathological scarring (1719). Limbal transplantation is a standard procedure to restore ocular surface disorders and, considering the shortage of corneal donors, is a viable alternative treatment strategy; however, the success rate remains low (20). Additionally, the separation and purification rates of limbal cells and the efficiency of migration require further investigation, and the therapeutic efficacy and safety of limbal transplantation should be clarified (21). Furthermore, the rejection rate of keratoplasty is high in cases of CAB, and the number of suitable donor corneas available is not sufficient to meet the demands (22,23). Corticosteriods are the predominant current treatment, and treat the inflammation associated with corneal NV (CNV); however, they can result in side-effects, such as cataracts and increased intraocular pressure (24). Further studies are required to understand stem cell applications targeting NV and the inflammatory and fibrotic processes associated with CAB (Fig. 1).

4. Topical CAB therapies from bench to clinic

A number of topical therapeutics against NV or inflammation associated with CAB are under investigation (25). Some of these potential topical therapeutics under investigation are aloe vera, prospero homeobox 1 short interfering RNA, Rho-associated protein kinase inhibitors (AMA0526), 0.5% ketorolac tromethamine, keratinocyte growth factor-2, omentum, protein phosphatase magnesium dependent-1 and melatonin, and may potentially be used for the treatment of CAB in clinical practice (2633). Subconjunctival bevacizumab injection may be considered as a secondary treatment for CNV caused by chemical injuries that are not responsive to conventional steroid therapy (34,35). These topical therapies may be effective treatments for severe cases of CAB, although further studies may be required to fully determine this.

5. PPAR-γ and the healing process of CAB

PPARs belong to a nuclear receptor superfamily that includes steroid, thyroid hormone, vitamin D and retinoid receptors. PPAR-γ is activated by transcription factors and plays an important role in the regulation of cell proliferation and inflammation (36,37). PPAR suppresses inflammatory cytokines, proteolytic enzymes, adhesion molecules, chemotactic and atherogenic factors (3840). Transforming growth factor (TGF) β1 has been shown to transdifferentiate keratocytes to myofibroblasts involved in the repair of the corneal epithelium, and stromal and corneal scar formation in CAB, by regulating monocytes, macrophages, vascular endothelial growth factor (VEGF), neutrophils and monocyte/macrophage chemotactic protein-1 (32,41). In a previous study, the expression of the PPAR-γ gene was shown to induce anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. Additionally, PPAR-γ gene expression suppressed TGFβ1 and MMP expression in macrophages, indicating a potentially effective strategy for the treatment of CAB (3). PPAR-γ expression has been reported to increase with the infiltration of numerous inflammatory cells in the pathological process of CAB. As previously demonstrated, treatment with an ophthalmic solution of a PPAR-γ agonist suppressed the expression levels of interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), TGFβ1 and VEGF-A in corneal inflammation induced by an alkali burn. An ophthalmic solution of the PPAR-γ agonist may provide a novel treatment strategy with useful clinical applications for corneal inflammation and wound healing (42). Burns induce the activation of an inflammatory cascade and wound progression. The PPAR-γ agonsist, rosiglitazone, reduces the percentage of unburned skin interspaces that progress to full necrosis in a rat model and prevent burn-induced organ damage. Therefore, the PPAR-γ agonists hold potential for clinical application (36,43). In this review, the potential role of PPAR-γ agonists in the treatment of CAB and the underlying molecular mechanisms are discussed.

6. Potential role of PPAR agonists in the treatment of CAB

PPAR-γ ligands are divided into endogenous (9, 13 and 15-hydroxyoctadecadienoic acid) and synthetic (pioglitazone, troglitazone, rosiglitazone, liglitazone and TZD18) compounds (44). PPAR isoforms (PPAR-γ, PPAR-α and PPAR-β/δ) have been shown to exhibit anti-inflammatory and immunomodulatory properties. PPARs may represent a novel target in the treatment of inflammatory and vascular diseases (45). Pioglitazone may inhibit corneal fibroblast migration and reduce corneal fibroblast-induced collagen contraction in the corneal wound healing process (46). Previous studies have supported the anti-inflammtory, anti-angiogenic and anti-fibrotic functions of PPAR-γ.

PPAR-γ, cytokines and cellular immunity

Toll-like receptors (TLRs) play key roles in innate immune responses. PPAR-γ gene silencing affects genes involved in the innate immune process (47). Injury primes the innate immune system for enhanced TLR-2- and TLR-4-mediated responses, and suggests that increasing TLR activity may contribute to the progression of systemic inflammation following severe injury (48). Previously, Th1-activated macrophages were considered a key cellular defense against intracellular pathogens. However, more recently, Th2-activated macrophages have been indicated to be involved in repair and tissue regeneration via the modulation of PPARs in immunological inflammation, and this may lead to new therapeutic approaches (4951). Dendritic cells (DCs) from burned skin notably express low levels of human leukocyte antigen-antigen D related and TLR-4 immediately following cell isolation. In the post-burn period, the ability of skin DCs to respond to bacterial stimuli is impaired. These alterations in DCs may contribute to impaired host defenses against bacteria, leading to post-burn infection (52). Burns are associated with γδ T-cell activation at the injury site, which initiates the infiltration of the wound with large numbers of αβ T-cells that may facilitate the transition from the inflammatory to the proliferative phase of healing (53). Burns and TLRs are associated with the induction of the innate immune system, with a greater number of TLR-2-induced Kupffer cells (KCs) and macrophage inflammatory protein (MIP)-1β production post-injury, whereas the levels of IL-6, IL-10 and MIP-1β and the number of KCs are greater following TLR-4-induced activation following burns. TLR-mediated inflammatory responses have been reported to be augmented post-burn by the induction of inflammatory mediators (54). TLR-5 is normally present on the superficial cells of the conjunctival epithelium, and may be upregulated following chemical burns (55). TLR activates the innate immune system to recognize antigens and induce the production of inflammatory cytokines and chemokines (56,57). The TLR-related genes, heat-shock 70kDa protein (HSP)A1A, Harvey rat sarcoma viral oncogene homolog, mitogen-activated protein kinase (MAPK) kinase 3, Toll interacting protein, v-rel avian reticuloendotheliosis viral oncogene homolog A, FBJ murine osteosarcoma viral oncogene homolog and TLR-1 have been observed to be reduced in the primary epidermal keratinocytes of patients with severe burns, and restoring the expression of these genes may improve clinical outcomes (58). High levels of cytokines promote collagen degradation, the apoptosis of keratinocytes and vascular compromise. Local inflammation induced by severe burns can clear cellular debris, protect against microbial agents and induce cell growth and proliferation (58,59). The reduction of the activation and recruitment of macrophages may be a potential therapeutic strategy for the corneal scarring of alkali-burned ocular surfaces (60). Agonists of TLR-4, 1/2 and -5 suppress the activity of PPAR-α and PPAR-γ in astrocytes (61). PPAR-β/δ expression is regulated in TLR agonist-stimulated astrocytes via the regulation of the pro-inflammatory genes. p38, MAP2K1/2, MAPK2/3 and c-Jun N-terminal kinase (JNK) (62). The PPAR-α agonist, WY14643, has been shown to significantly reduce amylase, lipase and myeloperoxidase activity, and IL-6, intercellular adhesion molecule-1, and TLR-2 and 4 levels (63). PPAR-γ inhibits interferon (IFN)-β production in TLR3- and 4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-β promoter (64). Treatment with rosiglitazone was previously shown to result in higher levels of PPARγ and a reduction in serum inflammatory cytokine levels, and the levels of TLR2/4 and nuclear factor-κB (NF-κB) activity in aortic tissues. These biological functions of rosiglitazone in P. gingivalis-accelerated atherosclerosis were shown to be dependent upon the inhibition of the inflammatory response and the TLR/NF-κB signaling pathway (65). PPAR-γ and TGF-β can enhance regulatory T cell (Treg) generation, providing a potential therapeutic strategy for the treatment of inflammatory and autoimmune diseases (66). PPAR-γ restores the abnormal immune gene expression of p38MAPK, activating transcription factor-2, MAPK-activated protein kinase 2 and HSP27 in T-cell mediated immune responses in vivo (67). Cell types in the innate and adaptive immune system, including neutrophils, macrophages, mast cells, B cells and T cells, have all been implicated to play a role in burn-induced immunology (68). Burn injury disrupts the immune system, resulting in the marked suppression of the immune response. The mononuclear phagocyte system (MPS) is a critical component of the innate immune response, and is able to initiate an adaptive immune response. Severe burns inhibits the functions of DCs, monocytes and macrophages. The MPS in the pathophysiology of severe burns will guarantee a more rational immunotherapy for patients with severe burns (69). These results collectively suggest that PPAR-α, -γ and -β/δ are likely mediators of TLR activation in transducing inflammation in CAB pathologies; however, the relative immune mechanisms require clarification. The molecular mechanisms of CAB are summarized in Fig. 2.

Cytokines and cellular immunity

As an anti-TNF-α monoclonal antibody, topical infliximab has been reported to significantly reduce corneal perforation, leukocyte infiltration, cluster of differentiation (CD)45+ cell infiltration and fibrosis in the eyelids. The topical application of infliximab may be useful in the treatment of ocular diseases (70). Topically applied IL-1 receptor antagonist (IL-1ra) may suppress corneal inflammation and promote recovery following CAB. All cytokine/chemokine levels, in particular IL-6 and IL-10, have been shown to be significantly reduced in IL-1ra-treated eyes, with the opposite effect observed in IL-1ra knockout mice (7174). The treatment of inflammation with minimal infiltrating cells and normal levels of IL-1α and IL-1β may accelerate the healing of CAB (75). A reduction in IL-6 and TGF-β1 expression has been indicated to protect the cornea from chemical damage (76). In addition, the inhibition of inflammation and NV has been reported to play a significant role in preventing corneal angiogenesis and inflammation in alkali-burned corneal beds, which results in higher allograft survival rates (77). Furthermore, in a CAB model, the infiltrated polymorphonuclear leukocytes and the mRNA expression of VEGF receptor 1 and 2, basic fibroblast growth factor, IL-1β, IL-6, MMP-2, -9 and -13, in addition to the protein expression levels of VEGFR2, IL-1β, IL-6 and MMP-2 and -9, were upregulated in the corneas. The suppression of CNV, inflammatory cytokines and MMPs aids in reducing the damage associated with CAB (78). Human peripheral blood mononuclear cells and inflammatory cytokines can be stimulated by chemically injured keratocytes. MMP-9 and macrophage migration inhibitory factor levels have been reported to be higher in burn injury (79). CD4 and CD44 (memory) CD8 T cells have been found to be significantly increased, in addition to TLR-4, post-burn injury, and functional T cell responses have additionally been demonstrated. Complex adaptive immune responses have been reported in burn injury (80); however, this differs in the process of CAB. IFN-γ and CD4 were not detected in rat corneas following alkali burns, indicating that cytokines were induced in the cornea by burn injury without a specific immunological stimulus (81). To inhibit excessive inflammatory damage, particular anti-inflammatory agents may be applied for the treatment of alkali burns. PPAR-γ agonists are a good candidate for anti-inflammatory activity in preventing TNF-α damage (82). Pioglitazone therapy has been demonstrated to suppress the mRNA levels of the inflammatory cytokines monocyte, MCP-1, IL-1 and IL-6, produced by macrophages in the cerebral arteries (83). PPAR-γ represents an appealing strategy for decreasing inflammation and improving the healing of chronic injuries, and PPAR-γ in inflammatory cells may be a potential therapeutic target (84,85). Pioglitazone has been shown to exert anti-inflammatory effects on acute gouty arthritis by inhibiting the expression of TNF-α and IFN-γ (86). Notably, there is anti-inflammatory therapeutic potential for the treatment of Alzheimer's disease, dental implants and lipid inflammation processes through the PPAR-γ pathway (47,87,88). PPAR-γ modulates macrophage and T cell-mediated inflammation. Reductions in the levels of PPAR-γ in T cells have been shown to result in an increased expression of adhesion molecules and pro-inflammatory cytokines (IL-6 and IL-1β), and to modulate Treg recruitment (89). Thus, PPAR-γ agonists are effective in controlling inflammation-related damage and inhibiting cytokines and chemokines, suggesting their therapeutic potential in the treatment of CAB.

PPAR-γ and NV

Pathological conditions including infection, trauma and loss of the limbal stem cell barrier can lead to CNV formation, from the limbal area to the vascular cornea (90). NV is mediated by cellular and molecular factors, such as VEGF and pigment epithelium-derived factor (PEDF), which play roles in the development of NV (91). Corneal transparency is essential for maintaining good visual acuity, and NV in CAB forms the basis of multiple visual pathologies that may result in blindness. However, CNV formations respond poorly to current therapies. Therefore, potential anti-angiogenic topical treatments against CNV resulting from alkali burns have been investigated in in vitro studies and clinical trials (25,9295). The suppression of VEGF and placental growth factor levels in the cornea in a mouse model of alkali burns was observed to significantly inhibit NV growth and the regression of established vessels (96). PPAR-γ agonists are potent inhibitors of NV and show potential for the treatment of inflammatory vasculoproliferative diseases (97100). Rosiglitazone has been shown to protect vascular endothelial cells by reducing the expression of the chemerin receptor, ChemR23 (101). Thiazolidinediones (TZDs) inhibit retinal and choroidal NV by suppressing tube formation in human umbilical vein endothelial cells (HUVECs). In addition, TZDs may inhibit VEGF induced non-inflammatory NV in vivo (102). PEDF is a potent anti-angiogenic factor and can induce endothelial cell apoptosis, and can inhibit angiogenesis by augmenting PPAR-γ expression in ischemic heart tissue (103). Therefore, PPAR-γ may be a useful target in the prevention and treatment of vascular inflammatory diseases.

PPAR-γ and fibrosis

Corneal fibrosis can result in visual impairment and blindness. Alkali burned corneas were observed to exhibit obvious interfibrillar distances with greater levels of the fibrotic marker α-smooth muscle actin (αSMA) (104). The TGFβ-induced differentiation of corneal fibroblasts to myofibroblasts could be prevented (105). The level of inflammation and scarring/fibrosis has been observed to increase during healing in injured tissue in a model of CAB. The prognosis of CAB is dependent upon ocular surface inflammation, and the scarring and fibrosis of the cornea and eyelid (70,106). PPAR-γ possess strong anti-fibrotic properties in the cornea and several other types of tissue, with PPAR-γ ligands blocking αSMA induction (107). A number of studies have demonstrated that treatment with ophthalmic solutions of PPAR-γ agonists reduced the fibrotic reaction in the early phase post-CAB and in additional fibrotic pathologies (106,108,109).

PPAR-γ agonists and cell signal transduction

PPAR-γ is an important modulator of lipid metabolism during inflammation, via the inhibition of the expression of proinflammatory molecules (110). NF-κB is activated and translocates to the nucleus where it controls the expression of a large number of target genes, which are involved in the regulation of inflammation and innate and adaptive immune responses (111). Telomeric repeat binding factor was discovered as a modulator that regulates NF-κB signaling. The inhibition of repeat binding factor may lead to the design of specific inhibitors of NF-κB for the treatment of ocular injuries (112). The effects of SN50, an inhibitor of NF-κB, were reported to be dependent on TNF-α/JNK signaling in a mouse model of CAB, with the topical application of SN50 shown to be effective in treating CAB (113). PPAR-γ has been indicated to be the predominant pathway involved in the inhibition of IL-1β-induced inflammation [nitric oxide and prostaglandin E2 production, in addition to inducible nitric oxide synthase and cyclooxygenase 2 (COX-2) expression, NF-κB and MAPK activation (114).

PPAR-γ agonists and chemokines

TC14012 [a chemokine (C-X-C motif) receptor 4 (CXCR4) antagonist and CXCR7 agonist] has been reported to initially enhance alkali burn-induced CNV, then reduce CNV in later stages. In addition to CXCR4, CXCR7 has been implicated in the pathogenesis of CNV (115). Granulocyte-colony stimulating factor (G-CSF) post-traumatic gene expression activates innate immune responses and suppresses adaptive immune responses. The G-CSF signal transducer and activator of transcription axis has been indicated to be a key protective mechanism post-injury in reducing the risk of infection (116). PPAR-γ reduces the expression levels of pro-inflammatory chemokines, including chemokine (C-C motif) ligand 20, CXC ligand (CXCL)2, CXCL3 and chemokine (C-X3-C motif) ligand 1 (CX3CL1) in colon tissues. It has been shown that increasing the transcriptional activity of PPAR-γ can modulate inflammatory signaling pathways, suggesting a novel target for therapeutic agents (117). The investigation of inflammatory markers in vascular disorders reveals augmented levels of circulating cytokines and chemokines among carriers of classic risk factors for atherosclerosis. Dysregulation of the PPAR signaling pathway may explain the association of IL-8/12 and very low density lipoprotein (VLDL)-c in the promotion of dysglycemia (118). The PPAR signaling pathway was shown to be important in the modulation of inflammatory factors, including MCP-1, TNF-α, IL-1 and IL-6, COX-2, nicotinamide adenine dinucleotide phosphate, protein kinase C, vascular cell adhesion molecule-1, NF-κB and monocyte expressions in HUVECs. The inhibition of the PPAR pathway in endothelial inflammation suggests a potential role of PPAR agonists in the treatment of vascular inflammation (119,120). Rosiglitazone has been shown to suppress angiogenesis by downregulating the expression of CXCR4 in a dose-, time- and PPAR-γ-dependent manner (121). Regulating the expression of MCP-1 and activating the 5′ AMP-activated protein kinase-sirtuin 1-PPAR signaling pathway may be a novel therapeutic agent for atherosclerosis (122). PPAR-γ has been indicated to regulate hypoxia/reoxygenation-stimulated IL-8 production in U937 cells (123). PPAR-γ serves an inhibitory role in hepatic injury by downregulating the local expression of proinflammatory cytokines, chemokines and adhesion molecules following reperfusion (124,125).

PPAR-γ agonists and MMPs

Keratocytes are able to directly degrade type I collagen and create stromal spaces, promoting CNV through VEGF induced MMP-13 expression (126). The inhibition of alkali burn-induced CNV in mice may be possible via reductions in the production of the angiogenic factors, inflammatory cytokines and MMPs involved in the angiogenic response (78,127,128). MMP-12 may disintegrate certain components of the extracellular matrix (ECM) released following severe alkali burn, which may be involved in ECM remodeling (129). Inhibiting alkali burn-induced CNV by accelerating corneal wound healing and by reducing the production of angiogenic factors, inflammatory cytokines and MMPs may be a potential therapeutic strategy (29,125,130133). PPAR-γ agonists are able to affect proliferation, differentiation, apoptosis and inflammation in different cell types. PPAR-γ ligands were able to inhibit K562 and HL-60 cell adhesion to ECM proteins by inhibiting the expression of MMP-2 and -9 (134). PPAR-γ agonists have been shown to inhibit macrophage infiltration, the expression of TNF-α and MMP-9 in aortic tissue, thus may be used as anti-inflammatory agents in cardiovascular fields (135). Degradation of the epithelial basement membrane in burned cornea in vivo was reversed by an MMP inhibitor (136), additionally; MMP inhibitors have been shown to block the progression of alkali burns to ulceration (137). These data may indicate that PPAR-γ agonists are a potential strategy for preventing CAB progression.

Taken together, the evidence suggests that PPAR-γ may lessen NV, inflammation and scarring. However, additional studies are necessary to evaluate the potential therapeutic effects of PPAR-γ in ocular NV, tissue inflammation and the resultant fibrosis following burn injury (Fig. 3).

Acknowledgments

The present study was supported by the Natural Science Foundation of China (grant no. 81300727) and Jilin University Basic Scientific Research Operating Expenses Fund (Research Fund of the Bethune B Plan of Jilin University; grant no. 2012230).

References

1 

Leong YY and Tong L: Barrier function in the ocular surface: From conventional paradigms to new opportunities. Ocul Surf. 13:103–109. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Cabalag MS, Wasiak J, Syed Q, Paul E, Hall AJ and Cleland H: Early and late complications of ocular burn injuries. J Plast Reconstr Aesthet Surg. 68:356–361. 2015. View Article : Google Scholar

3 

Saika S, Yamanaka O, Okada Y, Miyamoto T, Kitano A, Flanders KC, Ohnishi Y, Nakajima Y, Kao WW and Ikeda K: Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice. Am J Physiol Cell Physiol. 293:C75–C86. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Pargament JM, Armenia J and Nerad JA: Physical and chemical injuries to eyes and eyelids. Clin Dermatol. 33:234–237. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Zhang S, Gu H and Hu N: Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases. J Ophthalmol. 2015:2754352015. View Article : Google Scholar

6 

Hsu CC, Peng CH, Hung KH, Lee YY, Lin TC, Jang SF, Liu JH, Chen YT, Woung LC, Wang CY, et al: Stem cell therapy for corneal regeneration medicine and contemporary nanomedicine for corneal disorders. Cell Transplant. 24:1915–1930. 2015. View Article : Google Scholar

7 

Mittal V, Jain R, Mittal R, Vashist U and Narang P: Successful management of severe unilateral chemical burns in children using simple limbal epithelial transplantation (SLET). Br J Ophthalmol. 2015:3071792015.

8 

Movahedan A, Genereux BM, Darvish-Zargar M, Shah KJ and Holland EJ: Long-term management of severe ocular surface injury due to methamphetamine production accidents. Cornea. 34:433–437. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Kafle PA, Singh SK, Sarkar I and Surin L: Amniotic membrane transplantation with and without limbal stem cell transplantation in chemical eye injury. Nepal J Ophthalmol. 7:52–55. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Scholz SL, Thomasen H, Hestermann K, Dekowski D, Steuhl KP and Meller D: Long-term results of autologous transplantation of limbal epithelium cultivated ex vivo for limbal stem cell deficiency. Ophthalmologe. 113:321–329. 2016.In German. View Article : Google Scholar

11 

Almaliotis D, Koliakos G, Papakonstantinou E, Komnenou A, Thomas A, Petrakis S, Nakos I, Gounari E and Karampatakis V: Mesenchymal stem cells improve healing of the cornea after alkali injury. Graefes Arch Clin Exp Ophthalmol. 253:1121–1135. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Holan V, Trosan P, Cejka C, Javorkova E, Zajicova A, Hermankova B, Chudickova M and Cejkova J: Comparative Study of the Therapeutic Potential of Mesenchymal Stem Cells and Limbal Epithelial Stem Cells for Ocular Surface Reconstruction. Stem Cells Transl Med. 4:1052–1063. 2015. View Article : Google Scholar : PubMed/NCBI

13 

Sotozono C, Inatomi T, Nakamura T, Koizumi N, Yokoi N, Ueta M, Matsuyama K, Kaneda H, Fukushima M and Kinoshita S: Cultivated oral mucosal epithelial transplantation for persistent epithelial defect in severe ocular surface diseases with acute inflammatory activity. Acta Ophthalmol. 92:e447–e453. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Rudnisky CJ, Belin MW, Guo R and Ciolino JB: Boston Type 1 Keratoprosthesis Study Group: Visual Acuity Outcomes of the Boston Keratoprosthesis Type 1: Multicenter Study Results. Am J Ophthalmol. 162:89–98. 2016. View Article : Google Scholar

15 

Kammerdiener LL, Speiser JL, Aquavella JV, Harissi-Dagher M, Dohlman CH, Chodosh J and Ciolino JB: Protective effect of soft contact lenses after Boston keratoprosthesis. Br J Ophthalmol. 100:549–552. 2016. View Article : Google Scholar

16 

Iyer G, Srinivasan B, Rishi E, Rishi P, Agarwal S and Subramanian N: Large lamellar corneoscleral grafts: Tectonic role in initial management of severe ocular chemical injuries. Eur J Ophthalmol. 26:12–17. 2016. View Article : Google Scholar

17 

Prockop DJ: Inflammation, fibrosis, and modulation of the process by mesenchymal stem/stromal cells. Matrix Biol. 51:7–13. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Qi Y, Jiang D, Sindrilaru A, Stegemann A, Schatz S, Treiber N, Rojewski M, Schrezenmeier H, Vander Beken S, Wlaschek M, et al: TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds. J Invest Dermatol. 134:526–537. 2014. View Article : Google Scholar

19 

Prockop DJ and Oh JY: Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol Ther. 20:14–20. 2012. View Article : Google Scholar :

20 

Moreira PB, Magalhães RS, Pereira NC, Oliveira LA and Sousa LB: Limbal transplantation at a tertiary hospital in Brazil: A retrospective study. Arq Bras Oftalmol. 78:207–211. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Schimke MM, Marozin S and Lepperdinger G: Patient-Specific age: The other side of the coin in advanced mesenchymal stem cell therapy. Front Physiol. 6:3622015. View Article : Google Scholar : PubMed/NCBI

22 

Lamm V, Hara H, Mammen A, Dhaliwal D and Cooper DK: Corneal blindness and xenotransplantation. Xenotransplantation. 21:99–114. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Heindl LM and Cursiefen C: Split-cornea transplantation-a novel concept to reduce corneal donor shortage. Klin Monbl Augenheilkd. 229:608–614. 2012.In German. PubMed/NCBI

24 

Li X, Zhou Q, Hanus J, Anderson C, Zhang H, Dellinger M, Brekken R and Wang S: Inhibition of multiple pathogenic pathways by histone deacetylase inhibitor SAHA in a corneal alkali-burn injury model. Mol Pharm. 10:307–318. 2013. View Article : Google Scholar :

25 

Bakunowicz-Łazarczyk A and Urban B: Assessment of therapeutic options for reducing alkali burn-induced corneal neovascularization and inflammation. Adv Med Sci. 61:101–112. 2016. View Article : Google Scholar

26 

Atiba A, Wasfy T, Abdo W, Ghoneim A, Kamal T and Shukry M: Aloe vera gel facilitates re-epithelialization of corneal alkali burn in normal and diabetic rats. Clin Ophthalmol. 9:2019–2026. 2015.PubMed/NCBI

27 

Rho CR, Choi JS, Seo M, Lee SK and Joo CK: Inhibition of lymphangiogenesis and hemangiogenesis in corneal inflammation by subconjunctival Prox1 siRNA injection in rats. Invest Ophthalmol Vis Sci. 56:5871–5879. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Sijnave D, Van Bergen T, Castermans K, Kindt N, Vandewalle E, Stassen JM, Moons L and Stalmans I: Inhibition of Rho-associated kinase prevents pathological wound healing and neovascularization after corneal trauma. Cornea. 34:1120–1129. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Lima TB, Ribeiro AP, Conceição LF, Bandarra M, Manrique WG and Laus JL: Ketorolac eye drops reduce inflammation and delay re-epithelization in response to corneal alkali burn in rabbits, without affecting iNOS or MMP-9. Arq Bras Oftalmol. 78:67–72. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Cai J, Dou G, Zheng L, Yang T, Jia X, Tang L, Huang Y, Wu W, Li X and Wang X: Pharmacokinetics of topically applied recombinant human keratinocyte growth factor-2 in alkali-burned and intact rabbit eye. Exp Eye Res. 136:93–99. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Shadmani A, Kazemi K, Khalili MR and Eghtedari M: Omental transposition in treatment of severe ocular surface alkaline burn: An experimental study. Med Hypothesis Discov Innov Ophthalmol. 3:57–61. 2014.

32 

Dvashi Z, Sar Shalom H, Shohat M, Ben-Meir D, Ferber S, Satchi-Fainaro R, Ashery-Padan R, Rosner M, Solomon AS and Lavi S: Protein phosphatase magnesium dependent 1A governs the wound healing-inflammation-angiogenesis cross talk on injury. Am J Pathol. 184:2936–2950. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Crooke A, Guzman-Aranguez A, Mediero A, Alarma-Estrany P, Carracedo G, Pelaez T, Peral A and Pintor J: Effect of melatonin and analogues on corneal wound healing: Involvement of Mt2 melatonin receptor. Curr Eye Res. 40:56–65. 2015. View Article : Google Scholar

34 

Iannetti L, Abbouda A, Fabiani C, Zito R and Campanella M: Treatment of corneal neovascularization in ocular chemical injury with an off-label use of subconjunctival bevacizumab: A case report. J Med Case Reports. 7:1992013. View Article : Google Scholar

35 

Ozdemir O, Altintas O, Altintas L, Ozkan B, Akdag C and Yüksel N: Comparison of the effects of subconjunctival and topical anti-VEGF therapy (bevacizumab) on experimental corneal neovascularization. Arq Bras Oftalmol. 77:209–213. 2014. View Article : Google Scholar : PubMed/NCBI

36 

Taira BR, Singer AJ, McClain SA, Lin F, Rooney J, Zimmerman T and Clark RA: Rosiglitazone, a PPAR-gamma ligand, reduces burn progression in rats. J Burn Care Res. 30:499–504. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Pershadsingh HA and Moore DM: PPARgamma Agonists: Potential as Therapeutics for Neovascular Retinopathies. PPAR Res. 2008:1642732008. View Article : Google Scholar : PubMed/NCBI

38 

Gelman L, Fruchart JC and Auwerx J: An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci. 55:932–943. 1999. View Article : Google Scholar : PubMed/NCBI

39 

Chinetti G, Fruchart JC and Staels B: Peroxisome proliferator-activated receptors and inflammation: From basic science to clinical applications. Int J Obes Relat Metab Disord. 27(Suppl 3): S41–S45. 2003. View Article : Google Scholar

40 

Kostadinova R, Wahli W and Michalik L: PPARs in diseases: Control mechanisms of inflammation. Curr Med Chem. 12:2995–3009. 2005. View Article : Google Scholar : PubMed/NCBI

41 

Chen M, Matsuda H, Wang L, Watanabe T, Kimura MT, Igarashi J, Wang X, Sakimoto T, Fukuda N, Sawa M, et al: Pretranscriptional regulation of Tgf-β1 by PI polyamide prevents scarring and accelerates wound healing of the cornea after exposure to alkali. Mol Ther. 18:519–527. 2010. View Article : Google Scholar

42 

Uchiyama M, Shimizu A, Masuda Y, Nagasaka S, Fukuda Y and Takahashi H: An ophthalmic solution of a peroxisome proliferator-activated receptor gamma agonist prevents corneal inflammation in a rat alkali burn model. Mol Vis. 19:2135–2150. 2013.PubMed/NCBI

43 

Sener G, Sehirli AO, Gedik N and Dülger GA: Rosiglitazone, a PPAR-gamma ligand, protects against burn-induced oxidative injury of remote organs. Burns. 33:587–593. 2007. View Article : Google Scholar : PubMed/NCBI

44 

Pershadsingh HA, Benson SC, Marshall, Kurtz TW, Pravenec M, King JC, Stopa EG and Famiglietti EV: Ocular diseases and peroxisome proliferator-activated receptor-γ (PPAR-γ) in mammalian eye. Soc Neurosci Abstr. 25:21931999.

45 

Balachandar S and Katyal A: Peroxisome proliferator activating receptor (PPAR) in cerebral malaria (CM): A novel target for an additional therapy. Eur J Clin Microbiol Infect Dis. 30:483–498. 2011. View Article : Google Scholar

46 

Pan H, Chen J, Xu J, Chen M and Ma R: Antifibrotic effect by activation of peroxisome proliferator-activated receptor-γ in corneal fibroblasts. Mol Vis. 15:2279–2286. 2009.PubMed/NCBI

47 

Kaul D, Anand PK and Khanna A: Functional genomics of PPAR-gamma in human immunomodulatory cells. Mol Cell Biochem. 290:211–215. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Paterson HM, Murphy TJ, Purcell EJ, Shelley O, Kriynovich SJ, Lien E, Mannick JA and Lederer JA: Injury primes the innate immune system for enhanced Toll-like receptor reactivity. J Immunol. 171:1473–1483. 2003. View Article : Google Scholar : PubMed/NCBI

49 

Bashir S, Sharma Y, Elahi A and Khan F: Macrophage polarization: The link between inflammation and related diseases. Inflamm Res. 65:1–11. 2016. View Article : Google Scholar

50 

Valvis SM, Waithman J, Wood FM, Fear MW and Fear VS: The Immune Response to Skin Trauma Is Dependent on the Etiology of Injury in a Mouse Model of Burn and Excision. J Invest Dermatol. 135:2119–2128. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Fletcher HA, Keyser A, Bowmaker M, Sayles PC, Kaplan G, Hussey G, Hill AV and Hanekom WA: Transcriptional profiling of mycobacterial antigen-induced responses in infants vaccinated with BCG at birth. BMC Med Genomics. 2:102009. View Article : Google Scholar : PubMed/NCBI

52 

D'Arpa N, D'Amelio L, Accardo-Palumbo A, Pileri D, Mogavero R, Amato G, Napoli B, Alessandro G, Lombardo C and Conte F: Skin dendritic cells in burn patients. Ann Burns Fire Disasters. 22:175–178. 2009.PubMed/NCBI

53 

Rani M, Zhang Q, Scherer MR, Cap AP and Schwacha MG: Activated skin γδ T-cells regulate T-cell infiltration of the wound site after burn. Innate Immun. 21:140–150. 2015. View Article : Google Scholar

54 

Schwacha MG, Zhang Q, Rani M, Craig T and Oppeltz RF: Burn enhances toll-like receptor induced responses by circulating leukocytes. Int J Clin Exp Med. 5:136–144. 2012.PubMed/NCBI

55 

Yamada K, Ueta M, Sotozono C, Yokoi N, Inatomi T and Kinoshita S: Upregulation of Toll-like receptor 5 expression in the conjunctival epithelium of various human ocular surface diseases. Br J Ophthalmol. 98:1116–1119. 2014. View Article : Google Scholar : PubMed/NCBI

56 

West AP, Koblansky AA and Ghosh S: Recognition and signaling by toll-like receptors. Annu Rev Cell Dev Biol. 22:409–437. 2006. View Article : Google Scholar : PubMed/NCBI

57 

Drage MG, Pecora ND, Hise AG, Febbraio M, Silverstein RL, Golenbock DT, Boom WH and Harding CV: TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis. Cell Immunol. 258:29–37. 2009. View Article : Google Scholar : PubMed/NCBI

58 

Cornick SM, Noronha SA, Noronha SM, Cezillo MV, Ferreira LM and Gragnani A: Toll like receptors gene expression of human keratinocytes cultured of severe burn injury. Acta Cir Bras. 29(Suppl 3): 33–38. 2014. View Article : Google Scholar : PubMed/NCBI

59 

Shupp JW, Nasabzadeh TJ, Rosenthal DS, Jordan MH, Fidler P and Jeng JC: A review of the local pathophysiologic bases of burn wound progression. J Burn Care Res. 31:849–873. 2010. View Article : Google Scholar : PubMed/NCBI

60 

Kitano A, Okada Y, Yamanka O, Shirai K, Mohan RR and Saika S: Therapeutic potential of trichostatin A to control inflammatory and fibrogenic disorders of the ocular surface. Mol Vis. 16:2964–2973. 2010.

61 

Chistyakov DV, Aleshin SE, Astakhova AA, Sergeeva MG and Reiser G: Regulation of peroxisome proliferator-activated receptors (PPAR) a and -γ of rat brain astrocytes in the course of activation by toll-like receptor agonists. J Neurochem. 134:113–124. 2015. View Article : Google Scholar : PubMed/NCBI

62 

Chistyakov DV, Aleshin S, Sergeeva MG and Reiser G: Regulation of peroxisome proliferator-activated receptor β/δ expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astrocytes. J Neurochem. 130:563–574. 2014. View Article : Google Scholar : PubMed/NCBI

63 

Ding JL, Zhou ZG, Zhou XY, Zhou B, Wang L, Wang R, Zhan L, Sun XF and Li Y: Attenuation of acute pancreatitis by peroxisome proliferator-activated receptor-α in rats: The effect on Toll-like receptor signaling pathways. Pancreas. 42:114–122. 2013. View Article : Google Scholar

64 

Zhao W, Wang L, Zhang M, Wang P, Zhang L, Yuan C, Qi J, Qiao Y, Kuo PC and Gao C: Peroxisome proliferator-activated receptor gamma negatively regulates IFN-beta production in Toll-like receptor (TLR) 3- and TLR4-stimulated macrophages by preventing interferon regulatory factor 3 binding to the IFN-beta promoter. J Biol Chem. 286:5519–5528. 2011. View Article : Google Scholar

65 

Pan S, Lei L, Chen S, Li H and Yan F: Rosiglitazone impedes Porphyromonas gingivalis-accelerated atherosclerosis by down-regulating the TLR/NF-κB signaling pathway in atherosclerotic mice. Int Immunopharmacol. 23:701–708. 2014. View Article : Google Scholar : PubMed/NCBI

66 

Lian M, Luo W, Sui Y, Li Z and Hua J: Dietary n-3 PUFA protects mice from Con A induced liver injury by modulating regulatory T cells and PPAR-γ expression. PLoS One. 10:e01327412015. View Article : Google Scholar

67 

Li T, Wang W, Zhao JH, Zhou X, Li YM and Chen H: Pseudolaric acid B inhibits T-cell mediated immune response in vivo via p38MAPK signal cascades and PPARγ activation. Life Sci. 121:88–96. 2015. View Article : Google Scholar

68 

Kraft CT, Agarwal S, Ranganathan K, Wong VW, Loder S, Li J, Delano MJ and Levi B: Trauma-induced heterotopic bone formation and the role of the immune system: A review. J Trauma Acute Care Surg. 80:156–165. 2016. View Article : Google Scholar

69 

Xiu F and Jeschke MG: Perturbed mononuclear phagocyte system in severely burned and septic patients. Shock. 40:81–88. 2013. View Article : Google Scholar : PubMed/NCBI

70 

Ferrari G, Bignami F, Giacomini C, Franchini S and Rama P: Safety and efficacy of topical infliximab in a mouse model of ocular surface scarring. Invest Ophthalmol Vis Sci. 54:1680–1688. 2013. View Article : Google Scholar : PubMed/NCBI

71 

Yamada J, Dana MR, Sotozono C and Kinoshita S: Local suppression of IL-1 by receptor antagonist in the rat model of corneal alkali injury. Exp Eye Res. 76:161–167. 2003. View Article : Google Scholar : PubMed/NCBI

72 

Sotozono C, He J, Matsumoto Y, Kita M, Imanishi J and Kinoshita S: Cytokine expression in the alkali-burned cornea. Curr Eye Res. 16:670–676. 1997. View Article : Google Scholar : PubMed/NCBI

73 

Lu P, Li L, Liu G, Zhang X and Mukaida N: Enhanced experimental corneal neovascularization along with aberrant angiogenic factor expression in the absence of IL-1 receptor antagonist. Invest Ophthalmol Vis Sci. 50:4761–4768. 2009. View Article : Google Scholar : PubMed/NCBI

74 

Sakimoto T, Yamada A, Kanno H and Sawa M: Upregulation of tumor necrosis factor receptor 1 and TNF-alpha converting enzyme during corneal wound healing. Jpn J Ophthalmol. 52:393–398. 2008. View Article : Google Scholar : PubMed/NCBI

75 

Pattamatta U, Willcox M, Stapleton F and Garrett Q: Bovine lactoferrin promotes corneal wound healing and suppresses IL-1 expression in alkali wounded mouse cornea. Curr Eye Res. 38:1110–1117. 2013. View Article : Google Scholar : PubMed/NCBI

76 

Shin YJ, Hyon JY, Choi WS, Yi K, Chung ES, Chung TY and Wee WR: Chemical injury-induced corneal opacity and neovascularization reduced by rapamycin via TGF-β1/ERK pathways regulation. Invest Ophthalmol Vis Sci. 54:4452–4458. 2013. View Article : Google Scholar : PubMed/NCBI

77 

Ling S, Li W, Liu L, Zhou H, Wang T, Ye H, Liang L and Yuan J: Allograft survival enhancement using doxycycline in alkali-burned mouse corneas. Acta Ophthalmol. 91:e369–e378. 2013. View Article : Google Scholar : PubMed/NCBI

78 

Xiao O, Xie ZL, Lin BW, Yin XF, Pi RB and Zhou SY: Minocycline inhibits alkali burn-induced corneal neovascularization in mice. PLoS One. 7:e418582012. View Article : Google Scholar : PubMed/NCBI

79 

Jeon HS, Yi K, Chung TY, Hyon JY, Wee WR and Shin YJ: Chemically injured keratocytes induce cytokine release by human peripheral mononuclear cells. Cytokine. 59:280–285. 2012. View Article : Google Scholar : PubMed/NCBI

80 

Cairns B, Maile R, Barnes CM, Frelinger JA and Meyer AA: Increased Toll-like receptor 4 expression on T cells may be a mechanism for enhanced T cell response late after burn injury. J Trauma. 61:293–298; discussion 298–299. 2006. View Article : Google Scholar : PubMed/NCBI

81 

Planck SR, Rich LF, Ansel JC, Huang XN and Rosenbaum JT: Trauma and alkali burns induce distinct patterns of cytokine gene expression in the rat cornea. Ocul Immunol Inflamm. 5:95–100. 1997. View Article : Google Scholar : PubMed/NCBI

82 

De Nuccio C, Bernardo A, Cruciani C, De Simone R, Visentin S and Minghetti L: Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation. Exp Neurol. 271:506–514. 2015. View Article : Google Scholar : PubMed/NCBI

83 

Shimada K, Furukawa H, Wada K, Korai M, Wei Y, Tada Y, Kuwabara A, Shikata F, Kitazato KT, Nagahiro S, et al: Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture. Stroke. 46:1664–1672. 2015. View Article : Google Scholar : PubMed/NCBI

84 

Mirza RE, Fang MM, Novak ML, Urao N, Sui A, Ennis WJ and Koh TJ: Macrophage PPARγ and impaired wound healing in type 2 diabetes. J Pathol. 236:433–444. 2015. View Article : Google Scholar : PubMed/NCBI

85 

Lan LF, Zheng L, Yang X, Ji XT, Fan YH and Zeng JS: Peroxisome proliferator-activated receptor-γ agonist pioglitazone ameliorates white matter lesion and cognitive impairment in hypertensive rats. CNS Neurosci Ther. 21:410–416. 2015. View Article : Google Scholar : PubMed/NCBI

86 

Wang RC and Jiang DM: PPAR-γ agonist pioglitazone affects rat gouty arthritis by regulating cytokines. Genet Mol Res. 13:6577–6581. 2014. View Article : Google Scholar : PubMed/NCBI

87 

Cheng Y, Dong Z and Liu S: β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 mice through CB2 receptor activation and the PPARγ pathway. Pharmacology. 94:1–12. 2014. View Article : Google Scholar

88 

Bhattarai G, Lee YH and Yi HK: Peroxisome proliferator activated receptor gamma loaded dental implant improves osteogenesis of rat mandible. J Biomed Mater Res B Appl Biomater. 103:587–595. 2015. View Article : Google Scholar

89 

Guri AJ, Mohapatra SK, Horne WT II, Hontecillas R and Bassaganya-Riera J: The role of T cell PPAR γ in mice with experimental inflammatory bowel disease. BMC Gastroenterol. 10:602010. View Article : Google Scholar

90 

Amparo F, Sadrai Z, Jin Y, Alfonso-Bartolozzi B, Wang H, Shikari H, Ciolino JB, Chodosh J, Jurkunas U, Schaumberg DA, et al: Safety and efficacy of the multitargeted receptor kinase inhibitor pazopanib in the treatment of corneal neovascularization. Invest Ophthalmol Vis Sci. 54:537–544. 2013. View Article : Google Scholar :

91 

Huang X, Han Y, Shao Y and Yi JL: Efficacy of the nucleotide-binding oligomerzation domain 1 inhibitor Nodinhibit-1 on corneal alkali burns in rats. Int J Ophthalmol. 8:860–865. 2015.PubMed/NCBI

92 

Lee CM, Jung WK, Na G, Lee DS, Park SG, Seo SK, Yang JW, Yea SS, Lee YM, Park WS, et al: Inhibitory effects of the platelet-activating factor receptor antagonists, CV-3988 and Ginkgolide B, on alkali burn-induced corneal neovascularization. Cutan Ocul Toxicol. 34:53–60. 2015. View Article : Google Scholar

93 

Giacomini C, Ferrari G, Bignami F and Rama P: Alkali burn versus suture-induced corneal neovascularization in C57BL/6 mice: An overview of two common animal models of corneal neovascularization. Exp Eye Res. 121:1–4. 2014. View Article : Google Scholar : PubMed/NCBI

94 

Bignami F, Giacomini C, Lorusso A, Aramini A, Rama P and Ferrari G: NK1 receptor antagonists as a new treatment for corneal neovascularization. Invest Ophthalmol Vis Sci. 55:6783–6794. 2014. View Article : Google Scholar : PubMed/NCBI

95 

Koenig Y, Bock F, Kruse FE, Stock K and Cursiefen C: Angioregressive pretreatment of mature corneal blood vessels before keratoplasty: Fine-needle vessel coagulation combined with anti-VEGFs. Cornea. 31:887–892. 2012. View Article : Google Scholar : PubMed/NCBI

96 

Zhou AY, Bai YJ, Zhao M, Yu WZ and Li XX: KH902, a recombinant human VEGF receptor fusion protein, reduced the level of placental growth factor in alkali burn induced-corneal neovascularization. Ophthalmic Res. 50:180–186. 2013. View Article : Google Scholar : PubMed/NCBI

97 

Xin X, Yang S, Kowalski J and Gerritsen ME: Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem. 274:9116–9121. 1999. View Article : Google Scholar : PubMed/NCBI

98 

Vucic E, Dickson SD, Calcagno C, Rudd JH, Moshier E, Hayashi K, Mounessa JS, Roytman M, Moon MJ, Lin J, et al: Pioglitazone modulates vascular inflammation in atherosclerotic rabbits noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging. JACC Cardiovasc Imaging. 4:1100–1109. 2011. View Article : Google Scholar : PubMed/NCBI

99 

Usui T, Sugisaki K, Iriyama A, Yokoo S, Yamagami S, Nagai N, Ishida S and Amano S: Inhibition of corneal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 49:4370–4376. 2008. View Article : Google Scholar : PubMed/NCBI

100 

Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnés CM, Fannon M, Laforme AM, Chaponis DM, Folkman J and Kieran MW: PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci USA. 105:985–990. 2008. View Article : Google Scholar : PubMed/NCBI

101 

Hao F, Mu JW, Zhang HJ, Kuang HY, Yu QX, Bai MM and Meng P: Damage to vascular endothelial cells by high insulin levels is associated with increased expression of ChemR23, and attenuated by PPAR-gamma agonist, rosiglitazone. Neuro Endocrinol Lett. 36:59–66. 2015.PubMed/NCBI

102 

Sarayba MA, Li L, Tungsiripat T, Liu NH, Sweet PM, Patel AJ, Osann KE, Chittiboyina A, Benson SC, Pershadsingh HA and Chuck RS: Inhibition of corneal neovascularization by a peroxisome proliferator-activated receptor-gamma ligand. Exp Eye Res. 80:435–442. 2005. View Article : Google Scholar : PubMed/NCBI

Exp Eye Res. 80:435–442. 2005. View Article : Google Scholar

103 

Zhang H, Wei T, Jiang X, Li Z, Cui H, Pan J, Zhuang W, Sun T, Liu Z, Zhang Z and Dong H: PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL. Apoptosis. 21:60–68. 2016. View Article : Google Scholar

104 

Gronkiewicz KM, Giuliano EA, Kuroki K, Bunyak F, Sharma A, Teixeira LB, Hamm CW and Mohan RR: Development of a novel in vivo corneal fibrosis model in the dog. Exp Eye Res. 143:75–88. 2016. View Article : Google Scholar

105 

Donnelly KS, Giuliano EA, Sharm A and Mohan RR: Suberoylanilide hydroxamic acid (vorinostat): Its role on equine corneal fibrosis and matrix metalloproteinase activity. Vet Ophthalmol. 17(Suppl 1): 61–68. 2014. View Article : Google Scholar : PubMed/NCBI

106 

Zhou Q, Yang L, Qu M, Wang Y, Chen P, Wang Y and Shi W: Role of senescent fibroblasts on alkali-induced corneal neovascularization. J Cell Physiol. 227:1148–1156. 2012. View Article : Google Scholar

107 

Jeon KI, Phipps RP, Sime PJ and Huxlin KR: Inhibitory effects of PPARγ ligands on TGF-β1-induced CTGF expression in cat corneal fibroblasts. Exp Eye Res. 138:52–58. 2015. View Article : Google Scholar : PubMed/NCBI

108 

Yoon YS, Kim SY, Kim MJ, Lim JH, Cho MS and Kang JL: PPARγ activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis via regulation of efferocytosis and proresolving cytokines. Mucosal Immunol. 8:1031–1046. 2015. View Article : Google Scholar : PubMed/NCBI

109 

Luo H, Zhu H, Zhou B, Xiao X and Zuo X: MicroRNA-130b regulates scleroderma fibrosis by targeting peroxisome proliferator-activated receptor γ. Mod Rheumatol. 25:595–602. 2015. View Article : Google Scholar

110 

Zoccal KF, Paula-Silva FW, Bitencourt CS, Sorgi CA, Bordon KC, Arantes EC and Faccioli LH: PPAR-γ activation by Tityus serrulatus venom regulates lipid body formation and lipid mediator production. Toxicon. 93:90–97. 2015. View Article : Google Scholar

111 

Wang C, Zeng L, Zhang T, Liu J and Wang W: Tenuigenin prevents IL-1β-induced inflammation in human osteoarthritis chondrocytes by suppressing pi3k/akt/nf-κb signaling pathway. Inflammation. 39:807–812. 2016. View Article : Google Scholar : PubMed/NCBI

112 

Poon MW, Yan L, Jiang D, Qin P, Tse HF, Wong IY, Wong DS, Tergaonkar V and Lian Q: Inhibition of RAP1 enhances corneal recovery following alkali injury. Invest Ophthalmol Vis Sci. 56:711–721. 2015. View Article : Google Scholar : PubMed/NCBI

113 

Saika S, Miyamoto T, Yamanaka O, Kato T, Ohnishi Y, Flanders KC, Ikeda K, Nakajima Y, Kao WW, Sato M, et al: Therapeutic effect of topical administration of SN50, an inhibitor of nuclear factor-κB, in treatment of corneal alkali burns in mice. Am J Pathol. 166:1393–1403. 2005. View Article : Google Scholar : PubMed/NCBI

114 

Ma Z, Piao T, Wang Y and Liu J: Astragalin inhibits IL-1β-induced inflammatory mediators production in human osteoarthritis chondrocyte by inhibiting nf-κb and MAPK activation. Int Immunopharmacol. 25:83–87. 2015. View Article : Google Scholar : PubMed/NCBI

115 

Shen M, Yuan F, Jin J and Yuan Y: The effect of TC14012 on alkali burn-induced corneal neovascularization in mice. Ophthalmic Res. 52:17–24. 2014. View Article : Google Scholar : PubMed/NCBI

116 

Gardner JC, Noel JG, Nikolaidis NM, Karns R, Aronow BJ, Ogle CK and McCormack FX: G-CSF drives a posttraumatic immune program that protects the host from infection. J Immunol. 192:2405–2417. 2014. View Article : Google Scholar : PubMed/NCBI

117 

Choo J, Lee Y, Yan XJ, Noh TH, Kim SJ, Son S, Pothoulakis C, Moon HR, Jung JH and Im E: A Novel Peroxisome Proliferator-activated Receptor (PPAR)γ Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis. J Biol Chem. 290:25609–25619. 2015. View Article : Google Scholar : PubMed/NCBI

118 

Pires AS, Souza VC, Paula RS, Toledo JO, Lins TC, Moraes CF, Córdova C, Pereira RW and Nóbrega OT: Pro-inflammatory cytokines correlate with classical risk factors for atherosclerosis in the admixed Brazilian older women. Arch Gerontol Geriatr. 60:142–146. 2015. View Article : Google Scholar

119 

Zhang F, Sun D, Chen J, Guan N, Huo X and Xi H: Simvastatin attenuates angiotensin II-induced inflammation and oxidative stress in human mesangial cells. Mol Med Rep. 11:1246–1251. 2015.

120 

Xu S, Song H, Huang M, Wang K, Xu C and Xie L: Telmisartan inhibits the proinflammatory effects of homocysteine on human endothelial cells through activation of the peroxisome proliferator-activated receptor-δ pathway. Int J Mol Med. 34:828–834. 2014.PubMed/NCBI

121 

Qin L, Gong C, Chen AM, Guo FJ, Xu F, Ren Y and Liao H: Peroxisome proliferator-activated receptor γ agonist rosiglitazone inhibits migration and invasion of prostate cancer cells through inhibition of the CXCR4/CXCL12 axis. Mol Med Rep. 10:695–700. 2014.PubMed/NCBI

122 

Dong W, Wang X, Bi S, Pan Z, Liu S, Yu H, Lu H, Lin X, Wang X, Ma T and Zhang W: Inhibitory effects of resveratrol on foam cell formation are mediated through monocyte chemotactic protein-1 and lipid metabolism-related proteins. Int J Mol Med. 33:1161–1168. 2014.PubMed/NCBI

123 

Higashihara H, Kokura S, Imamoto E, Ueda M, Naito Y, Yoshida N and Yoshikawa T: Hypoxia-reoxygenation enhances interleukin-8 production from U937 human monocytic cells. Redox Rep. 9:365–369. 2004. View Article : Google Scholar

124 

Akahori T, Sho M, Hamada K, Suzaki Y, Kuzumoto Y, Nomi T, Nakamura S, Enomoto K, Kanehiro H and Nakajima Y: Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia/reperfusion injury in mice. J Hepatol. 47:784–792. 2007. View Article : Google Scholar : PubMed/NCBI

125 

Sakimoto T and Ishimori A: Anti-inflammatory effect of topical administration of tofacitinib on corneal inflammation. Exp Eye Res. 145:110–117. 2016. View Article : Google Scholar

126 

Ma J, Zhou D, Fan M, Wang H, Huang C, Zhang Z, Wu Y, Li W, Chen Y and Liu Z: Keratocytes create stromal spaces to promote corneal neovascularization via MMP13 expression. Invest Ophthalmol Vis Sci. 55:6691–6703. 2014. View Article : Google Scholar : PubMed/NCBI

127 

Zhang H, Li C and Baciu PC: Expression of integrins and MMPs during alkaline-burn-induced corneal angiogenesis. Invest Ophthalmol Vis Sci. 43:955–962. 2002.PubMed/NCBI

128 

Yang JW, Lee SM, Oh KH, Park SG, Choi IW and Seo SK: Effects of topical chondrocyte-derived extracellular matrix treatment on corneal wound healing, following an alkali burn injury. Mol Med Rep. 11:461–467. 2015.

129 

Iwanami H, Ishizaki M, Fukuda Y and Takahashi H: Expression of matrix metalloproteinases (MMP)-12 by myofibroblasts during alkali-burned corneal wound healing. Curr Eye Res. 34:207–214. 2009. View Article : Google Scholar : PubMed/NCBI

130 

Bian F, Pelegrino FS, Tukler Henriksson JT, Pflugfelder SC, Volpe EA, Li DQ and de Paiva CS: Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye. Ocul Surf. 14:242–254. 2016. View Article : Google Scholar : PubMed/NCBI

131 

Yang SJ, Jo H, Kim KA, Ahn HR, Kang SW and Jung SH: Diospyros kaki Extract Inhibits Alkali Burn-Induced Corneal Neovascularization. J Med Food. 19:106–109. 2016. View Article : Google Scholar

132 

Ke Y, Wu Y, Cui X, Liu X, Yu M, Yang C and Li X: Polysaccharide hydrogel combined with mesenchymal stem cells promotes the healing of corneal alkali burn in rats. PLoS One. 10:e01197252015. View Article : Google Scholar : PubMed/NCBI

133 

Liu J, Lu H, Huang R, Lin D, Wu X, Lin Q, Wu X, Zheng J, Pan X, Peng J, et al: Peroxisome proliferator activated receptor-gamma ligands induced cell growth inhibition and its influence on matrix metalloproteinase activity in human myeloid leukemia cells. Cancer Chemother Pharmacol. 56:400–408. 2005. View Article : Google Scholar : PubMed/NCBI

134 

Motoki T, Kurobe H, Hirata Y, Nakayama T, Kinoshita H, Rocco KA, Sogabe H, Hori T, Sata M and Kitagawa T: PPAR-γ agonist attenuates inflammation in aortic aneurysm patients. Gen Thorac Cardiovasc Surg. 63:565–571. 2015. View Article : Google Scholar : PubMed/NCBI

135 

Kato T, Saika S and Ohnishi Y: Effects of the matrix metalloproteinase inhibitor GM6001 on the destruction and alteration of epithelial basement membrane during the healing of post-alkali burn in rabbit cornea. Jpn J Ophthalmol. 50:90–95. 2006. View Article : Google Scholar : PubMed/NCBI

136 

Fini ME, Cui TY, Mouldovan A, Grobelny D, Galardy RE and Fisher SJ: An inhibitor of the matrix metalloproteinase synthesized by rabbit corneal epithelium. Invest Ophthalmol Vis Sci. 32:2997–3001. 1991.PubMed/NCBI

Related Articles

Journal Cover

October-2016
Volume 38 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Zhou H, Zhang W, Bi M and Wu J: The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review). Int J Mol Med 38: 1003-1011, 2016
APA
Zhou, H., Zhang, W., Bi, M., & Wu, J. (2016). The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review). International Journal of Molecular Medicine, 38, 1003-1011. https://doi.org/10.3892/ijmm.2016.2699
MLA
Zhou, H., Zhang, W., Bi, M., Wu, J."The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)". International Journal of Molecular Medicine 38.4 (2016): 1003-1011.
Chicago
Zhou, H., Zhang, W., Bi, M., Wu, J."The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)". International Journal of Molecular Medicine 38, no. 4 (2016): 1003-1011. https://doi.org/10.3892/ijmm.2016.2699