重组人血管抑素对碱烧伤角膜新生血管作用的实验研究
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摘要
背景与目的
眼碱烧伤是严重的致盲性眼病,碱烧伤后角膜新生血管(corneal neovascularization,CNV)形成是导致视力下降的主要原因。其病理过程复杂,涉及诸多因素,确切的发病机理尚未完全阐明。CNV的治疗方法较多,但目前的治疗效果仍不太理想,因此研究CNV发病机制和探讨有效的治疗措施,将对防治CNV、防盲、治盲都具有极其重要的现实意义。
重组人血管抑素(angiostatin,AS)是近年来发现的血纤溶酶原的裂解片段,其前3个Kringle片段(Kringle 1-3,K1-3)对新生血管有较强的抑制作用,但作用机理尚未完全阐明,亦尚未见其对碱烧伤CNV中炎症细胞浸润、成纤维细胞及IL-1α表达影响的报道。本课题从建立角膜碱烧伤CNV模型着手,探讨AS对碱烧伤CNV的作用,利用免疫组化、ELISA和大鼠白细胞耗竭模型,探讨炎症细胞浸润、白细胞介素-1α(interleukin-1α,IL-1α)以及血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)等在AS对碱烧伤CNV抑制作用中的作用机制。
材料与方法
1、30只SD大鼠制作左眼碱烧伤CNV模型,碱烧伤后观察角膜及新生血管动态生长情况,于碱烧伤后6h、1、3、7、14、21天随机取5只大鼠处死,取角膜行组织病理学检查了解碱烧伤后角膜组织学变化及炎症细胞浸润情况,探索合适的CNV模型。
2、重组人血管抑素K1-3:灭菌生理盐水无菌操作配制成10μg/ml、20μg/ml滴眼液,4℃冰箱保存备用。
3、105只SD大鼠随机取5只作正常对照(不作任何处理,取角膜作正常对照),其余100只制作左眼碱烧伤CNV模型,随机分为4组(每组25只):实验对照组、地塞米松组、K1组、K2组,分别点生理盐水、0.1%地塞米松眼液和10μg/ml、20μg/ml的K1-3滴眼液;于碱烧伤后1、3、7、14、21天每组随机取5只大鼠,测量CNV长度,计算CNV面积,分析K1-3眼液对CNV的作用。随后处死大鼠,取角膜备组织病理学检查、电镜检查、免疫组化和ELISA检测。
3、角膜切片HE染色,观察角膜组织学变化,各组碱烧伤后不同时间炎症细胞计数,比较各组角膜组织变化及炎症细胞浸润情况。
4、电镜观察碱烧伤后K1-3治疗组与对照组角膜超微结构改变。
5、制作大鼠白细胞耗竭模型,角膜碱烧伤,观察白细胞耗竭后角膜炎症细胞浸润及CNV生长情况,分析白细胞在碱烧伤角膜炎症反应及CNV形成中的作用及K1-3对碱烧伤角膜CNV及炎症细胞浸润的作用。
6、免疫组化检测4组碱烧伤后不同时间角膜VEGF表达,病理图像分析仪测量平均光密度值(optical density,OD)。CD34标记新生血管,检测各组角膜新生血管密度(microvessel density,MVD)。分析K1-3对碱烧伤角膜VEGF表达及MVD的影响。
7、ELISA检测各组角膜IL-1α表达,分析K1-3对碱烧伤角膜IL-1α表达的影响。
结果
1、成功建立碱烧伤CNV模型,大鼠角膜碱烧伤40s,为较理想的时间。
2、碱烧伤后3天对照组出现CNV,碱烧伤后7天生长旺盛,14天达高峰,布满角膜,21天略消退,但仍占据大部分角膜;K1-3治疗组碱烧伤后3天未见明显CNV,7天仅达碱烧伤斑边缘,14天仅少量CNV长至瞳孔区,21天消退明显。各时间点K1-3治疗组CNV面积及MVD均较对照组减少(P<0.05),表明AS对碱烧伤CNV有明显的抑制作用。
3、碱烧伤后1-3天,对照组角膜切片中可见大量炎症细胞浸润(主要是中性粒细胞),7-14天时炎症细胞仍较多,21天时炎症细胞减少;碱烧伤后1、3、7、14天,K1组、K2组、地塞米松组角膜中炎症细胞浸润较对照组少(P<0.05),K2组较K1组和地塞米松组少(P<0.05)。21天时地塞米松组炎症细胞较K1-3治疗组增多(P<0.05)。提示局部浸润的炎症细胞在角膜碱烧伤CNV形成过程中起重要作用;AS可通过抑制炎症细胞浸润而抑制CNV,其效果优于地塞米松。
4、角膜组织切片显示,碱烧伤后21天,对照组角膜中央混浊,K1-3治疗组角膜较透明。电镜超微结构显示,碱烧伤后对照组角膜上皮基底膜连接松散,前弹力膜和基质层间半桥粒数量减少,细胞间隙变宽。基质胶原纤维排列紊乱,成纤维细胞增大,细胞内线粒体、粗面内质网增多;K1-3治疗组角膜损伤较对照组轻,细胞间连接较对照组紧密,基质层胶原纤维排列相对整齐,成纤维细胞形态及结构变化不明显。显示AS可抑制角膜成纤维细胞过度增生,抑制角膜瘢痕形成。
5、大鼠灌服环磷酰胺3天后外周血白细胞总数及淋巴细胞、中性粒细胞数均明显下降(P<0.05);白细胞耗竭鼠角膜碱烧伤,发现角膜中浸润的炎症细胞及CNV面积较对照组减少(P<0.05)。
6、正常角膜中VEGF无表达或仅在上皮层有微弱表达,碱烧伤后4组角膜VEGF表达上升,1周左右达高峰,主要表达于新生血管内皮细胞及浸润的炎症细胞内,碱烧伤后各时间点K1-3治疗组VEGF表达及OD值均明显低于对照组(P<0.05)。提示AS可降低碱烧伤角膜VEGF表达,从而抑制CNV。
7、IL-1α在正常角膜中有少量表达,碱烧伤后4组IL-1α表达均明显升高,3天时达高峰,7天后开始回落,21天回落至正常水平。碱烧伤后各时间点K1-3治疗组IL-1α表达均明显低于对照组(P<0.05),表明AS可降低IL-1α表达,从而抑制CNV。
结论
1、角膜碱烧伤40s是一种简单方便的CNV模型,可成功诱导CNV,且无严重并发症。
2、重组人血管抑素K1-3可抑制碱烧伤CNV形成、减轻炎症反应、促进角膜愈合,作用呈剂量依赖性。
3、重组人血管抑素K1-3抑制碱烧伤CNV形成的作用机制可能是通过抑制角膜IL-1α、VEGF的表达及抑制炎症细胞浸润实现的。
4、重组人血管抑素K1-3可抑制成纤维细胞的过度激活,抑制瘢痕形成,减轻角膜混浊。
5、电镜超微结构显示K1-3治疗CNV未见角膜细胞损伤,对角膜无毒副作用,提示K1-3可能成为临床治疗CNV的一个新途径。
Background and Objective
Alkali injury of the eye is a serious blinding disease. Corneal neovascularization (CNV) after alkali burn is the major cause that influences the vision. The blindness cause by CNV becomes a prominent problem in our country. Multiple factors take part in the complex process of CNV formation. The exact mechanism of CNV is unknown. There isn’t ideal medical treatment of CNV though there are many therapies. Investigate the mechanism and the antiangiogenic drug is extremely important.
Recombinant human angiostatin is a kringle-containing fragment of plasminogen. The kringle1-3(K1-3) is a potent inhibitor of angiogenesis in vivo. The antiangiogenic mechanism of K1-3 is unknown. The previous study about AS was focus on the antiangiogenic effect of tumor angiogenesis and the inhibition of vascular endothelial cells. There are no publications of K1-3 eye drops on CNV and corneal inflammatory cells and the expression of IL-1αin rat after alkali burn. Leukocyte depletion rat models were established to investigate the effect of leukocyte on CNV induced by alkali burn. Rat CNV models were established to investigate the anti-angiogenenesis effect of K1-3 eye drops on CNV and the effect on the expression of IL-1αand VEGF.
Materials and Methods
1. 30 SD rats were burned on central cornea of left eye by 1mol/L NaOH for 40s to observe the change of cornea and the development of CNV after alkali burn. Five rats were killed randomly at 6th hour(6h)、1、3、7、14、21day(d) after alkali burn. The corneas were taken for histopathological examinations.
2. 105 SD rats were devided into five groups at ramdon, five for normal control (the rats were sacrificed and corneas were taken for control before the experiment). 100 rats for experiment (four groups, 25 rats each group) were burned on the central cornea of left eye by 1mol/L NaOH for 40s. saline to the control group , dexamethasone eye drops to dexamethasone group , K1-3 eye drops with different concentrations to group K1、K2. The eye drops were applied four times daily. Observe the cornea and CNV by ophthalmic surgical microscope, calculated the area of CNV on day 3、7、14、21. Then 5 rats of each group were killed randomly and the corneas were taken for histopathological、transmission electron microscop(eTEM)examinations、Immunohistochemistry and ELISA test.
3. The corneas were stained with hematoxylin and eosine and leukocytes were counted by microscope. Observe the cornea ultrastructure of group K2 and saline group by TEM.
4. Leukocyte depletion and CNV rat models were established to observe the occurrence and development of CNV after alkali burn. Compare the number of inflammatory cells and the area of CNV between leukocyte depletion group and control group, determine the effect of leukocyte in the development of CNV.
5. Test the expression of VEGF and IL-1αof cornea at different time after alkali burn between four groups. The average optical density and microvessel density of cornea were analyzed.
Result
1. CNV in rats is successful induced by 1mol/L NaOH for 40s. On 3rd day after alkali burn, short vessels at the edge of the cornea can be seen, on 7th、14th day the vessels become very dense, the vessels growth slower after that. There were leukocytes in the cornea 6h after alkali burn, the leukocytes increased on 1st day and at the top of peak on 3rd day after alkali burn, after three days, the leukocytes decreased.
2. Cornea ultrastructure: after alkali burn, the junction between the epithelial basement membrane and the stroma was loosed, the semidesmosomes decreased. The extracellular space was wider and the fibroblasts were larger than normal. Mitochondrions and rough endoplasmic reticulums were inceased in the control group. The damage of cornea in group K2 was lighter than that in control group.
3. On 1st、3rd、7th、14th day after alkali burn, the number of leukocytes in group K1、K2、dexamethasone was less than that in control group(P<0.05). On 21th day, no significant difference was found between K1、K2 group and control group(P>0.05). But the leukocytes in dexamethasone group were increased. The MVD and area of CNV in group K1、K2 was smaller than that in group control(P<0.05).
4. Significant difference(P<0.05)in the number of leukocytes、lymphocytes、neutrophils was found between cyclophosphamide group and control group. Area of CNV and the number of infiltrated inflammatory cells in the cyclophosphamide group were less than that in control group(P<0.05).
5. VEGF was expressed in the epithelial weakly, the expression increased after alkali burn, the expression of VEGF arrived it’s peak on 7th day. Significant difference(P<0.05)in the expression was found between K1-3 treated group and control group.
6. Little IL-1αcan be tested in normal cornea, the expression of IL-1α increased after alkali burn and arrived it’s peak on 3rd day , decreased on 7th day. Compared with control group, the expression of IL-1αdecreased significant(P<0.05)in K1-3 treated group.
Conclusion
1. Injury by 1mol/L NaOH for 40s is a simple and successful way to induced CNV. There is no severe complication take place in the cornea.
2. The inflammatory cells play an important role in the occurrence and development of CNV, exhaust the leukocytes in the peripheral blood of rats can significant suppress inflammatory cell infiltration and the development of CNV.
3. K1-3 can suppress inflammatory cell infiltration, inhibit inflammatory response, promote the healing of cornea and suppress the development of CNV in a dose-dependent manner.
4. The anti CNV mechanism of K1-3 is that it can suppress inflammatory cell infiltration and inhibit the expression of VEGF and IL-1α.
5. No toxicity was found in K1-3 treated cornea. K1-3 is hopeful to be applied in the future clinical therapy of CNV.
眼碱烧伤是严重的致盲性眼病,碱烧伤后角膜新生血管(corneal neovascularization,CNV)形成是导致视力下降的主要原因。其病理过程复杂,涉及诸多因素,确切的发病机理尚未完全阐明。CNV的治疗方法较多,但目前的治疗效果仍不太理想,因此研究CNV发病机制和探讨有效的治疗措施,将对防治CNV、防盲、治盲都具有极其重要的现实意义。
重组人血管抑素(angiostatin,AS)是近年来发现的血纤溶酶原的裂解片段,其前3个Kringle片段(Kringle 1-3,K1-3)对新生血管有较强的抑制作用,但作用机理尚未完全阐明,亦尚未见其对碱烧伤CNV中炎症细胞浸润、成纤维细胞及IL-1α表达影响的报道。本课题从建立角膜碱烧伤CNV模型着手,探讨AS对碱烧伤CNV的作用,利用免疫组化、ELISA和大鼠白细胞耗竭模型,探讨炎症细胞浸润、白细胞介素-1α(interleukin-1α,IL-1α)以及血管内皮细胞生长因子(vascular endothelial growth factor,VEGF)等在AS对碱烧伤CNV抑制作用中的作用机制。
材料与方法
1、30只SD大鼠制作左眼碱烧伤CNV模型,碱烧伤后观察角膜及新生血管动态生长情况,于碱烧伤后6h、1、3、7、14、21天随机取5只大鼠处死,取角膜行组织病理学检查了解碱烧伤后角膜组织学变化及炎症细胞浸润情况,探索合适的CNV模型。
2、重组人血管抑素K1-3:灭菌生理盐水无菌操作配制成10μg/ml、20μg/ml滴眼液,4℃冰箱保存备用。
3、105只SD大鼠随机取5只作正常对照(不作任何处理,取角膜作正常对照),其余100只制作左眼碱烧伤CNV模型,随机分为4组(每组25只):实验对照组、地塞米松组、K1组、K2组,分别点生理盐水、0.1%地塞米松眼液和10μg/ml、20μg/ml的K1-3滴眼液;于碱烧伤后1、3、7、14、21天每组随机取5只大鼠,测量CNV长度,计算CNV面积,分析K1-3眼液对CNV的作用。随后处死大鼠,取角膜备组织病理学检查、电镜检查、免疫组化和ELISA检测。
3、角膜切片HE染色,观察角膜组织学变化,各组碱烧伤后不同时间炎症细胞计数,比较各组角膜组织变化及炎症细胞浸润情况。
4、电镜观察碱烧伤后K1-3治疗组与对照组角膜超微结构改变。
5、制作大鼠白细胞耗竭模型,角膜碱烧伤,观察白细胞耗竭后角膜炎症细胞浸润及CNV生长情况,分析白细胞在碱烧伤角膜炎症反应及CNV形成中的作用及K1-3对碱烧伤角膜CNV及炎症细胞浸润的作用。
6、免疫组化检测4组碱烧伤后不同时间角膜VEGF表达,病理图像分析仪测量平均光密度值(optical density,OD)。CD34标记新生血管,检测各组角膜新生血管密度(microvessel density,MVD)。分析K1-3对碱烧伤角膜VEGF表达及MVD的影响。
7、ELISA检测各组角膜IL-1α表达,分析K1-3对碱烧伤角膜IL-1α表达的影响。
结果
1、成功建立碱烧伤CNV模型,大鼠角膜碱烧伤40s,为较理想的时间。
2、碱烧伤后3天对照组出现CNV,碱烧伤后7天生长旺盛,14天达高峰,布满角膜,21天略消退,但仍占据大部分角膜;K1-3治疗组碱烧伤后3天未见明显CNV,7天仅达碱烧伤斑边缘,14天仅少量CNV长至瞳孔区,21天消退明显。各时间点K1-3治疗组CNV面积及MVD均较对照组减少(P<0.05),表明AS对碱烧伤CNV有明显的抑制作用。
3、碱烧伤后1-3天,对照组角膜切片中可见大量炎症细胞浸润(主要是中性粒细胞),7-14天时炎症细胞仍较多,21天时炎症细胞减少;碱烧伤后1、3、7、14天,K1组、K2组、地塞米松组角膜中炎症细胞浸润较对照组少(P<0.05),K2组较K1组和地塞米松组少(P<0.05)。21天时地塞米松组炎症细胞较K1-3治疗组增多(P<0.05)。提示局部浸润的炎症细胞在角膜碱烧伤CNV形成过程中起重要作用;AS可通过抑制炎症细胞浸润而抑制CNV,其效果优于地塞米松。
4、角膜组织切片显示,碱烧伤后21天,对照组角膜中央混浊,K1-3治疗组角膜较透明。电镜超微结构显示,碱烧伤后对照组角膜上皮基底膜连接松散,前弹力膜和基质层间半桥粒数量减少,细胞间隙变宽。基质胶原纤维排列紊乱,成纤维细胞增大,细胞内线粒体、粗面内质网增多;K1-3治疗组角膜损伤较对照组轻,细胞间连接较对照组紧密,基质层胶原纤维排列相对整齐,成纤维细胞形态及结构变化不明显。显示AS可抑制角膜成纤维细胞过度增生,抑制角膜瘢痕形成。
5、大鼠灌服环磷酰胺3天后外周血白细胞总数及淋巴细胞、中性粒细胞数均明显下降(P<0.05);白细胞耗竭鼠角膜碱烧伤,发现角膜中浸润的炎症细胞及CNV面积较对照组减少(P<0.05)。
6、正常角膜中VEGF无表达或仅在上皮层有微弱表达,碱烧伤后4组角膜VEGF表达上升,1周左右达高峰,主要表达于新生血管内皮细胞及浸润的炎症细胞内,碱烧伤后各时间点K1-3治疗组VEGF表达及OD值均明显低于对照组(P<0.05)。提示AS可降低碱烧伤角膜VEGF表达,从而抑制CNV。
7、IL-1α在正常角膜中有少量表达,碱烧伤后4组IL-1α表达均明显升高,3天时达高峰,7天后开始回落,21天回落至正常水平。碱烧伤后各时间点K1-3治疗组IL-1α表达均明显低于对照组(P<0.05),表明AS可降低IL-1α表达,从而抑制CNV。
结论
1、角膜碱烧伤40s是一种简单方便的CNV模型,可成功诱导CNV,且无严重并发症。
2、重组人血管抑素K1-3可抑制碱烧伤CNV形成、减轻炎症反应、促进角膜愈合,作用呈剂量依赖性。
3、重组人血管抑素K1-3抑制碱烧伤CNV形成的作用机制可能是通过抑制角膜IL-1α、VEGF的表达及抑制炎症细胞浸润实现的。
4、重组人血管抑素K1-3可抑制成纤维细胞的过度激活,抑制瘢痕形成,减轻角膜混浊。
5、电镜超微结构显示K1-3治疗CNV未见角膜细胞损伤,对角膜无毒副作用,提示K1-3可能成为临床治疗CNV的一个新途径。
Background and Objective
Alkali injury of the eye is a serious blinding disease. Corneal neovascularization (CNV) after alkali burn is the major cause that influences the vision. The blindness cause by CNV becomes a prominent problem in our country. Multiple factors take part in the complex process of CNV formation. The exact mechanism of CNV is unknown. There isn’t ideal medical treatment of CNV though there are many therapies. Investigate the mechanism and the antiangiogenic drug is extremely important.
Recombinant human angiostatin is a kringle-containing fragment of plasminogen. The kringle1-3(K1-3) is a potent inhibitor of angiogenesis in vivo. The antiangiogenic mechanism of K1-3 is unknown. The previous study about AS was focus on the antiangiogenic effect of tumor angiogenesis and the inhibition of vascular endothelial cells. There are no publications of K1-3 eye drops on CNV and corneal inflammatory cells and the expression of IL-1αin rat after alkali burn. Leukocyte depletion rat models were established to investigate the effect of leukocyte on CNV induced by alkali burn. Rat CNV models were established to investigate the anti-angiogenenesis effect of K1-3 eye drops on CNV and the effect on the expression of IL-1αand VEGF.
Materials and Methods
1. 30 SD rats were burned on central cornea of left eye by 1mol/L NaOH for 40s to observe the change of cornea and the development of CNV after alkali burn. Five rats were killed randomly at 6th hour(6h)、1、3、7、14、21day(d) after alkali burn. The corneas were taken for histopathological examinations.
2. 105 SD rats were devided into five groups at ramdon, five for normal control (the rats were sacrificed and corneas were taken for control before the experiment). 100 rats for experiment (four groups, 25 rats each group) were burned on the central cornea of left eye by 1mol/L NaOH for 40s. saline to the control group , dexamethasone eye drops to dexamethasone group , K1-3 eye drops with different concentrations to group K1、K2. The eye drops were applied four times daily. Observe the cornea and CNV by ophthalmic surgical microscope, calculated the area of CNV on day 3、7、14、21. Then 5 rats of each group were killed randomly and the corneas were taken for histopathological、transmission electron microscop(eTEM)examinations、Immunohistochemistry and ELISA test.
3. The corneas were stained with hematoxylin and eosine and leukocytes were counted by microscope. Observe the cornea ultrastructure of group K2 and saline group by TEM.
4. Leukocyte depletion and CNV rat models were established to observe the occurrence and development of CNV after alkali burn. Compare the number of inflammatory cells and the area of CNV between leukocyte depletion group and control group, determine the effect of leukocyte in the development of CNV.
5. Test the expression of VEGF and IL-1αof cornea at different time after alkali burn between four groups. The average optical density and microvessel density of cornea were analyzed.
Result
1. CNV in rats is successful induced by 1mol/L NaOH for 40s. On 3rd day after alkali burn, short vessels at the edge of the cornea can be seen, on 7th、14th day the vessels become very dense, the vessels growth slower after that. There were leukocytes in the cornea 6h after alkali burn, the leukocytes increased on 1st day and at the top of peak on 3rd day after alkali burn, after three days, the leukocytes decreased.
2. Cornea ultrastructure: after alkali burn, the junction between the epithelial basement membrane and the stroma was loosed, the semidesmosomes decreased. The extracellular space was wider and the fibroblasts were larger than normal. Mitochondrions and rough endoplasmic reticulums were inceased in the control group. The damage of cornea in group K2 was lighter than that in control group.
3. On 1st、3rd、7th、14th day after alkali burn, the number of leukocytes in group K1、K2、dexamethasone was less than that in control group(P<0.05). On 21th day, no significant difference was found between K1、K2 group and control group(P>0.05). But the leukocytes in dexamethasone group were increased. The MVD and area of CNV in group K1、K2 was smaller than that in group control(P<0.05).
4. Significant difference(P<0.05)in the number of leukocytes、lymphocytes、neutrophils was found between cyclophosphamide group and control group. Area of CNV and the number of infiltrated inflammatory cells in the cyclophosphamide group were less than that in control group(P<0.05).
5. VEGF was expressed in the epithelial weakly, the expression increased after alkali burn, the expression of VEGF arrived it’s peak on 7th day. Significant difference(P<0.05)in the expression was found between K1-3 treated group and control group.
6. Little IL-1αcan be tested in normal cornea, the expression of IL-1α increased after alkali burn and arrived it’s peak on 3rd day , decreased on 7th day. Compared with control group, the expression of IL-1αdecreased significant(P<0.05)in K1-3 treated group.
Conclusion
1. Injury by 1mol/L NaOH for 40s is a simple and successful way to induced CNV. There is no severe complication take place in the cornea.
2. The inflammatory cells play an important role in the occurrence and development of CNV, exhaust the leukocytes in the peripheral blood of rats can significant suppress inflammatory cell infiltration and the development of CNV.
3. K1-3 can suppress inflammatory cell infiltration, inhibit inflammatory response, promote the healing of cornea and suppress the development of CNV in a dose-dependent manner.
4. The anti CNV mechanism of K1-3 is that it can suppress inflammatory cell infiltration and inhibit the expression of VEGF and IL-1α.
5. No toxicity was found in K1-3 treated cornea. K1-3 is hopeful to be applied in the future clinical therapy of CNV.
引文
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2. Azar DT. Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc, 2006; 104:264-302.
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4. Edelman JL, Castro MR, Wen Y. Correlation of VEGF expression by leukocytes with the growth and regression of blood vessels in the rat cornea. Invest Ophthalmol Vis Sci, 1999; 40(6):1112-23.
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6. Jackson JR, Seed MP, Kircher CH, et al. The codependence of angiogenesis and chronic inflammation. Faseb J, 1997; 11(6):457-65.
7. Riazi-Esfahani M, Peyman GA, Aydin E, et al. Prevention of corneal neovascularization: evaluation of various commercially available compounds in an experimental rat model. Cornea, 2006; 25(7):801-5.
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18. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood, 1996; 87(6):2095-147.
19. Lu Y, Fukuda K, Liu Y, et al. Dexamethasone inhibition of IL-1-induced collagen degradation by corneal fibroblasts in three-dimensional culture. Invest Ophthalmol Vis Sci, 2004; 45(9):2998-3004.
20. Keadle TL, Usui N, Laycock KA, et al. IL-1 and TNF-alpha are important factors in the pathogenesis of murine recurrent herpetic stromal keratitis.Invest Ophthalmol Vis Sci, 2000; 41(1):96-102.
21. Rudner XL, Kernacki KA, Barrett RP, et al. Prolonged elevation of IL-1 in Pseudomonas aeruginosa ocular infection regulates macrophage-inflammatory protein-2 production, polymorphonuclear neutrophil persistence, and corneal perforation. J Immunol, 2000; 164(12):6576-82.
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