**3. Regional mediatory hormonal mechanisms of impaired eye drainage function at primary open-angle and pseudoexfoliative glaucomas (Results of own research investigation)**

It is rather difficult to interpret issues relevant to pathogenesis of primary open-angle glauco‐ ma, as this type malady is frequently associated with cataract and pseudoexfoliative syndrome.

In particular, according to D.S. Krol (1968; 1970), among the randomly selected contingent the pseudoexfoliative syndrome was observed in 6.2% subjects above 50, in 24% patients with senile cataract and in 47% patients with open-angle glaucoma. P.P. Frolova and G.Kh. Khamitova (1984) provided similar data, according to which pseudoexfoliative syndrome was diagnosed in 5.8% examined persons above 40. Furthermore, the higher the age, the more frequent was pseudoexfoliative syndrome encountered: at the age of 40-48 years old in 1% patients, at 50-59 – in 6.4%, at 60-69 – in 12.5%, above 70 – in 36.8%. It is especially important that among persons with pseudoexfoliative syndrome glaucoma was diagnosed in 35% cases, while cataracts made 69%.

According to clinical observations of A.P. Nesterov (2008) in persons with the pseudoexfolia‐ tive syndrome glaucoma originates 20 time more often than in the general population of the same age group. According to the author, approximately in 50% patients with open-angle glaucoma symptoms of pseudoexfoliative syndrome are revealed. The type of glaucoma associated with the pseudoexfoliative syndrome is called "pseudoexfoliative glaucoma".

Nowadays, amongst the mechanisms of cataract induction and course, an importance is attributed to local immunepathological disorders, which all in all are defined as "anterior chamber associated immune deviation (ACAID) [*Wilbanks G., Streilein J., 1990; Streilein J. et al., 1992; Abrahamian A. et al., 1995; Muhaya M. et al., 1999; Fleenor D. et al., 2006*].

In pathogenesis of the primary open-angle glaucoma the specific gravity of regional immu‐ nepathological disorders, which are pathognomonic for cataracts, are open for a special discussion, because data of available scientific publications are scarce, fragmentary, sometimes contradictory and inconsistent.

At the same time, to our mind, it is rather expedient to perform studies at which in case of complicated cataracts associated with glaucoma and pseudoexfoliative syndrome the subject matter would be the entire specter of biologically active substances produced in eye mem‐ branes, which were earlier considered by us as pathogenetic factors of open-angle glaucoma. Such scientific and methodical approach is rather substantiated, as it will allow to answer the question: to what extent the processes of impaired synthesis of fibronectin, IGF-1, PgE2 and cortisol in eye membranes are engaged in mechanisms of primary open-angle glaucoma, namely: in pathogenesis of impaired drainage function and increase of intraocular pressure.

Under our observation there were 960 patients with the senile and complicated cataracts operated at "Shengavit" Medical Center within a period of 2008-2012. The degree of lens opacity was assessed according to Emery colorimetric classification and generally accepted classification of cataracts proposed by Buratto. Undoubtedly, the state of lens capsule, folding, presence of elements of fibrous filaments, pseudoexfoliative deposits on the anterior surface of the capsule, lens subluxation to some degree, were taken into consideration together with classification of phakodonesis suggested by Pashtaev. Actual expressiveness of the pseudoex‐ foliative syndrome was considered based on the classification proposed by Yeroshevskaya.

All operated patents were divided into three groups.

more efficient engraftment. Moreover, the terms of engraftment correlated with the low

A. Southren et al. (1979) performed experiments in rabbits and revealed endoplasmatic reception of glucocorticoids in corneal cells and the ciliary body. Translocation of cortisol from the surface of the cell nucleus occurred within 30 minutes after injection. As to authors, this

It is important to note the following phenomenon as well. Similar translocation was not observed when experimental animals were administered testosterone, estradiol and proges‐ terone. At the same time, different membranes and liquid media of the eye possess different ability of affinity to glucocorticoids and their realization (accumulation and excretion).

In 1977, B. Kasavina et al. (1977) studied cortisol distribution in sclera, ciliary body, cornea, iris, lens capsule, vitreous body and the aqueous humour. Radionuclide methods of investi‐ gation allowed to reveal that tissues and media of the eye have different intensity of cortisol absorption and excretion. According to authors, the sclera, ciliary body, and lens capsule

**3. Regional mediatory hormonal mechanisms of impaired eye drainage function at primary open-angle and pseudoexfoliative glaucomas (Results**

It is rather difficult to interpret issues relevant to pathogenesis of primary open-angle glauco‐ ma, as this type malady is frequently associated with cataract and pseudoexfoliative syndrome.

In particular, according to D.S. Krol (1968; 1970), among the randomly selected contingent the pseudoexfoliative syndrome was observed in 6.2% subjects above 50, in 24% patients with senile cataract and in 47% patients with open-angle glaucoma. P.P. Frolova and G.Kh. Khamitova (1984) provided similar data, according to which pseudoexfoliative syndrome was diagnosed in 5.8% examined persons above 40. Furthermore, the higher the age, the more frequent was pseudoexfoliative syndrome encountered: at the age of 40-48 years old in 1% patients, at 50-59 – in 6.4%, at 60-69 – in 12.5%, above 70 – in 36.8%. It is especially important that among persons with pseudoexfoliative syndrome glaucoma was diagnosed in 35% cases,

According to clinical observations of A.P. Nesterov (2008) in persons with the pseudoexfolia‐ tive syndrome glaucoma originates 20 time more often than in the general population of the same age group. According to the author, approximately in 50% patients with open-angle glaucoma symptoms of pseudoexfoliative syndrome are revealed. The type of glaucoma associated with the pseudoexfoliative syndrome is called "pseudoexfoliative glaucoma".

Nowadays, amongst the mechanisms of cataract induction and course, an importance is attributed to local immunepathological disorders, which all in all are defined as "anterior

mechanism is a stereotype for glucocorticoids towards other sensitive tissues.

expression of cytokines, especially IL-I [*Pleyer U. et al., 2005*].

served as target tissues for cortisol.

84 Glaucoma - Basic and Clinical Aspects

**of own research investigation)**

while cataracts made 69%.

The studied groups of patients involved civil contingent: residents of Yerevan and different provinces (marzes) of Armenia; age range was from 40 to 82 years.

The first group included patients with senile cataract. The second group was made up of patients with the complicated cataract on the background of existing anterior open-angle glaucoma, with initial and developed stages of the glaucomatous process. The third group involved patients with complicated cataract on the background of existing pseudoexfoliative glaucoma and pseudoexfoliative syndrome.

The analyses were performed using the main clinical laboratory methods accepted in oph‐ thalmology.

Irrespective of the cataract degree and stage, all patients underwent microaxial Phacoemulsi‐ fication ‒ Microincision Cataract Surgery (MICS) through 2.2 *mm* incision with implantation of posterior chamber intraocular lens. Intra-chamber administration of antibiotics was not applied in these groups.

The methodical procedure of extracting aqueous humour was used intra-operatively under conditions of sterility. The corneocentis was done by insulin syringe through the limb; 0.1-0.2 *ml* aqueous humour was extracted. The fluid remained in a syringe until laboratory research was performed immediately after delivery of the material to the Scientific-Research Center of the Yerevan State Medical University after M. Heratsi.

cataract was observed on the background of pseudoexfoliative glaucoma (study group III) the highest indices of fibronectin were determined in the aqueous humour; these indices were 3.0

Modern Aspects of Glaucoma Pathogenesis Local Factors for Development of Primary Open-Angle Glaucoma…

A similar regularity was traced upon revealing shifts in PgE2 and IGF-1 content in aqueous humour of patients in study groups I and II. Thus, the level of PgE2 in aqueous humour of the study group II patients 1.5 times exceeded PgE2 level in aqueous humour of the study group I patients. In study group III PgE2 high levels were also determined (compared to the study group I), being similar to those revealed in aqueous humour of the study group II patients. As obvious from the Table, in the aqueous humour of patients in study groups II and III we recorded approximately the same IGF-1 indices, which exceeded similar values in aqueous

Table 2 presents the results of immune enzyme assay for determination of cortisol in the

I 12.90±0.64 56.90±4.15

23.38±1.46 р<0.0005

30.4±1.56 р<0.0005

**Table 2.** Cortisol content in blood serum and aqueous humour of patients with the senile and complicated cataracts

As obvious from Table 2, in patients of study group II the level of cortisol in aqueous humour markedly increased (as compared to hormone levels determined in aqueous humour of patients with the senile cataract – control group). Thus, the level of cortisol in aqueous humour of patients with cataract on the background of primary open-angle glaucoma was 1.8 times higher compared to norm. The highest indices of cortisol were observed in aqueous humour of patients of the study group III. In particular, cortisol levels in aqueous humour of patients with the senile cataract on the background of primary open-angle glaucoma and pseudoexfo‐ liative glaucoma increased 2.3 times. The results of immune enzyme assays performed on aqueous humour were compared with cortisol levels in blood serum of the same cohort of patients. As demonstrated by the research findings, the level of cortisol in blood serum of patients of all the 3 study groups was almost similar and within the range of cortisol deter‐ mined in actually healthy subjects. This latter, though indirectly, signifies in favour of the local synthesis of cortisol in the eye membranes, the cells of which apart from their main functions

**Studied indices Aqueous humour Blood serum**

> 64.84±7.28 0.1<р<0.25

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87

50.70±6.91 0.1<р<0.25

and 1.6 times higher compared to those in patients of groups I and II, appropriately.

humour of study group I patients 2.27 and 2.36 times, correspondingly.

aqueous humour of patients with senile and complicated cataracts.

Note: p – indices of complicated cataracts as related to indices of senile cataracts.

ensure processes of *in situ* cortisol secretion as well.

**Study groups of patients**

II

III

All the operated patients were under intense observation and got the appropriate postoperative treatment and medical rehabilitation. We observed the patients in the early postoperative period.

Unfortunately, rather low amounts of isolated aqueous humour (0.1-0.2 *ml*) for immune enzyme assays and ion-selective analyses due to objective reasons, do not allow us simulta‐ neously (in one and the same sample) determine two parameters of studied biological active compounds. Inclusion of a relatively high number of operated patients (by 320 persons) in each study group is connected with the mentioned circumstance. Thereby, in all the three study groups by 40 samples of aqueous humour and blood serum were allocated for each test.

The content of fibronectin, IGF-1, PgE2 and cortisol in aqueous humour was determined with the use of appropriate kits (DRG-International Inc., USA). The immune enzyme assay was performed on the automatic spectrophotometer "Stat-Fax 3200" (USA) in the absorbance wavelength range 420-450 *nm*.

Determination of potassium, sodium and calcium ions was done according to ion-selective method of analysis with use of Kone-microlyte analyzer (Finland).

The obtained results were exposed to statistical analysis using Student's criteria and applica‐ tion of SPSS-13 programme (one Sample T-Test and Paired Sample T-Test).

The results of immune enzyme assay for fibronectin, IGF-1, and PgE2 in aqueous humour of patients with the senile and complicated cataracts are presented in Table 1.


Notes: p1 –indices of groups II and III compared to indices of the study group I; p2 – indices of group II compared to indices of the study group III.

**Table 1.** Fibronectin, IGF-1, and PgE2 content in aqueous humour of patients with the senile and complicated cataracts

As obvious from the Table, in patients with cataracts on the background of primary open-0an‐ gle glaucoma (study group II) the level of fibronectin in aqueous humour 1.8 times exceeded analogous level in aqueous humour of patients with senile cataracts. In those cases when cataract was observed on the background of pseudoexfoliative glaucoma (study group III) the highest indices of fibronectin were determined in the aqueous humour; these indices were 3.0 and 1.6 times higher compared to those in patients of groups I and II, appropriately.

was performed immediately after delivery of the material to the Scientific-Research Center of

All the operated patients were under intense observation and got the appropriate postoperative treatment and medical rehabilitation. We observed the patients in the early post-

Unfortunately, rather low amounts of isolated aqueous humour (0.1-0.2 *ml*) for immune enzyme assays and ion-selective analyses due to objective reasons, do not allow us simulta‐ neously (in one and the same sample) determine two parameters of studied biological active compounds. Inclusion of a relatively high number of operated patients (by 320 persons) in each study group is connected with the mentioned circumstance. Thereby, in all the three study groups by 40 samples of aqueous humour and blood serum were allocated for each test.

The content of fibronectin, IGF-1, PgE2 and cortisol in aqueous humour was determined with the use of appropriate kits (DRG-International Inc., USA). The immune enzyme assay was performed on the automatic spectrophotometer "Stat-Fax 3200" (USA) in the absorbance

Determination of potassium, sodium and calcium ions was done according to ion-selective

The obtained results were exposed to statistical analysis using Student's criteria and applica‐

The results of immune enzyme assay for fibronectin, IGF-1, and PgE2 in aqueous humour of

Notes: p1 –indices of groups II and III compared to indices of the study group I; p2 – indices of group II compared to indices

As obvious from the Table, in patients with cataracts on the background of primary open-0an‐ gle glaucoma (study group II) the level of fibronectin in aqueous humour 1.8 times exceeded analogous level in aqueous humour of patients with senile cataracts. In those cases when

**Table 1.** Fibronectin, IGF-1, and PgE2 content in aqueous humour of patients with the senile and complicated

I 11.26±0.99 1.10±0.18 43.05±4.13

**Studied indices Fibronectin (ng/ml) IGF-1 (ng/ml) PgE2 (pg/ml)**

> 2.50±0.46 0.0005<p1<0.005

> 2.60±0.39 0.0005<p1<0.005 p2"/>0.4

66.11±7.40 0.0005<p1<0.005

> 76.64±7.78 p1<0.0005 0.10<p2<0.25

method of analysis with use of Kone-microlyte analyzer (Finland).

tion of SPSS-13 programme (one Sample T-Test and Paired Sample T-Test).

patients with the senile and complicated cataracts are presented in Table 1.

20.71±2.37 p1<0.0005

33.83±5.97 p1<0.0005 0.025<p2<0.05

the Yerevan State Medical University after M. Heratsi.

operative period.

86 Glaucoma - Basic and Clinical Aspects

wavelength range 420-450 *nm*.

**Study groups of patients**

II

III

of the study group III.

cataracts

A similar regularity was traced upon revealing shifts in PgE2 and IGF-1 content in aqueous humour of patients in study groups I and II. Thus, the level of PgE2 in aqueous humour of the study group II patients 1.5 times exceeded PgE2 level in aqueous humour of the study group I patients. In study group III PgE2 high levels were also determined (compared to the study group I), being similar to those revealed in aqueous humour of the study group II patients. As obvious from the Table, in the aqueous humour of patients in study groups II and III we recorded approximately the same IGF-1 indices, which exceeded similar values in aqueous humour of study group I patients 2.27 and 2.36 times, correspondingly.

Table 2 presents the results of immune enzyme assay for determination of cortisol in the aqueous humour of patients with senile and complicated cataracts.


**Table 2.** Cortisol content in blood serum and aqueous humour of patients with the senile and complicated cataracts

As obvious from Table 2, in patients of study group II the level of cortisol in aqueous humour markedly increased (as compared to hormone levels determined in aqueous humour of patients with the senile cataract – control group). Thus, the level of cortisol in aqueous humour of patients with cataract on the background of primary open-angle glaucoma was 1.8 times higher compared to norm. The highest indices of cortisol were observed in aqueous humour of patients of the study group III. In particular, cortisol levels in aqueous humour of patients with the senile cataract on the background of primary open-angle glaucoma and pseudoexfo‐ liative glaucoma increased 2.3 times. The results of immune enzyme assays performed on aqueous humour were compared with cortisol levels in blood serum of the same cohort of patients. As demonstrated by the research findings, the level of cortisol in blood serum of patients of all the 3 study groups was almost similar and within the range of cortisol deter‐ mined in actually healthy subjects. This latter, though indirectly, signifies in favour of the local synthesis of cortisol in the eye membranes, the cells of which apart from their main functions ensure processes of *in situ* cortisol secretion as well.

The next stage of our investigation involved biochemical analysis with the use of ion-selective method aimed to determine ions of sodium, potassium and calcium in the aqueous humour of patients with senile and complicated cataracts.

biological effects realized at the level of inter-cellular relations in different cell populations of

Modern Aspects of Glaucoma Pathogenesis Local Factors for Development of Primary Open-Angle Glaucoma…

http://dx.doi.org/10.5772/55037

89

In line with this, first of all, we considered the essential role that is related to the biological activity of TGF2 produced in cornea and trabecular meshwork of an eye in mechanisms of inter-

It is considered to be generally accepted that in case of senile and complicated cataracts processes of TGFβ-2 synthesis are markedly intensified in the cornea and trabecular meshwork [*de Iongh R.U. et al., 2005; Stefan C. et al., 2008; Dawes L.J. et al., 2009; Pattabiraman P.P., Rao P.V., 2010*]. Therefore, we cannot exclude that relatively high levels of fibronectin and IGF-1 in the aqueous humour of patients with complicated cataracts are resulting from a direct stimulating influence of TGFβ-2 to cell populations localized in the cornea and trabecular meshwork of the

The proposed statement, to a known extent, is also confirmed by the available literature data relevant to the biological activity of TGFβ-2 – in the aspect of its selective modulatory impact to the processes of fibronectin and PgE2 synthesis and secretion in the eye membranes.

As known, keratocytes of the cornea and trabecular meshwork cells of the eye serve as the main sources of fibronectin synthesis *in situ*, i.e. in the eye tissues. Dose-dependent stimulant effect of TGFβ-2 to processes of fibronectin synthesis was established [*Wordinger R. et al., 2007; Hindman H. et al., 2010; Karamichos D. et al., 2010*] under the conditions of mentioned cells cultivation. Moreover, according to [*Stefan C. et al., 2008*], TGFβ-2 produced in eye membranes should be considered as a "special" cytokine that under conditions of the eye barrier functions disturbance might increase fibronectin concentration in cells of trabecular meshwork of the

The IGF-1 elevated level revealed in aqueous humour of patients with the complicated cataracts should be considered as a factor hindering drainage function of trabecular meshwork and thus facilitating the increase of intraocular pressure. It is not excluded that similar mechanism functions in association with fibronectin-dependent mechanisms underlying the disturbed drainage function of the trabecular meshwork in the senile and, moreover, in the

Literature data [*Izumi K. et al., 2006; Yanai R. et al., 2006; Ko J. et al., 2009*] signify in favour to the proposed assumption: IGF-1 produced in corneal epitheliocytes and cells of the trabecular meshwork significantly activates fibroplastic processes *in situ.* To our mind, in processes of IGF-1 enhanced synthesis in the above mentioned structures of an eye the role should be assigned to TGFβ-2 produced in the same eye membranes, because the latter is known to markedly activate synthesis of IGF-1 and mediators, which take an active part in stimulation of fibroplastic processes [*Yamada N. et al., 2005; Izumi K. et al., 2006; Ko J. et al., 2009*], in corneal

In the light of our own and literature data, the role of TGFβ-2 in mechanisms of ACAID induction and withdrawal should be considered from qualitatively new positions. No doubt, the immunomodulatory effect of TGFβ-2 *in situ* that is conditioned by the targeted activation of the

cellular relations *in situ* ensuring the drainage function of the eye.

eye selectively synthesizing fibronectin and IGF-1.

epitheliocytes and cells of trabecular meshwork.

eye anterior chamber's angle.

complicated cataracts.

the eye.

Table 3 presents results of analyses performed on the aqueous humour of patients with senile and complicated cataracts.


**Table 3.** K+, Na+ and Ca++ content in aqueous humour of patients with senile and complicated cataracts

As obvious from Table 3, the levels of K+ , Na+ and Ca++ in aqueous humour of patients with senile cataracts were similar to those in actually healthy cohort of subjects (we compared indices of ions in aqueous humour of patients with senile cataracts with the indices indicated in monograph of A. Pirie and R. van Heyningen (1968)). In aqueous humour of patients with cataract on the background of primary open-angle glaucoma low level of potassium ions was determined, it was 2.2 times lower than the level in aqueous humour of patients from the study group I. The lowest indices of potassium ions were recorded in the study group III, i.e., at cataracts on the background of pseudoexfoliative glaucoma. Thus, the level of potassium ions in aqueous humour of this study group decreased 2.15 times.

Unlike the shifts in potassium content in the aqueous humour of patients from study groups II and III, regarding the increase of sodium and calcium ions content a diametrically opposite picture was observed in the same groups. The content of sodium ions in the study group II increased 1.3 times, in the study group III – 1.5 times, compared to corresponding indices in aqueous humour of patients with senile cataracts.

Similar tendency was also observed on calcium ions content in aqueous humour of patients from study groups II and III. Thus, the level of calcium ions in aqueous humour of patients with cataracts on the background of primary open-angle glaucoma was 2.0 times above the control (group I), while in patients with cataracts on the background of pseudoexfoliative glaucoma it was 2.4 times higher.

We considered purposeful to present interpretation of our research findings of immune enzyme assay for determination of fibronectin, IGF-1, PgE2, and cortisol in the aqueous humour of patients with cataracts associated with primary open-angle glaucoma and pseu‐ doexfoliative glaucoma taking into account data of scientific publications relevant to sources for the synthesis of mentioned substances in specific eye membranes and their possible biological effects realized at the level of inter-cellular relations in different cell populations of the eye.

The next stage of our investigation involved biochemical analysis with the use of ion-selective method aimed to determine ions of sodium, potassium and calcium in the aqueous humour

Table 3 presents results of analyses performed on the aqueous humour of patients with senile

I 5.00±0.21 133.3±14.4 0.99±0.06

177.6±17.2 0.025<р<0.05

196.7±18.2 0.005<р<0.01

and Ca++ in aqueous humour of patients with

1.99±0.18 р<0.0005

2.40±0.26 р<0.0005

**Study groups of patients K+ Na+ Ca++**

2.30±0.26 р<0.0005

1.92 ±0.28 р<0.0005

**Table 3.** K+, Na+ and Ca++ content in aqueous humour of patients with senile and complicated cataracts

, Na+

senile cataracts were similar to those in actually healthy cohort of subjects (we compared indices of ions in aqueous humour of patients with senile cataracts with the indices indicated in monograph of A. Pirie and R. van Heyningen (1968)). In aqueous humour of patients with cataract on the background of primary open-angle glaucoma low level of potassium ions was determined, it was 2.2 times lower than the level in aqueous humour of patients from the study group I. The lowest indices of potassium ions were recorded in the study group III, i.e., at cataracts on the background of pseudoexfoliative glaucoma. Thus, the level of potassium ions

Unlike the shifts in potassium content in the aqueous humour of patients from study groups II and III, regarding the increase of sodium and calcium ions content a diametrically opposite picture was observed in the same groups. The content of sodium ions in the study group II increased 1.3 times, in the study group III – 1.5 times, compared to corresponding indices in

Similar tendency was also observed on calcium ions content in aqueous humour of patients from study groups II and III. Thus, the level of calcium ions in aqueous humour of patients with cataracts on the background of primary open-angle glaucoma was 2.0 times above the control (group I), while in patients with cataracts on the background of pseudoexfoliative

We considered purposeful to present interpretation of our research findings of immune enzyme assay for determination of fibronectin, IGF-1, PgE2, and cortisol in the aqueous humour of patients with cataracts associated with primary open-angle glaucoma and pseu‐ doexfoliative glaucoma taking into account data of scientific publications relevant to sources for the synthesis of mentioned substances in specific eye membranes and their possible

Note: p – indices of complicated cataracts as related to indices of senile cataracts

in aqueous humour of this study group decreased 2.15 times.

aqueous humour of patients with senile cataracts.

glaucoma it was 2.4 times higher.

of patients with senile and complicated cataracts.

and complicated cataracts.

88 Glaucoma - Basic and Clinical Aspects

II

III

As obvious from Table 3, the levels of K+

In line with this, first of all, we considered the essential role that is related to the biological activity of TGF2 produced in cornea and trabecular meshwork of an eye in mechanisms of intercellular relations *in situ* ensuring the drainage function of the eye.

It is considered to be generally accepted that in case of senile and complicated cataracts processes of TGFβ-2 synthesis are markedly intensified in the cornea and trabecular meshwork [*de Iongh R.U. et al., 2005; Stefan C. et al., 2008; Dawes L.J. et al., 2009; Pattabiraman P.P., Rao P.V., 2010*]. Therefore, we cannot exclude that relatively high levels of fibronectin and IGF-1 in the aqueous humour of patients with complicated cataracts are resulting from a direct stimulating influence of TGFβ-2 to cell populations localized in the cornea and trabecular meshwork of the eye selectively synthesizing fibronectin and IGF-1.

The proposed statement, to a known extent, is also confirmed by the available literature data relevant to the biological activity of TGFβ-2 – in the aspect of its selective modulatory impact to the processes of fibronectin and PgE2 synthesis and secretion in the eye membranes.

As known, keratocytes of the cornea and trabecular meshwork cells of the eye serve as the main sources of fibronectin synthesis *in situ*, i.e. in the eye tissues. Dose-dependent stimulant effect of TGFβ-2 to processes of fibronectin synthesis was established [*Wordinger R. et al., 2007; Hindman H. et al., 2010; Karamichos D. et al., 2010*] under the conditions of mentioned cells cultivation. Moreover, according to [*Stefan C. et al., 2008*], TGFβ-2 produced in eye membranes should be considered as a "special" cytokine that under conditions of the eye barrier functions disturbance might increase fibronectin concentration in cells of trabecular meshwork of the eye anterior chamber's angle.

The IGF-1 elevated level revealed in aqueous humour of patients with the complicated cataracts should be considered as a factor hindering drainage function of trabecular meshwork and thus facilitating the increase of intraocular pressure. It is not excluded that similar mechanism functions in association with fibronectin-dependent mechanisms underlying the disturbed drainage function of the trabecular meshwork in the senile and, moreover, in the complicated cataracts.

Literature data [*Izumi K. et al., 2006; Yanai R. et al., 2006; Ko J. et al., 2009*] signify in favour to the proposed assumption: IGF-1 produced in corneal epitheliocytes and cells of the trabecular meshwork significantly activates fibroplastic processes *in situ.* To our mind, in processes of IGF-1 enhanced synthesis in the above mentioned structures of an eye the role should be assigned to TGFβ-2 produced in the same eye membranes, because the latter is known to markedly activate synthesis of IGF-1 and mediators, which take an active part in stimulation of fibroplastic processes [*Yamada N. et al., 2005; Izumi K. et al., 2006; Ko J. et al., 2009*], in corneal epitheliocytes and cells of trabecular meshwork.

In the light of our own and literature data, the role of TGFβ-2 in mechanisms of ACAID induction and withdrawal should be considered from qualitatively new positions. No doubt, the immunomodulatory effect of TGFβ-2 *in situ* that is conditioned by the targeted activation of the cytotoxic lymphocytes subpopulations (T-suppressors and T-killers) is determinant in processes of forming intercellular correlation among different lymphocytic subpopulations localized in eye membranes, hence ensuring reactions underlying ACAID. However, it is not excluded that the sphere of TGFβ-2 activity under conditions of norm is more versatile, as *in situ* produced mentioned cytokine directly and/or indirectly (activating the synthesis of fibronectin and IGF-1 in a mediated manner) participates in processes of maintaining the drainage function of trabecular meshwork, thus ensuring the constant level of intraocular pressure. Apparently, the above-mentioned mediatory effects of TGFβ-2 are strictly dosedependent, as under conditions of pathology (in the given case: at senile and, especially, at the complicated cataracts) a significant elevation of TGFβ-2 in eye membranes brings to trabecular meshwork dysfunction; the latter is fraught with the increase of intraocular pressure.

One of severe complications of glaucoma is the steady persistent increase of intraocular pressure that is fraught with compression of the head of optic nerve that results in its partial or complete atrophy with the partial and/or complete sight loss. Currently, the majority of specialists engaged in clinical and experimental ophthalmology are inclined to the opinion that the increase of intraocular pressure is not the consequence of general hemodynamic disorders resulting from the permeability increase in hematoophthalmic barrier, but rather originates from pathological processes occurring in the membranes and chambers of an eye.

Modern Aspects of Glaucoma Pathogenesis Local Factors for Development of Primary Open-Angle Glaucoma…

In line with the modern views, processes underlying the increased intraocular pressure originate in the eye structures as such: in connective-tissue, epithelial and endothelial cells of the ciliary body, cornea, retina, lens, trabecular apparatus of the angle of the anterior chamber of an eye. These cells possess selective secretory activity in the aspect of producing a number of biologically active substances exerting direct and/or indirect action to the processes

Moreover, numerous pathological processes proceeding in case of primary open-angle glaucoma at the site of eye membranes are fraught with the infringement of chamber humour osmolarity; furthermore, one of mechanisms increasing the volume of aqueous humour and

Available literary data of the last 30 years which discuss mediatory functions realized by cells of fibroblastic, epithelial and endothelial line in a ciliary body, cornea, retina, lens, a trabecular network formed a basis for carrying out the research directed at clarification of a role of *in*

The drainage function of trabecular meshwork of an angle of the anterior chamber of an eye is an active process, in which the leading role belongs to secretory cells of this network. As it was specified above, secretory cells of the trabecular meshwork develop TGFβ-2, fibronectin and an insulin-like growth factor -1, PgЕ2. It is not excluded that the mentioned substances play an important role in ensuring drainage function of a trabecular meshwork, and thus, to

For this reason, high indices of fibronectin and IGF-1 found in aqueous humour of patients with primary open-angle glaucoma testify in favor of hypersecretion of mentioned cytokines by cells of a trabecular meshwork. The presence of fibronectin and insulin-like growth factor-1 high concentrations at the primary open-angle glaucoma, and also at pseudoexfoliative glaucoma, testifies to violation of drainage function of a trabecular meshwork of an angle of the anterior chamber of an eye; this latter, to a certain extent, preconditions the high level of intraocular pressure. At the same time, the specific weight of fibronectin and insulin-like of growth factor -1 in hypertension formation in the aqueous humour is far from being equivalent, as on the one hand, fibronectin level in aqueous humour of patients from investigated groups II and III 10 times exceeds concentration of insulin-like growth factor-1 in the same liquid, on the other hand, as known, the weight of soluble fibronectin makes 440.000-150.000 D, while

*situ* produced fibronectin, IgF-1 and a cortisol at primary open-angle glaucoma.

a certain extent, in maintenance of an optimum level of the intraocular pressure.

the mass of insulin-like growth factor-1 is 7.649 D [*Panteleev M. A. et al., 2011*].

/Na+

balance in favour of the accu‐

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91

regulating intraocular pressure.

not infrequently hindering its outflow is the impaired K+

mulation of this latter in the anterior chamber of an eye.

The analysis of our own research results in the context of available publications allows to consider the important role of TGFβ-2 and IGF-1, which are produced in cornea and trabecular meshwork, in mechanisms ensuring the drainage function of an eye.

The facts of detection of receptors to PgE2in cells of trabecular meshwork and sclera allow possibility of PgE2 participation in processes of intraocular pressure regulation.

The high level of PgE<sup>2</sup> found by us in aqueous humour allows possibility of its participation in processes of the impaired drainage function and increase of intraocular pressure at cataracts proceeding on the background of primary open-angle glaucoma pseudoexfoliative glaucoma.

The following phenomenon of no less importance should specially mentioned: high levels of fibronectin IGF-1 and PgE2 in the aqueous humour of patients under study were pathogno‐ monic for the course of the primary open-angle glaucoma and not for cataracts, as in this latter case all the indices studied in aqueous humour were much lower than analogous indices at senile non-complicated cataract.

Our research revealed a direct correlation dependence between the high level of cortisol, on the one hand, and the content of sodium and calcium ions, on the other hand. Based on the results obtained a conclusion might be drawn that the increase of intraocular pressure in persons with complicated cataracts on the background of glaucoma is mostly conditioned by impairment of ion transfusion between the ciliary body and aqueous humour and the proc‐ esses of cortisol "hyperproduction" by hormone-producing cells in post-barrier membranes of the eye.
