Pterygium is defined as overgrowth of abnormal conjunctival tissue on the cornea. Many proinflammatory cytokines and various growth factors have been implicated in the pathogenesis of pterygium. Cyclophilin A (CyPA) is a protein that is used by cyclosporin A (CsA) as the intracellular receptor and is secreted in response to inflammatory stimuli. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor. This study aimed to assessment CyPA and VEGF immunoreactivity in pterygium specimens.
Material and Methods
In this cross-sectional study, 32 primary pterygium samples, 25 recurrent pterygium samples and 25 normal bulbar conjunctiva samples were included. The histopathological features, CyPA and VEGF immunoreactivity of surgically excised pterygium specimens were compared with control conjunctiva specimens obtained from normal bulbar conjunctiva.
Results
CyPA immunoreactivity in vascular endothelial cells, epithelial cells, and stromal cells was remarkably higher in pterygium specimens than control conjunctiva specimens (p = 0.004, p = 0.012, p = 0.001, respectively). Morever, VEGF immunoreactivity in endothelial cells was remarkably higher in pterygium specimens than control conjunctiva specimens (p < 0.001). When recurrent and primary pterygium specimens were compared, CyPA and VEGF immunoreactivity was remarkably higher in recurrent pterygium (p = 0.001, p = 0.001, respectively). Pearson correlation showed that CyPA immunoreactivity correlated with stromal vascularity, stromal inflammation, and mast cell count in pterygium specimens.
Conclusion
This study aimed to assess CyPA and VEGF may have a important function in the pathogenesis and recurrence of pterygium.
SpraulCWGrossniklausHE. Tumors of the cornea and conjunctiva. Curr Opin Ophthalmol1996; 7(4): 28–34. DOI:10.1097/00055735-199608000-00006
2.
LuanratanakornPRatanapakornTSuwan-ApichonO, et al. Randomized controlled study of conjunctival autograft versus amniotic membrane graft in pterygium excision. Br J Ophthalmol2006; 90(12): 1476–1480. DOI:10.1136/bjo.2006.095018
3.
Di GirolamoNChuiJCoroneoMT, et al. Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res2004; 23(2): 195–228. DOI:10.1016/j.preteyeres.2004.02.002
4.
Di GirolamoNKumarRKCoroneoMT, et al. UVB- Mediated indication of interleukin-6 and 8 in pterigia and cultured human pterigium epithelial cells. Inves Opthalmol Vis Sci2002; 43(11): 3430–3437.
5.
KumarHLimHWMoreSV, et al. The role of free radicals in the aging brain and Parkinson’s disease: convergence and parallelism. Int J Mol Sci2012; 13(8): 10478–10504. DOI:10.3390/ijms130810478
6.
WuWS. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev2006; 25(4): 695–705. DOI:10.1007/s10555-006-9037-8
7.
SanoIKaidzuSTanitoM, et al. 4-Hydroxyhexenal And 4-hydroxynonenal-modified proteins in pterygia. Oxid Med Cell Longev2013; 2013:602029. DOI:10.1155/2013/602029
8.
BalciMSahinSMutluFM, et al. Investigation of oxidative stress in pterygium tissue. Mol Vis2011; 9;17: 443–447.
9.
AkarsuCTanerPErginA. 5-Fluorouracil As chemo adjuvant for primary pterygium surgery: preliminary report. Cornea2003; 22(6): 522–526. DOI:10.1097/00003226-200308000-00007
BekibeleCOBaiyerojuAMAjayiBG. 5-fluorouracil Vs. beta-irradiation in the prevention of pterygium recurrence. Int J Clin Pract2004; 58(10): 920–923. DOI:10.1111/j.1742-1241.2004.00007.x
12.
Turan-VuralETorun-AcarBKivancSA, et al. The effect of topical 0.05% cyclosporine on recurrence following pterygium surgery. Clin Ophthalmol2011; 5: 881–885. DOI:10.2147/OPTH.S19469
13.
FernandesMSangwanVSBansalAK, et al. Outcome of pterygium surgery: analysis over 14 years. Eye (Lond)2005; 19(11): 1182–1190. DOI:10.1038/sj.eye.6701728
BillichAWinklerGAschauerH, et al. Presence of cyclophilin A in synovial fluids of patients with rheumatoid arthritis. J Exp Med1995; 185(5): 975–980. DOI:10.1084/jem.185.5.975
16.
YangHChenJYangJ, et al. Cyclophilin A is upregulated in small cell lung cancer and activates ERK1/2 signal. Biochem Biophys Res Commun2007; 361(3): 763–767. DOI:10.1016/j.bbrc.2007.07.085
17.
NigroPSatohKO’DellMR, et al. Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice. J Exp Med2011; 208(1): 53–66. DOI:10.1084/jem.20101174
18.
StemmyEJBalsleyMAJurjusRA, et al. Blocking cyclophilins in the chronic phase of asthma reduces the persistence of leukocytes and disease reactivation. Am J Respir Cell Mol Biol2011; 45(5): 991–998. DOI:10.1165/rcmb.2011-0007OC
19.
RamachandranSVenugopalAKuttyVR, et al. Plasma level of cyclophilin A is increased in patients with type 2 diabetes mellitus and suggests presence of vascular disease. Cardiovasc Diabetol2014;7; 13: 38. DOI:10.1186/1475-2840-13-38
20.
SatohKNigroPZeidanA, et al. Cyclophilin A promotes cardiac hypertrophy in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol2011; 31(5): 1116–1123. DOI:10.1161/ATVBAHA.110.214601
21.
KumarVAbbasAKFaustoN. Tissue renewal and repair: regeneration, healing, and fibrosis. In: KumarVAbbasAKFaustoN (eds.) Robbins pathologic basis of disease. 7th ed.China: Elsevier Saunders, 2005, pp. 87–118.
22.
LivezeanuCCrăiţoiuMMMănescuR, et al. Angiogenesis in the pathogenesis of pterygium. Rom J Morphol Embryol2011; 52(3): 837–844.
23.
ClearfieldEMuthappanVWangX, et al. Conjunctival autograft for pterygium. Cochrane Database Syst Rev2016; 2(2): CD011349. DOI:10.1002/14651858.CD011349.pub2
24.
TuranMTuranG. Overexpression of fractalkine and its histopathological characteristics in primary pterygium. Graefes Arch Clin Exp Ophthalmol2019; 257(12): 2743–2750. DOI:10.1007/s00417-019-04463-3
25.
CoroneoMTDi GirolamoNWakefieldD. The pathogenesis of pterygia. Curr Opin Ophthalmol1999; 10(4): 282–288. DOI:10.1097/00055735-199908000-00011
26.
ChenYYTsaiCFTsaiMC, et al. Inhibitory effects of rosmarinic acid on pterygium epithelial cells through redox imbalance and induction of extrinsic and intrinsic apoptosis. Exp Eye Res2017; 160: 96–105 DOI:10.1016/j.exer.2017.05.008
27.
JinZGMelaragnoMGLiaoDF, et al. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res2000; 87(9): 789–796. DOI:10.1161/01.res.87.9.789
28.
SatohKNigroPMatobaT, et al. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat Med2009; 15(6): 649–656. DOI:10.1038/nm.1958
29.
NardoGPozziSPignataroM, et al. Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells. PLoS One2011; 6(10): e25545. DOI:10.1371/journal.pone.0025545
30.
StemmyEJBentonASLernerJ, et al. Extracellular cyclophilin levels associate with parameters of asthma in phenotypic clusters. J Asthma2011; 48(10): 986–993. DOI:10.3109/02770903.2011.623334
31.
ZhouWPZhuYFZhangB, et al. The role of ultraviolet radiation in the pathogenesis of pterygia (review). Mol Med Rep2016; 14(1): 3–15. DOI:10.3892/mmr.2016.5223
32.
KheirkhahACasasVShehaH, et al. Role of conjunctival inflammation in surgical outcome after amniotic membrane transplantation with or without fibrin glue for pterygium. Cornea2008; 27(1): 56–63. DOI:10.1097/ICO.0b013e31815873da
33.
LiQVermaIM. NF-kB regulation in the immune system. Nat Rev Immunol2002; 2(10); 725–734. DOI:10.1038/nri910
34.
WangLJiaJWangC, et al. Inhibition of synovitis and joint destruction by a new single domain antibody specific for cyclophilin A in two different mouse models of rheumatoid arthritis. Arthritis Res Ther2013; 15(6): R208. DOI:10.1186/ar4401
35.
NigroPPompilioGCapogrossiMC. Cyclophilin A: a key player for human disease. Cell Death Dis2013; 31;4(10): e888. DOI:10.1038/cddis.2013.410
36.
WeidleUHScheuerWEggleD, et al. Cancer-related issues of CD147. Cancer Genom Proteom2010; 7(3): 157–169.
37.
ZhangQBaoNLiangK,et al.Adjuvant use of cyclosporine A in the treatment of primary pterygium: a systematic review and meta-analysis. Cornea2018; 37(8): 1000–1007. DOI:10.1097/ICO.0000000000001542
38.
MarcovichALMoradYSandbankJ, et al. Angiogenesis in pterygium: morphometric and immunohistochemical study. Curr Eye Res2002; 25(1): 17–22. DOI:10.1076/ceyr.25.1.17.9959
39.
LiangKJiangZZhaoB, et al. The expression of vascular endothelial growth factor in mast cells promotes the neovascularization of human pterygia. Br J Ophthalmol2012; 96(9): 1246–1251. DOI:10.1136/bjophthalmol-2012-301540
40.
KhalfaouiTMkannezGColinD, et al. Immunohistochemical analysis of vascular endothelial growth factor (VEGF) and p53 expression in pterygium from Tunisian patients. Pathol Biol (Paris)2011; 59(3): 137–141. DOI:10.1016/j.patbio.2009.04.006
41.
GalorAYooSHPiccoliFV,et al.Phase I study of subconjunctival ranibizumab in patients with primary pterygium undergoing pterygium surgery. Am J Ophthalmol2010; 149(6): 926–31e2. DOI: 10.1016/j.ajo.2010.01.015
