Glucocorticoids and ß2-agonists regulate the pathologic metabolism of hyaluronic acid in COPD.

BACKGROUND AND OBJECTIVE: We have previously shown that airway smooth muscle cells (ASMC) from COPD patients exhibit an abnormal metabolism of hyaluronic acid (HA) and that COPD exacerbations are associated with pro-inflammatory degradation of HA. In the present study, we investigated the effect of glucocorticoids and long-acting ß2-agonists (LABA) on the pathologic HA metabolism in COPD. METHODS: Primary cultures of ASMC, established from endo-bronchial biopsies of COPD patients, were treated with glucocorticoids and LABA. Secretion of HA was measured by ELISA and HA synthase-1 (HAS-1) and hyaluronidase-1 (HYAL-1) were assessed by RT-PCR and western blotting. Furthermore, from a cohort of 97 patients that underwent diagnostic bronchoscopy, we identified 11 treatment-naïve patients and 13 patients on inhaled corticosteroids (ICS) and LABA prior to bronchoscopy. HA, HAS-1 and HYAL-1 were measured in bronchoalveolar lavage (BAL) of these patients by ELISA and hyaluronidase activity by reverse zymography. RESULTS: The combination of glucocorticoids and LABA stimulated the secretion of HA with high molecular mass by ASMC from COPD patients. This effect was associated with increased expression of HAS-1 and reduced expression of HYAL-1. The effect of the drugs was mediated via their specific receptors since it was inhibited by specific receptor antagonists. Patients on ICS and LABA presented increased levels of HA and decreased levels of HYAL-1 and HYAL-1 activity in BAL. CONCLUSIONS: The combination of glucocorticoids with LABA counteracts the pathologic metabolism of HA in patients with COPD, suggesting an additional beneficial effect of the drugs when used for the treatment of COPD.

Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction, emphysema and infection.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL). METHODS: COPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,-9,-12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography. RESULTS: We observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking. CONCLUSIONS: The results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline.

COPD Exacerbations Are Associated With Proinflammatory Degradation of Hyaluronic Acid.

BACKGROUND: COPD is characterized by chronic airway inflammation and remodeling, with serious modifications of the extracellular matrix (ECM). Hyaluronic acid (HA) is an abundant ECM molecule in the lung with various biologic functions that depend on its molecular weight (MW). High-MW HA exhibits antiinflammatory and immunosuppressive effects, whereas low-MW HA is proinflammatory. In this study, we investigated whether acute exacerbations of COPD (AECOPDs), which affect patient quality of life and survival, are associated with altered HA turnover in BAL. METHODS: We used BAL from patients with stable COPD (n = 53) or during AECOPD (n = 44) matched for demographics and clinical characteristics and BAL from control subjects (n = 15). HA, HA synthase-1 (HAS-1), and hyaluronidase (HYAL) values were determined by enzyme-linked immunosorbent assay, and HYAL activity was determined by HA zymography. The MW of HA was analyzed by agarose electrophoresis. RESULTS: Levels of HA, HAS-1, and HYAL were significantly increased in BAL of patients with stable COPD and during exacerbations compared with control subjects. HYAL activity was significantly increased in BAL of patients with AECOPD, resulting in an increase of low-MW HA during exacerbations. In patients with AECOPD, we also observed a significant negative correlation of HA and HYAL levels with FEV1 % predicted but not with diffusing capacity of lung for carbon monoxide % predicted, indicating that increased HA degradation may be more associated with airway obstruction than with emphysema. CONCLUSIONS: AECOPDs are associated with increased HYAL activity in BAL and subsequent degradation of HA, which may contribute to airway inflammation and subsequent lung function decline during exacerbations.

Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen. RESULTS: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.

Diabetic retinopathy treated with laser photocoagulation and the indirect effect on glycaemic control.

PURPOSE: To identify any possible relation between glycaemic control and previous laser photocoagulation for diabetic retinopathy. METHODS: Seventy-two patients with diabetes were included in the study and were separated into 2 groups according to previous treatment (group A) or not (group B) with argon laser photocoagulation. Glycaemic control was estimated by measuring blood levels of HbA1c in four consecutive measurements. RESULTS: Blood levels of HbA1c in group A were significantly lower 3, 6, and 12 months after laser treatment as compared to blood levels of HbA1c before laser treatment (7.1 ± 0.4% versus 7.6 ± 0.9%, 7.2 ± 0.2% versus 7.6 ± 0.9%, and 7.1 ± 0.2% versus 7.6 ± 0.9%, resp., all P < 0.05). Blood levels of HbA1c in group B did not differ significantly in four consecutive measurements. CONCLUSION: Our results suggest that we should anticipate a better glycaemic control in cases of patients with diabetes previously treated with laser photocoagulation.

Comparison of interleukin-6 and matrix metalloproteinase expression in the subretinal fluid and the vitreous during proliferative vitreoretinopathy: correlations with extent, duration of RRD and PVR grade.

INTRODUCTION: The full extent of IL-6 involvement in PVR pathophysiology has not yet been comprehensively investigated. The aim of this study was the comparison of the IL-6 effect on MMP expression between SRF and the vitreous in the context of RRD complicated by PVR. MATERIALS AND METHODS: Thirty-one SRF samples from 31 eyes of 31 consecutive patients suffering from RRD with PVR were collected during treatment by scleral buckling. Twenty-eight vitreous samples from 28 eyes of 28 RRD patients with PVR were collected during surgical management with pars plana vitrectomy (PPV). Enzyme Linked Immunosorbent Assay was employed for the measurement of MMP-1, -3, -8 and TIMP-1 concentrations (in ng/ml). MMP gelatinolytic activity was determined with the use of gelatin zymography analysis using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: Correlation analysis in the SRF revealed a significant correlation between MMP-1/IL6 and RRD duration. Regression analysis in the SRF revealed a significant correlation between the MMP-9/IL-6 and RRD extent. In the same fluid, with respect to PVR grade, ANOVA revealed a significant relationship with the proMMP-2/IL-6, MMP-2/IL6 and TIMP-1/IL-6 ratios. Graphical representation of the results revealed that, between the SRF and vitreous groups, significant peak values were observed for all MMP/IL-6 and TIMP-1/IL-6 ratios included in this study with the exception of the MMP-2/IL-6 ratio. CONCLUSIONS: It appears that there is a significant correlation between the presence of IL-6 and MMP/TIMP ratio in the SRF, indicating that IL-6 may contribute to the increased MMP/TIMP ratio during PVR.

Infrared irradiation alters the expression of matrix metalloproteinases and glycosaminoglycans in the cornea and crystalline lens.

BACKGROUND: Prolonged exposure to infrared (IR) radiation is associated with different types of damage to cornea and lens. The aim of our study was to investigate the effect of acute and chronic exposure to IR radiation on the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 and on the expression of glycosaminoglycans (GAG) in the rabbit cornea and crystalline lens. METHODS: New Zealand rabbits were subjected to IR radiation for 4 months (chronic exposure to IR) or to normal light (control group). In experiments regarding acute exposure, animals were subjected to IR radiation or normal light for 12 h, in the presence of 0.1% diclofenac sodium (eye drops instilled in the right eye of animals) or saline (instilled in the left eye of animals). The cornea and lens were dissected away and homogenized. The activity of MMP-2 and MMP-9 was assayed by gelatine zymography. Total GAG were isolated from tissue specimens after lipid extraction and extensive digestion with pronase and DNase and characterized by treatment with GAG-degrading enzymes, followed by electrophoresis on cellulose acetate membranes. RESULTS: Acute or chronic exposure to IR radiation induced the activity of MMP-2 in cornea and lens, whereas only acute IR radiation increased the content of heparan sulphate in crystalline lens. Local administration of diclofenac sodium did not prevent the above effects of acute IR radiation. CONCLUSIONS: The detrimental effects of excessive or prolonged exposure of the eyes to IR radiation are associated with induced activity of MMP-2 in cornea and lens and alterations in the content of heparan sulphate in lens. Thus, MMP and GAG may offer alternative targets for pharmacological intervention to confront ocular damages associated with IR radiation.

Alterations in serum MMP and TIMP concentrations following chronic heroin abuse.

UNLABELLED: Abstract Context: Although opiate abuse is known to affect matrix metalloproteinases (MMPs), data on these enzymes and their tissue inhibitors in heroin addicts are scarce. OBJECTIVE: In the present study, we determined serum concentrations of MMP-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in heroin users, and compared them with healthy individuals. We evaluated whether 21 d of abstinence are adequate to reverse the effect of opiates and we compared seropositive with seronegative, for anti-HCV antibodies, heroin users. MATERIALS AND METHODS: Twenty-six heroin-dependent male volunteers and an equal number of healthy individuals participated in this study. ELISA was used to assess the serum levels of MMP-2, MMP-9, TIMP-1 and TIMP-2. Heroin users were assessed both upon admission and upon completion of a 21-d detoxification program. RESULTS: Serum TIMP-1 concentrations were significantly lower and the ratios MMP-2/TIMP-1, MMP-9/TIMP-1 and MMP-2/TIMP-2 were significantly higher in heroin users compared to healthy individuals. Heroin users who were seropositive had lower MMP concentrations, as well as lower MMP/TIMP ratios, compared to those who were seronegative. DISCUSSION: Our results showed that in heroin-addicted individuals, and especially those who are positive for anti-HCV antibodies, the balance between MMPs and TIMPs in serum is disrupted and this disruption cannot be restored within 21 d of abstinence. CONCLUSION: Chronic heroin abuse disrupts the balance between MMPs and TIMPs in serum and this effect is not reversible within 21 d of abstinence.

Muscarinic receptors and their antagonists in COPD: anti-inflammatory and antiremodeling effects.

Muscarinic receptors are expressed by most cell types and mediate cellular signaling of their natural ligand acetylcholine. Thereby, they control numerous central and peripheral physiological organ responses to neuronal activity. In the human lung, muscarinic receptors are predominantly expressed by smooth muscle cells, epithelial cells, and fibroblasts. Antimuscarinic agents are used for the treatment of chronic obstructive pulmonary disease and to a lesser extent for asthma. They are primarily used as bronchodilators, but it is now accepted that they are also associated with anti-inflammatory, antiproliferative, and antiremodeling effects. Remodeling of the small airways is a major pathology in COPD and impairs lung function through changes of the extracellular matrix. Glycosaminoglycans, particularly hyaluronic acid, and matrix metalloproteases are among extracellular matrix molecules that have been associated with tissue inflammation and remodeling in lung diseases, including chronic obstructive pulmonary disease and asthma. Since muscarinic receptors have been shown to influence the homeostasis of glycosaminoglycans and matrix metalloproteases, these molecules may be proved valuable endpoint targets in clinical studies for the pharmacological exploitation of the anti-inflammatory and antiremodeling effects of muscarinic inhibitors in the treatment of chronic obstructive pulmonary disease and asthma.

Steroids and ß2-agonists regulate hyaluronan metabolism in asthmatic airway smooth muscle cells.

Glycosaminoglycans (GAGs), especially hyaluronic acid (HA), regulate tissue flexibility, cell motility, and inflammation. Airway smooth muscle cells (ASMCs) of patients with asthma exhibit abnormal HA metabolism, which contributes to inflammation and remodeling. Here, we investigated the effects of glucocorticoids and long-acting ß(2)-agonists (LABAs) on GAG synthesis and HA metabolism by human primary ASMCs. ASMCs were isolated from airway specimens of 10 patients without asthma and 11 patients with asthma. ASMCs were incubated with glucocorticoids, LABAs, or their combination, as well as with their specific receptor antagonists. Secreted and deposited total GAGs were measured by [(3)H]-glucosamine incorporation. The expression of specific GAGs was determined by ELISA and electrophoresis. The expression of HA synthases (HAS), of hyaluronidases (HYALs), and of the HA receptor CD44 was determined by RT-PCR, immunoblotting in cell cultures, and immunohistochemistry in tissue sections of asthmatic lungs. In serum-activated asthmatic ASMCs, glucocorticoids and LABAs significantly inhibited the increased secretion and deposition of total GAGs, but they stimulated secreted and deposited HA of high molecular mass. This effect was attributed to increased mRNA and protein expression of HAS-1 and to the reduced expression of HYAL-1. Furthermore, drug treatment stimulated the expression of CD44 receptors in asthmatic ASMCs. These effects of the drugs were eliminated by their respective receptor inhibitors. Our findings indicate that the combination of glucocorticoids with LABAs counteracts the pathologic degradation of HA, and thereby may reduce the proinflammatory potential of asthmatic ASMCs.

Differential expression of matrix metalloproteinases in the serum of patients with mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) represent a heterogeneous group of hereditary disorders, characterized by accumulation of glycosaminoglycans within the lysosomes. The objective of this study was to elucidate the expression and activity of matrix metalloproteinases (MMPs) in the serum of pediatric patients with MPS. Serum gelatinase activity was assessed by gelatin zymography and the concentration of circulating MMP-2, MMP-9, and of tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 was measured by ELISA in the serum of seven patients with MPS (five with MPS III, 1 with MPS II and 1 with MPS VI), and healthy age- and sex-matched participants. Serum activity and protein levels of MMP-9 were significantly reduced whereas of MMP-2 were significantly increased in patients with MPS III, as compared to controls. There were no significant alterations in serum protein levels of TIMP-1 and TIMP-2 in patients with MPS III, as compared to controls. In MPS II, proMMP-2 activity and protein levels of MMP-2 were significantly increased, as compared to control. In MPS VI, enzyme replacement therapy reduced the activity and protein levels of MMP-9 up to 4 months after the initiation of treatment. The reported alterations in the expression of MMPs in the serum of patients with MPS suggest that these molecules may be used as potential biomarkers for the diagnosis, follow-up and response to therapy in patients with MPS.

Hyaluronic acid: A key molecule in skin aging.

SKIN AGING IS A MULTIFACTORIAL PROCESS CONSISTING OF TWO DISTINCT AND INDEPENDENT MECHANISMS: intrinsic and extrinsic aging. Youthful skin retains its turgor, resilience and pliability, among others, due to its high content of water. Daily external injury, in addition to the normal process of aging, causes loss of moisture. The key molecule involved in skin moisture is hyaluronic acid (HA) that has unique capacity in retaining water. There are multiple sites for the control of HA synthesis, deposition, cell and protein association and degradation, reflecting the complexity of HA metabolism. The enzymes that synthesize or catabolize HA and HA receptors responsible for many of the functions of HA are all multigene families with distinct patterns of tissue expression. Understanding the metabolism of HA in the different layers of the skin and the interactions of HA with other skin components will facilitate the ability to modulate skin moisture in a rational manner.

Interleukin-6 and the matrix metalloproteinase response in the vitreous during proliferative vitreoretinopathy.

PURPOSE: To investigate the levels of IL-6 in the vitreous of patients with RRD complicated with PVR and correlate the IL-6 levels with matrix metalloproteinase (MMP)-1,-2,-3,-8,-9 and tissue inhibitor of metalloproteinases (TIMP)-1 with respect to RRD extent, duration and PVR grade. DESIGN: Cohort study. PARTICIPANTS: Twenty-eight vitreous samples from 28 eyes of 28 patients with RRD complicated with PVR. METHODS: Institutional study. Twenty-eight vitreous samples from 28 eyes of 28 patients with RRD complicated with PVR were collected during pars plana vitrectomy (PPV) and were compared to vitreous control samples. IL-6, MMP-1,-3,-8 and TIMP-1 levels were measured using ELISA while enzymatic activity of MMP-2, and -9 was determined employing gelatin zymography. RESULTS: Protein IL-6 (p=0.030), MMP-1 (p=0.003), MMP-3 (p=0.003), TIMP-1 (p=0.001) levels as well as enzymatic activity of proMMP-9 (p=0.013), MMP-9 (p=0.017) and proMMP-2 (p=0.010), were significantly increased in PVR patients as compared to controls. IL-6 levels correlated with MMP-1 (p=0.002), proMMP-2 (p=0.006), MMP-3 (p=0.001) and TIMP-1 (p=0.006). Regression analysis revealed positive correlations between IL-6 and all MMPs and TIMP-1. CONCLUSIONS: Taking into account the previously established effect of interleukins in MMP activity, the findings of this study suggest a role of IL-6 in MMP stimulation during PVR development.

Differential expression of matrix metalloproteinases and proteoglycans in Juvenile Hyaline Fibromatosis.

BACKGROUND: Juvenile Hyaline Fibromatosis (JHF) is a rare autosomal recessive disorder, histologically characterized by the production and deposition of an unidentified hyaline material in the skin and other organs. Extracellular matrix molecules are implicated in the development of skin lesion which is debilitating and recurrent and, so far, no treatment is satisfactory. OBJECTIVE: To investigate the expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs) and proteoglycans in lesional as compared to site-matched lesion-free skin tissue specimens of a JHF patient, aiming to elucidate the aetiopathological mechanisms involved in the development of JHF skin lesions. METHODS: Gelatinase activity of MMP-2 and MMP-9 was investigated by gelatine zymography. Protein levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in skin tissue extracts were measured by ELISA. Gene expression of MMPs, TIMPs and proteoglycans was examined by quantitative RT-PCR. RESULTS: JHF lesions exhibited significantly higher activity as well as elevated protein and gene expression of MMP-2 and MMP-9, as compared to lesion-free skin tissue specimens. Decorin was downregulated and aggrecan was upregulated in lesional skin, as compared to normal skin. CONCLUSION: The results presented in this study indicate that MMPs and proteoglycans may be involved in the pathogenesis of JHF and therefore these molecules may offer alternative targets for pharmacological intervention to achieve more radical and effective treatment.

Vitreous and serum levels of vascular endothelial growth factor and platelet-derived growth factor and their correlation in patients with non-proliferative diabetic retinopathy and clinically significant macula oedema.

PURPOSE: To investigate possible correlations between vitreous and/or serum levels of platelet-derived growth factor isoforms (PDGF-AA, -AB and -BB) with parameters associated with non-proliferative diabetic retinopathy (NPDR) and clinically significant macula oedema (CSMO); to compare the results to relevant results regarding vascular endothelial growth factor (VEGF), which is an established growth factor affecting NPDR. METHODS: Fifteen patients with NPDR, 31 patients with proliferative diabetic retinopathy (PDR) and 15 non-diabetic patients were included in the study. Vitreous and serum samples were obtained during vitrectomy. PDGF-AA, -AB and -BB, as well as VEGF, were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: PDGF-AA, -AB and -BB and VEGF were all expressed in the serum and vitreous of controls and patients with NPDR. The levels of PDGF-AA, PDGF-AB and VEGF in vitreous were significantly increased in the NPDR group compared to controls, while PDGF-BB levels were significantly decreased in the NPDR group compared to controls. The levels of all PDGF isoforms and VEGF in vitreous were significantly increased in the PDR group compared to the NPDR group. No such differences were evident in serum. PDGF-AA and VEGF correlated significantly to the severity of NPDR. PDGF or VEGF in vitreous of NPDR patients did not correlate with retinal photocoagulation (RP) or the serum levels of haemoglobin A1c (HbA1c). There was no correlation between the vitreous and serum levels of VEGF or PDGF in patients with PDR. Only PDGF-AB vitreous levels correlated significantly with PDGF-BB vitreous levels in the NPDR group. CONCLUSION: It appears that in addition to VEGF, almost all PDGF isoforms in the vitreous are also correlated with NPDR and CSMO.

Correlation of matrix metalloproteinase levels with the grade of proliferative vitreoretinopathy in the subretinal fluid and vitreous during rhegmatogenous retinal detachment.

PURPOSE: We investigated the activity of matrix metalloproteinase (MMP)-2 and -9 and their latent pro-forms (proMMP-2, -9), and protein levels of MMP-1, -3, -8 and tissue inhibitor of MMPs (TIMP)-1 in the subretinal fluid (SRF) and vitreous of patients with rhegmatogenous retinal detachment (RRD). Potential correlations with proliferative vitreoretinopathy (PVR) grade were determined. METHODS: Thirty-seven SRF and 32 vitreous samples from RRD patients and nine vitreous samples from human organ donors (controls), were collected and assayed for MMP-1, -3, -8/TIMP-1 levels using enzyme-linked immunosorbent assay (ELISA), and for proMMP-2, -9, MMP-2, -9 activity employing gelatine zymography. RESULTS: ProMMP-2, -9, MMP-1, -3, -9, TIMP-1 were significantly higher in the SRF and vitreous of RRD patients compared to the vitreous of organ donors. MMP-8 levels were higher in RRD patients' SRF. Regarding PVR grade, MMPs and TIMP-1 were differentially present in SRF and vitreous. PVR grade correlated significantly with the levels of MMP-2 in SRF, while proMMP-2, MMP-1, -2, -3, -8, -9 and TIMP-1 levels correlated with PVR grade in the vitreous. CONCLUSION: MMP/TIMP-1 levels are elevated in SRF and vitreous during RRD. Significant correlations between PVR grade and MMP-2 in SRF and proMMP-2, MMP-1, -2, -3, -8, -9 and TIMP-1 levels in vitreous were revealed. Investigation of MMP activity in vitreous may provide more valid conclusions compared to SRF pertaining to the role of the MMPs during RRD. The observations of the present study suggest a possible role for MMPs and TIMP-1 in PVR pathophysiology.

Angiogenic growth factors and their inhibitors in diabetic retinopathy.

Diabetic retinopathy is considered one of the vision-threatening diseases among working-age population. The pathogenesis of the disease is regarded multifactorial and complex: capillary basement membrane thickening, loss of pericytes, microaneuryms, loss of endothelial cells, blood retinal barrier breakdown and other anatomic lesions might contribute to macular edema and/or neovascularization the two major and sight threatening complications of diabetic retinopathy. A number of proangiogenic, angiogenic and antiangiogenic factors are involved in the pathogenesis and progression of diabetic retinal disease, Vascular Endothelial Growth Factor (VEGF) being one of the most important. Other growth factors, which are known to participate in the pathogenesis of the disease, are: Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factor (FGF), Hepatocyte Growth Factor (HGF), Transforming Growth Factor (TGF), Placental Endothelial Cell Growth Factor (PlGF), Connective Tissue Growth Factor (CTGF). Other molecules that are involved in the disease mechanisms are: intergrins, angiopoietins, protein kinase C (PKC), ephrins, interleukins, leptin, angiotensin, monocyte chemotactic protein (MCP), vascular cell adhesion molecule (VCAM), tissue plasminogen activator (TPA), and extracellular matrix metalloproteinases (ECM-MMPs). However, the intraocular concentration of angiogenic factors is counterbalanced by the ocular synthesis of several antioangiogenic factors such as pigment epithelial derived factor (PEDF), angiostatin, endostatin, thrombospondin, steroids, atrial natriuretic peptide (ANP), inteferon, aptamer, monoclonal antibodies, VEGF receptor blocker, VEGF gene suppressors, intracellular signal transduction inhibitors, and extracellular matrix antagonists. Growth stimulation or inhibition by these factors depends on the state of development and differentiation of the target tissue. The mechanisms of angiogenesis factor action are very different and most factors are multipotential; they stimulate proliferation or differentiation of endothelial cells. This review attempts to briefly outline the knowledge about peptide growth factor involvement in diabetic retinopathy. Further ongoing research may provide better understanding of molecular mechanisms, disease pathogenesis and therapeutic interactions.