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Левицкая Г.В. Уровень фактора некроза опухоли α и фактора роста эндотелия сосудов у больных с разной степенью тяжести отслойки сетчатки
22.07.2014, 13:09

Резюме
Левицька Г.В. Рівень фактора некрозу пухлини α і фактора росту ендотелію судин у хворих з різним ступенем важкосі відшарування сітківки.
У хворих на регматогенне відшарування сітківки визначено рівень ФНП-α і ФРЕС в склоподібному тілі і віт реальній рідині з урахуванням важкості захворювання. Виявлено, що їх концентрація значно вище в вітреальній рідині, ніж у склоподібному тілі. Встановлено прямий достовірний кореляційний зв’язок високого і середнього ступеня між розпосюдженістю, висотою, тривалістю відшарування сітківки і рівнем визначених цитокінів як у склоподібному тілі, так і у вітреальній рідині. Крім того, визначена більш виразна активація досліджуваних цитокінів в склоподібному тілі порівняно з вітреальним вмістом при більш тяжкій вихідній клінічній характристиці захворювання.
Ключові слова: регматогенне відшарування сітківки, фактор некрозу пухлини α, фактор росту ендотелію судин, скловидне тіло, вітреальний вміст.

Резюме
Левицкая Г.В. Уровень фактора некроза опухоли α и фактора роста эндотелия сосудов у больных с разной степенью тяжести отслойки сетчатки.
У больных регматогенной отслойкой сетчатки определен уровень ФНО-α и ФРЭС  в стекловидном теле и витреальном содержимом с учетом тяжести заболевания. Выявлено, что их концентрация значительно выше в витреальном содержимом, чем в стекловидном теле. Установлена прямая достоверная корреляционная связь высокой и средней степени между протяженностью, высотой, длительностью отслойки сетчатки и уровнем определяемых цитокинов как в стекловидном теле, так и в витреальном содержимом. Кроме того, определена более выраженная активация исследуемых цитокинов в стекловидном теле по сравнению с витреальным содержимым при более тяжелой исходной клинической характеристике заболевания.
Ключевые слова: регматогенная отслойка сетчатки, фактор некроза опухоли α, фактор роста эндотелия сосудов, стекловидное тело, витреальное содержимое.

Summary
Levitska G.V. The level of tumor necrosis factor α and vascular endothelial growth factor in patients with different severity of rhegmatogenous retinal detachment.
Сytokines level was studied in patients with rhegmatogenous retinal detachment. In cases with PVR A tumor necrosis factor α level in vitreous was – 39,98 ± 21,95 pg/ml and - increased with increasing proliferation in 2 and 3.5 times in grades B and C. In vitreal contents it increased in PVR B – 1.4 times and PVR C –  2.5. Concentration of VEGF in vitreous was also increasing by enhancing PVR. Grade A to B – 1.7 times, PVR A to C – 2 times. In vitreal contents VEGF level in PVR B group was higher by 31.7% and in PVR C by 150% than in PVR A group. A direct strong correlation was found between cytokines level in the vitreous and vitreous contents and degree of PVR.
Key words: rhegmatogenous retinal detachment, proliferative vitreoretinopathy, tumor necrosis factor α , vascular endothelial growth factor, vitreous, vitreous contents.

Рецензент: д.мед.н., проф. А.М. Петруня

УДК 671.735–007.281-036-097-092.18

ГУ «Институт глазных болезней и тканевой терапии им. В.П. Филатова НАМН Украины» (Одесса)

SI “The Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine” (Odessa)

g.levytskaya@mail.ru

Background. Fundus pathology including treatment outcomes of rhegmatogenous retinal detachment in 2012 amounted 17.4% of primary vision disability in Ukraine. Absence of complete visual acuity recovery in positive results of surgical treatment, which can lead to restriction of working capacity determines the socio-economic importance of RRD.

According to this, it is actual to find out the basic pathogenesis of retinal detachment in order to correct metabolic violations. In scientific literature is presented considerable number of studies devoted to various aspects of the disease, however, most of them remain unanswered [12].

An important role in the mechanisms of pathological process in retinal detachment assign to primarily genetic, hemodynamic, mechanical and metabolic factors [10, 16]. Among them should be highlighted chain disorders leading to an imbalance of production of reactive oxygen species and eliminative ability of antioxidants that cause oxidative stress of neurons and chronic hypoxia, which is the cause of the systemic inflammatory reaction.

Neural retinal cells damaged by ischemia increase secretion of inflammatory cytokines with subsequent development of secondary local inflammation [6, 17].

Cytokines are protein or polypeptide products of activated immune cells that regulate the nature of the immune response [9]. Most cytokines act locally as paracrine or autocrine, to a lesser extent - distant as endocrine, taking part in all major local and systemic reactions which provide inflammation, reparation and angiogenesis [3].

It is revealed that proinflammatory cytokines concentration in structures and fluids of eye during different conditions and pathological states is much higher than the systemic level. That could indicate their synthesis in eye tissues and importance of local immune conflict [9].

Increased synthesis of growth factors is revealed in ischemic retina that can be considered as the main proliferation and neovascularization stimulus [13, 18].

The most important regulator of endothelial cell proliferation, vasculogenesis, vascular permeability and mediator of angiogenesis is vascular endothelial growth factor (VEGF) [4, 8, 14], which is released by endothelial, ganglional and glial cells, Müller cells, pigment epithelium, choroid and retinal pericytes both in normal and pathological conditions [7].

Angiogenic and fibroplastic retinal possibilities are also affected by tumour necrosis factor a (TNF-a), which is involved in development of the immune response causing proliferation of B and T lymphocytes and prevents the occurrence of immunological tolerance.

The basic features of TNFa action are cytotoxic (for tumor cells and cells infected by viruses), immunomodulatory and anti-inflammatory (activating macrophages, neutrophils, eosinophils and endothelial cells) and the metabolіzm influence. TNF a is synthesized by monocytes/macrophages, eosinophils, endothelial, mast and myeloid cells, glial cells in some cases - by activated T lymphocytes. As a result of the TNF a release capillary permeability increases, damages vascular endothelium, increases microvascular permeability which causes the activation of the hemostatic system and complement [15].

At the same time anti-inflammatory cytokines (which include TNFa and VEGF) activates the metabolism of connective tissue, stimulate the proliferation of fibroblasts and epithelial cells which is important to restore the integrity of damaged tissue [11].

Aim to identify the features of pro-inflammatory cytokine TNF-a and stimulator of VEGF neovascularization expression in the vitreous and vitreous fluid of patients with different RRD types.

Material and method. We observed 79 patients (79 eyes) with RRD (36 men, 43 women), aged 18 - 77 years. All patients underwent standard ophthalmologic examination (visometry, tonometry, refractometry, biomicroscopy, indirect ophthalmoscopy, b-scan, optical coherence tomography).

Retinal detachment extended up to 6 hours in 17 cases (21,5%), high detachment was in 37 eyes (47,%), in 7 patients (8,9%) detachment duration was  less than 10 days.

The TNF-a and VEGF cytokines level determined in vitreous (27 samples) and vitreous contents (60 samples) using ELISA test systems and instructions for use of reagents for the quantitative determination of human interleukins in biological fluids and tissue culture. It should be noted that amount of samples is more than the number of patients, because in eight cases both vitreous and vitreous content was taken.

Collection of vitreous for study performed during vitrectomy, vitreous contents during additional replacement of the gas tamponade in the postoperative period (1-2 days after surgery) [5].

Analysis of cytokines in the vitreous humor and vitreous content performed depending on the length, the height and duration of retinal detachment.

Statistical analysis of the data was performed using Statistica 6.0. For pairwise comparison of two groups parametric t-test with a preliminary estimate of normality was used, to determine the correlation - Spearman's rank correlation coefficient [2].

Results and discussion

Previously, we determined level (M ± SD) of TNF-a and VEGF in vitreous and vitreous contents in RRD patients, regardless to the clinical picture of the disease. These results showed that the content of TNF-a as well as VEGF are higher in vitreous contents (129,3 ± 61,03 pg / ml 1388,1 ± 401,5 pg / ml) than in vitreous (89.28 ± 43,54 pg / ml and 929,0 ± 351,8 pg / ml).

In this study, we analyzed the levels of cytokines according to severity of the pathological process.

In table 1 presented data describing these parameters in patients with varying length of retinal detachment. In all cases cytokines level was significantly higher for longer detachment. Thus, TNF- a level in vitreous body is 2.3 times higher in cases with more than 6 hours detachment length compared with up to 6 hours length group, in the vitreous contents - 1.7 times. VEGF content in eye with longer detachment is 1.9 times higher in vitreous and 1.3 times - in vitreous contents.

Data analysis corresponding to detachment height revealed a similar trend of changes in both parameters in vitreous and in vitreous content (Table 2). More pronounced differences observed in vitreous. TNF-a level in cases with high retinal detachment is 2.2 times higher in vitreous and 1.7 times in vitreous contents. VEGF level - 1.7 and 1.4 times respectively.

Patients with retinal detachment duration more than 10 days had significantly higher cytokine level concerning persons with fresh detachment (less than 10 days). These differences are for TNF a – 113,9% in the vitreous and 65.5% in the vitreous content and 149.6% and 29.2% respectively for VEGF (Table 3).

Determination of the Spearman rank correlation coefficient revealed a direct high and medium reliable correlation between the length, height, duration of retinal detachment and the cytokines level in the vitreous and in the vitreous contents (Table 4).

Identified patterns suggest a role of cytokines expression violations in the mechanisms of RRD development.

Table 1

Cytokine levels in patients with varying retinal detachment length (pg/ml)

 

RRD lenght

Stat. data

Vitreous

Vitreous contents

TNF a

VEGF

TNF a

VEGF

< 6 hour

n

7

7

13

13

М±SD

44,97±20,38

559,6±249,8

85,59±25,05

1138,0±271,3

 

> 6 hour

n

20

20

47

47

М±SD

104,8±38,56

1058,3±285,9

141,4±62,65

1457,2±406,2

p

0,0007

0,0004

0,003

0,010

 

Table 2

Cytokine levels in patients with different height of macular detachment (pg/ml)

RRD hight

Stat. data

Vitreous

Vitreous contents

TNF a

VEGF

TNF a

VEGF

 

Hight

n

14

14

27

27

М±SD

57,33±20,21

93,12±27,37

705,1±277,4

1123,1±265,1

 

Bullous

n

13

13

33

33

М±SD

123,7±34,52

158,9±65,20

1170,1±251,5

1604,8±364,0

p

0,000002

0,0001

0,000008

0,000000

 

Table 3

Cytokine levels in patients with different RRD durations (pg/ml)

RRD duration

Stat. data

Vitreous

Vitreous contents

TNF a

VEGF

TNF a

VEGF

< 10 days

n

3

3

6

6

М±SD

44,37±29,86

398,7±165,2

81,35±24,65

1099,0±283,2

> 10 days

n

24

24

54

54

М±SD

94,89±42,07

995,3±310,2

134,6±61,65

1420,2±401,7

p

0,056

0,003

0,042

0,063

Table 4

The rank correlation between the levels of cytokines and clinical characteristics of RRD

Clinical sign

Studied cytokines

Vitreous

Vitreous contents

n

r Spearman

p

n

r Spearman

p

RRD lenght

TNF a

27

0,705301

0,000040

60

0,392465

0,001925

VEGF

27

0,661898

0,000170

60

0,301353

0,019292

RRD hight

TNF a

27

0,846992

0,000000

60

0,518451

0,000022

VEGF

27

0,732791

0,000014

60

0,586151

0,000001

RRD duration

TNF a

27

0,393398

0,042344

60

0,290327

0,024432

VEGF

27

0,514443

0,006044

60

0,219747

0,091596

Conclusions

  1. TNF-a and VEGF level in the vitreous contents of RRD patients are 129,3 ± 61,03 pg/ml and 1388,1 ± 401,5 pg/ml, which is 1.5 times higher than the average values ​​of such parameters in the vitreous.
  2. Cytokines level were significantly higher in cases with RRD length more than 6 hours as compared to detachment up to 6 hours: TNF a in the vitreous body – 2.3 times, vitreous contents – 1.7 times; VEGF - 1.9 and 1.3 times - accordingly.
  3. In cases with bullous RRD cytokine levels were significantly higher comparing to high: TNFa in the vitreous – 2.2 times and in vitreous contents – 1.7 times and 1,7 and 1,4 times for VEGF respectively.
  4. In patients with RRD duration more than 10 days cytokines concentration was significantly increased relative to patients with less than 10 days detachment: TNF a 113,9% in the vitreous and 65.5% in the vitreous contents, 149.6 and 29.2% for VEGF – respectively.

Литература

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