Author Affiliations: Department of Medical Chemistry, Medical University of Lublin, Chod?ki 4a, Lublin 20-093, Poland (Kurzepa Ja); Department of Gastrology, Medical University of Lublin, Jaczweskiego 8, Lublin 20-954, Poland (M?dro A, Czechowska G, Celi��ski K, Kazmierak W and S?omka M); and 1st Department of Radiology, University Hospital No. 4, Jaczewskiego 8, Lublin 20-954, Poland (Kurzepa Jo)

Corresponding Author: Jacek Kurzepa, MD, Department of Medical Chemistry, Medical University of Lublin, Chod?ki 4a, Lublin 20-093, Poland (Tel: +48-81-5357390; Fax: +48-81-5357361; Email: jacek.kurzepa@umlub.pl)

 

© 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(14)60261-7

Published online May 29, 2014.

 

 

Contributors: KJa proposed the study and prepared the chapter relating to gelatinases description. MA, KJo and KW prepared the chapters relating to non-specific inflammatory bowel diseases and chronic pancreatitis. CG prepared the chapter relating to liver fibrosis. CK and SM revised the review. KJa is the guarantor.

Funding: This study was supported by a grant from own resources of Medical University of Lublin.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: There is a growing evidence that matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases) play an important role in the pathogenesis of numerous disorders, especially with inflammatory etiology and extracellular matrix (ECM) remodeling. Despite the fact that gelatinases involve in liver cirrhosis is provided in the literature, their role in the pathogenesis of chronic pancreatitis and non-specific inflammatory bowel diseases is still under investigation.

 

DATA SOURCES: We carried out a PubMed search of English-language articles relevant to the involvement of gelatinases in the pathogenesis of liver fibrosis, pancreatitis, and non-specific inflammatory bowel diseases.

 

RESULTS: The decreased activity of gelatinases, especially MMP-2, is related to the development of liver fibrosis, probably due to the decrease of capability for ECM remodeling. Similar situation can be found in chronic pancreatitis; however, reports on this matter are rare. The presence of non-specific inflammatory bowel diseases results in MMP-9 activity elevation.

 

CONCLUSION: The fluctuation of gelatinases activity during liver fibrosis, chronic pancreatitis and non-specific inflammatory bowel diseases is observed, but the exact role of these enzymes demands further studies.

 

(Hepatobiliary Pancreat Dis Int 2014;13:570-579)

 

KEY WORDS: matrix metalloproteinase; liver fibrosis; chronic pancreatitis; non-specific inflammatory bowel diseases

Matrix metalloproteinases (MMPs) are a group of enzymes, endopeptidases, involved in the degradation of extracellular matrix (ECM) proteins, such as collagen, proteoglycans, elastin or fibronectin. Thanks to their ability to modify the activity of some biologically active compounds, e.g. tumor necrosis factor α (TNF-α), CXCL-8 chemokine, transforming growth factor β (TGF-β), MMPs affect the pathogenesis of many diseases, mainly those associated with the inflammatory process. They play an important role in both physiological processes (e.g. wound healing and embryogenesis) and pathological conditions (neoplastic diseases, atherosclerosis, liver fibrosis, neurological diseases, e.g. multiple sclerosis, or cerebral stroke).^[1-3]

 

Reports on the involvement of MMPs into the pathogenesis of digestive tract diseases are scant. Searching for the term e.g. "chronic pancreatitis MMP" in the PubMed database, we only found 44 articles (August 2013), of which most are associated with pancreatic cancer or acute pancreatitis (AP). Ten-fold more articles are related to "liver cirrhosis MMP". Among 35 000 articles in the PubMed database related to MMPs, 13 000 are associated with MMP-9 (gelatinase A), and 10 000 with MMP-2 (gelatinase B). In contrast, MMP-1, the first discover MMP, has 4000 articles. The intense examination of gelatinases is due to their proofed and important role in the development of inflammation and metastasis. This review aims to emphasize the role of gelatinase in the development of cirrhosis, pancreatitis and non-specific inflammatory bowel diseases.

 

 

The history of MMPs dates back to 1962 when Gross and Lapiere demonstrated the presence of a proteolytic enzyme in tadpole tails.^[4] The enzyme, later called collagenase, enables the tail atrophy during the tadpole metamorphosis.

 

To date, over twenty enzymes belonging to MMPs have been identified. Their common feature is a zinc ion in the active center, which is essential for catalysis. Based on the differences in their amino acid structure and affinity to substrates, MMPs could be classified into several groups:^[5]

 

1. collagenases (MMP-1, MMP-8 and MMP-13);

 

2. gelatinases (MMP-2 and MMP-9);

 

3. stromelysins (MMP-3, MMP-10 and MMP-11);

 

4. matrilysins (MMP-7 and MMP-26);

 

5. membrane-type matrix metalloproteinases (MT-MMPs); and

 

6. non-classified MMPs (MMP-12, MMP-19, MMP-20, MMP-21 and MMP-23).

 

Like other proteolytic enzymes, the majority of MMPs are produced and secreted from cells in the form of zymogens (proenzymes). Their activation occurs in the extracellular space, at the site of their action, where the MMP activity is regulated mainly by natural tissue inhibitors of metalloproteinases (TIMPs). At present, four types of TIMPs are numbered 1 through 4.^[3]

 

Most of MMPs have common structural elements: signal peptide, propeptide (dissociated during enzyme activation), catalytic domain with the zinc-containing active center, hinge region, and hemopexin-like domain showing similarity to plasma hemopexin, the heme-transporting protein. The last domain is responsible for binding TIMPs to the enzyme.^{[6, 7]}

 

Gelatinases are one of the best-known groups of MMPs. Since a variety of cells are capable of producing them, these enzymes are involved in physiological processes and in the pathogenesis of numerous diseases.

 

 

MMP-2 is a carbohydrate residue-free gelatinase with a proenzyme molecular weight of 72 kDa. MMP-2 does not contain carbohydrate residues, therefore, its molecular mass corresponds to protein part of particle. The pro-MMP-9 form is of a molecular weight of 92 kDa, with the enzyme protein part constituting 76.2 kDa. The remaining weight comes from the sugar residues attached to the enzyme during the post-translational processing.^[8] Beside the structural elements characteristic of the group of "typical" MMPs, gelatinases have the hydrophobic fragment structurally resembling type II fibronectin in the catalytic domain, which is involved in gelatine binding.^{[7, 9, 10]} Moreover, MMP-9 possesses a unique domain structurally similar to type V collagen.^[11]

 

The common substrates of gelatinase include: partially denaturated collagen (gelatine), various native types of collagens, with type IV collagen forming the endothelial basement membrane, fibronectin, elastin, interleukin 1β (IL-1β), and TGF-β. Another MMP-2 substrate is pro-MMP-9. MMP-9 is capable of activating chemokine CXCL-8.^{[10, 12]} The effects of the activity of some biologically active compounds are associated with the capacity of their proteolytic activation (e.g. IL-1β) and increased bioavailability of these compounds due to the digestion of bonds with ECM proteins e.g. vascular endothelial growth factor (VEGF) or TGF-β activated by separation from the latency-associated protein blocking its activity.^[13] Furthermore, gelatinases are capable of degrading proteolytically such proteins as myelin basic protein^[14] and insulin.^[15]

 

 

Gelatinases, as other MMPs, are involved in the degradation of ECM components. However, their high affinity to collagen type IV, an important element of basement membranes, makes the gelatinases essentially for crossing through the endothelium by inflammatory cells (e.g. neutrophils, T and B cells) as well as tumor cells.

 

Numerous papers demonstrated that gelatinases with their natural inhibitors are especially important in tumor invasion, progression, and metastasis, as well as in carcinogenesis.^{[1, 11, 16, 17]} The activity of gelatinases is often higher in plasma and tumor surrounding tissues of patients with different types of tumors.^[11] For example, the high activity of MMP-2 and MMP-9 is a strong predictive factor for poor prognosis in patients with colorectal cancer.^[17] In case of pancreatic cancer, the activity of MMP-9 in tumor samples is positively correlated with histological grade of the tumor.^[18] On the other hand, the substrates for gelatinases belong to pro-inflammatory cytokines. Due to proteolytic cleavage, gelatinases increase the biological activity of CXCL-8, IL-1β, and TNF-α, leading to the exacerbation of inflammatory process.^[5]

 

The activity of all MMPs is regulated at several levels: gene transcription, proenzyme activation and through the action of natural inhibitors.

 

Many cytokines and chemokines are able to affect the initiation of gelatinase expression. The cytokines inducing the expression of MMP-2 include IL-1β and TNF-α. The additional activators of MMP-9 expression are adhesive molecules, lectins, some components of the ECM, extracellular MMP inducer,^[19] and adhesion of MMP-9-producing cells to other cells.^[20] The inhibitors of MMP-9 expression are anti-inflammatory molecules, such as IL-4, IL-10, interferon β (IFN-β), retinoids and glucocorticosteroids.^[10]

 

Since MMP-2 and MMP-9 promoters have different structures, they are characterized by susceptibility to different biologically active compounds. PGE₂-induced transcription factor Ets-1 enhances the expression of MMP-2 in the pancreatic cancer cells.^[21] The ability to activate MMP-2 transcription in vitro is also shown by C-reactive protein and VEGF.^[22,23] The expression of MMP-9 occurs in neutrophils, monocytes, macrophages, microglial cells, lymphocytes, dendritic cells, fibroblasts, vascular endothelial cells, keratinocytes, and neoplastic cells.^{[10, 24, 25]} The expression of MMP-2 takes place in microglial cells, adipocytes,^[24] astrocytes,^[25] vascular endothelial cells, macrophages,^[23] and smooth muscles.^[22]

 

Due to their proteolytic properties, gelatinases are secreted to the extracellular space in the form of zymogens (proenzymes). The presence of propeptide in the zymogen prevents binding of an appropriate substrate with the enzyme active center by blocking the zinc atom involved in catalysis. The thiol group of propeptide cysteine residue forms the bond coordinating with the zinc atom of the active center, thus expelling the water molecule indispensible as a substrate of the catalyzed reaction. The activation of gelatinases is the two-stage process. During the first stage, low-molecular-weight compounds with the affinity to the SH group, which blocks the zinc atom, disrupt the above-mentioned bond. The examples of such compounds are 4-aminophenylmercuric acetate, which is the mercury compound^[26] used in in vitro studies or nitric oxide, the endogenous activator of pro-MMP, which is the product of nitric oxide synthase. The thiol group site in the activated enzyme is taken by a water molecule.^[27] The process in question is reversible and is associated only with altered conformation of the enzyme, therefore, it is called the "cysteine switch".^[25] During the cysteine switch-mediated activation, the enzyme weight does not change.

 

The next stage of activation is propeptide proteolysis. This process is irreversible and is associated with a decrease in enzyme weight. The weight of an active form of MMP-9 is 86 kDa, whereas that of MMP-2 is about 66 kDa. The activation of pro-MMP-9 under in vitro conditions occurs in the presence of cathepsin G, α-chymotrypsin, trypsin, MMP-2, MMP-3, MMP-10, MMP-13,^[28] plasmin^[29] and hyaluronic acid.^[30] The in vivo activation of pro-MMP-9 is associated with the cascade activation of serine proteases (plasminogen activators, tissue and urokinase-type, plasmin) and other MMPs.^[31] The mechanisms of in vivo activation of pro-MMP-2 and of pro-MMP-9 are completely different (Fig.). The former takes place on the cell surface with MT1-MMP (MMP-14) and TIMP-2 involved.^[32] The other membrane-type MMPs, MT2-MMP, and MT3-MMP can play a similar role to MT1-MMP. According to some other studies, the integrin β1 receptor is also likely to be involved in the activation of pro-MMP-2, of which the role in this case is similar to that of the MT1-MMP/TIMP-2 complex.^[33]

 

In the extracellular space, the MMPs activity can be inhibited by natural TIMPs, the proteins of the 21-34 kDa molecular weights. Two out of four, TIMP-1 and TIMP-2, show a high affinity to gelatinases.^[27]

 

Besides inhibiting MMPs, tissue inhibitors significantly affect the induction of erythropoiesis (TIMP-1, -2),^{[34, 35]} mitogenesis (TIMP-1, -2) and apoptosis.^[36]

 

 

The metabolism of ECM proteins is highly dynamic. The health and life-threatening pathological conditions develop when the production of ECM proteins is excessive and uncontrolled. Impaired collagenolytic enzyme activities (MMPs) contribute to the development of such conditions due to the altered expression of MMPs and their natural inhibitors. The studies on liver fibrosis and regeneration demonstrate an important, yet dubious role of MMPs and TIMPs in these processes. During the regeneration of hepatocytes, the ECM undergoes an active transformation due to the persistently present inflammatory factor, which leads to pathological accumulation of collagen type I and III, and ultimately to fibrosis.^{[36, 37]}

 

Metalloproteinases, like ECM structural proteins, are synthesized by active hepatic stellate cells (HSCs); the varied expressions of MMPs are dependent on the HSC activity. The early phase of liver injury results in the increase of MMP-3 and MMP-13 expression (Table). However, during the later phase of HSC activation the expression of MMP-2 is elevated.^{[38, 39]}

 

The above findings were confirmed in the rat experimental model of liver fibrosis induced by a single dose of CCl₄; the study showed a similar increase in the activity of both gelatinases, as well as MT1-MMP, MMP-3, MMP-10 and MMP-13, with peak expressions coinciding with the induction of pro-inflammatory cytokines.^[38] In rats with fibrosis induced by common bile duct ligation, the activity of MMP-2 and MMP-9 increased two days after ligation, reached its maximum on day 10, and remained high throughout the experiment. This suggests that the tissues were permanently damaged and the ongoing inflammation caused by cholestasis enhanced the synthesis of gelatinases.^[39]

 

Another finding that MMP expression can be considered an early signal of the liver tissue response to the action of pro-inflammatory cytokines is a measurable increase in the activity of MMP-2 and MMP-9 after partial hepatectomy already after 15-30 minutes and reaching its peak value between hour 3 and 12.^{[40, 41]}

 

The similar results were observed in CCl₄-induced damage, during which the noticeable MMP-3 concentration occurred at post-damage hour 6, reaching the peak value after 48-72 hours.^[42] Among the causes of early increases in MMP activity in the liver, mesenchymal stem cells from the bone marrow are believed to be relevant, which migrating to the fibrosis-damaged liver are responsible for secretion of MMP-9 and MMP-13.^[43]

 

In the study by Han et al, carried out to confirm the relation between inflammation and fibrosis, a synthetic MMP inhibitor, marimastat, was used. It was demonstrated that the presence of the inhibitor, hence the inhibition of the activity of MMP-2 and MMP-9, blocked the regeneration of the liver in mice after hepatectomy.^[44] Moreover, increased concentration of IL-6 was found to enhance the expression of MMPs.

 

Some studies have emphasized the key role of MT1-MMP in the process of liver fibrosis.^{[44, 45]} Han et al^[44] demonstrated the cascade activation of MMPs secreted by active HSCs, starting with MT1-MMP, which activates pro-MMP-13. The MMP-13 substrate is pro-MMP-9, which once activated to MMP-9 is capable of activating reversibly pro-MMP-13. Both metalloproteinases, MMP-9 and MMP-13, are the major factors enabling the collagen degradation in the ECM and their activation can be blocked by TIMP-1 or TIMP-2, respectively.^[44]

 

To analyze comprehensively the mechanism of liver fibrosis and activity of metalloproteinases, the levels of their natural tissue inhibitors have to be determined. Increased concentrations of TIMPs are observed simultaneously with increased activities of MMPs in the damaged livers. TIMPs, being metalloproteinase antagonists, prevent the ECM degradation simultaneously inhibiting the programmed death of HSCs.^{[46, 47]} The regulation of MMP/TIMP balance is essential for the transformation of physiological ECM into the pathological one. Therefore, literature data rightly suggest that the assessment of progressing liver fibrosis should consider the presence of TIMPs, not only the activity of MMPs.^[47] For instance, the decreased MMP-2/TIMP-1 ratio was observed in patients with liver cirrhosis.^[48] This ratio reflects the extent of hepatocyte injury and the necrotic-inflammatory activity; however, these enzymes are not specific for liver fibrosis and can serve as an additional tool to assess the fibrosis extent, especially in progressing fibrosis where re-biopsy is not always possible.^[47] The above suggestion was confirmed by the study conducted in HCV patients, in which, concentrations of hyaluronate, procollagen III N-terminal propeptide (PIIINP), MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined and histologically evaluated using the METAVIR scale.^[49] The concentrations of hyaluronate, PIIINP, TIMP-1 and TIMP-2 were found elevated compared to the control group; moreover, these concentrations were positively correlated with the extent of fibrosis.^[43] Another study in HCV patients treated with IFN-α and ribavirin for 24-48 weeks showed that serum concentrations of hyaluronates and TIMP-1 were significantly lower by the end of the therapy.^[50] In vitro studies demonstrated the inhibitory effect of IFN-α on proliferation of HSCs responsible for TIMP-1 synthesis during fibrosis. In still another study,^[51] MMP-2 and TIMP-1 concentrations were used as non-invasive parameters of liver fibrosis by comparing them with the histological picture in HCV patients. The histological changes were estimated using the Ishak scale. The activities of MMP-2 were comparable in controls and patients with hepatitis C yet markedly higher in patients with cirrhosis. The values of TIMP-1 showed a continuous increase in controls, patients with hepatitis, with fibrosis and cirrhosis.^[52] The findings revealed that activities of MMP-2 and TIMP-1 were able to detect cirrhotic changes with a high sensitivity; moreover, regular determinations of TIMP-1 and MMP-2 levels in HCV patients might be used as a marker of progressing fibrosis and development of cirrhosis.^[52]

 

The available literature data demonstrate that MMPs and TIMPs can be used as promising non-invasive markers of hepatitis and fibrosis. The long-term experiences with liver biopsies show that they are not ideal in each situation, particularly that they cannot be repeated frequently. Currently, determinations of non-invasive markers will not eliminate the morphological evaluation of liver punctates, yet can serve as an additional measure to assess disease progression and liver condition.

 

 

Chronic pancreatitis (CP) is a long-term disease. Its incidence is estimated at 30 cases per 100 000 people.^[53] Because of repeatedly needed hospitalizations, continuous demands for many drugs, as well as numerous problems of patients and their families, CP constitutes an important problem the modern medicine has to face. The biochemical processes in the pancreas during CP inevitably lead to the impairment of both exo- and endocrine functions of the organ. Therefore, in-depth knowledge about the mechanism of CP development is essential for proper and, more importantly, effective treatment. Although many aspects of CP pathogenesis have been elucidated, the role of extracellular MMPs in this process remains insufficiently documented.

 

When the properties modulating ECM constituents are considered, metalloproteinases of the ECM including gelatinases can be assumed to be involved in the pathogenesis of CP. However, the literature data regarding this issue are scarce. Searching for the term "chronic pancreatitis MMP" in the PubMed database, we found only 44 articles (August 2013), most of which are associated with pancreatic cancer or AP. Only two studies focused on the involvement of the activity of MMP-9 in the pathogenesis of CP. One showed elevated total levels of serum MMP-9 in patients with recurrent CP.^[54] The other demonstrated that the active form of MMP-9 could contribute to the development of diabetes mellitus in the course of CP, which is associated with proteolytic degradation of insulin caused by this enzyme.^[15]

 

Earlier studies indicated that the serum concentrations of MMP-9 increased in cases of severe AP. Increased MMP-9 concentrations were likely to result from enhanced expression of pro-inflammatory cytokines (TNF-α, IL-1β, CXCL-8) accompanied by suppressed expression of anti-inflammatory cytokines, such as IL-4 and IL-10, which is observed in the acute phase of AP.^[55] The activity of MMP-9 in serum largely depended on the severity of AP. The study conducted in the animal model of streptozotocin-induced AP demonstrated that pro-MMP-9 could be activated by trypsin. The presence of locally formed (within the pancreas) active form of MMP-9 exerted additional diabetogenic effects through its capacity to degrade insulin.^[15] Another study in arginine-induced AP showed enhanced activity of MMP-2 at the basement membrane of pancreatic ducts and progressing atrophy of follicular cells.^[56] Additionally, the researchers observed damage to the basement membrane of pancreatic ducts. As one of the main substrates for both gelatinases is considered type IV collagen composing the basement membranes, their destruction and damage to the follicular cells in AP are attributed to MMP-2.

 

Ng et al^[57] found reduced activities of both gelatinases in pancreatic homogenates of animals with pancreatitis induced by surgical pancreatic duct obstruction and administration of cerulein. They concluded that decreased activities of gelatinases are one of the factors responsible for pancreatic fibrosis during pancreatitis. The research team supervised by Michalski hypothesized that inflammation and increased fibrosis of the pancreas during CP was caused by interactions between mononuclear cells and pancreatic stellate cells.^[58] Stellate cells are responsible, among other things, for the synthesis of ECM constituents including collagens, which is similar to the process occurring in the liver. Manjari et al^[59] found the increased serum level of MMP-9 in patients with CP.

 

 

Non-specific inflammatory bowel diseases (IBDs), e.g. Crohn's disease (CD) and ulcerative colitis (UC), are characterised by the presence of inflammatory infiltrations and ulcerations within the gastrointestinal tract, and their pathogenesis has not been fully elucidated. Among various factors involved in the development, modification and healing of inflammatory lesions, extracellular MMPs are essential. As mentioned earlier, potential inducers of MMPs include many pro-inflammatory cytokines.^[60] The studies with animal models of colitis demonstrated increased expression of MMP-9 and MMP-3.^{[61, 62]} Their overexpression is thought to be associated with the damage to the mucous membrane and formation of fistulas in patients with CD;^[63] moreover, overexpression of MMP-3 is linked with increased tissue damage and migration of neutrophils.^[64] Furthermore, altered expressions of TIMPs play an important role in the pathogenesis of IBD. In the inflammation-altered mucous membrane in patients with IBD, the expression of TIMPs correlates reversely with the synthesis of pro-inflammatory cytokines and extent of inflammatory lesions.^[65] Lakatos et al^[66] confirmed higher serum MMP-9 levels in patients with UC and CD than in the control group. The result is consistent with the earlier report that high tissue expression of MMP-9 correlates with increased inflammation in patients with UC.^[67] However, immunohistochemical studies revealed that MMP-9 seems to play no role in the inflammatory process of lymphocytic colitis and collagenous colitis.^[67]

 

MMP-9 is suggested to be the key factor determining mucous membrane damage in IBD,^[68,69] thus it can be a useful marker for the severity of inflammation in IBD. Although the sensitivity of MMPs for determination of inflammation severity is high, their specificity is not sufficiently high.^[70] In search for new therapeutic strategies in IBD, much attention was paid to MMP-9, which seems to have beneficial effects on the course of IBD.^[71] It was noted that the treatment with infliximab might induce the genotype-associated matrix protective phenotype by downregulating MMP-9 activity, which should result in positive effects of this drug on IBD.^[72] The anti-TNF-α therapy contributes to increased synthesis of TIMP-1, the most potent natural inhibitor of MMP-9, which reduces the activity of MMP-9 and accelerates mucous membrane healing.^[73]

 

On the other hand, MMP-2 and MMP-7 are connected with the physiological processes of mucous membrane protection by forming the barrier against unfavorable factors, particularly bacterial ones.^{[74, 75]} They participate in tissue remodelling, angiogenesis and re-epithelization.^{[68, 76]} MMP-7 could be detected in the mucous membrane around ulcerations, suggesting its role in epithelial repair around the wound.^[64,75] Hayden et al^[74] studied the relation between the MMP-7 expression and wound healing under normal and inflammatory conditions in in vitro model. He demonstrated that increased expression of MMP-7 was necessary for proper wound healing, yet its overexpression could delay or deregulate proper healing. In several studies,^{[77, 78]} MMP-7 was associated with the degree of cancer invasiveness, poor clinical prognosis, and shorter survival.

 

Morgan et al^[79] suggested a strong relation of other metalloproteinases (MMP-8, MMP-10, MMP-3 and MMP-14) with UC. Analysis of phenotypes showed a correlation between the above-mentioned MMPs and the diagnosis at older age, which is most likely associated with the effects of environmental factors, including cigarette smoking in individuals genetically predisposed. Phenotypic analysis disclosed also the relationship between MMPs versus location, aggressiveness of the disease and necessary resection. In the group of MMPs mentioned above, MMP-10 is also upregulated in IBD and is associated with macrophage movement, epithelial cell shedding and wound healing.^[80] MT1-MMP-related observations are of interest. This enzyme activates MMPs, can enhance their action and affect their degradation.^[63]

 

Motawi et al^[81] studied possible effects of curcumin and G. biloba on reduced inflammation in the experimental model of IBD induced by intrarectal administration of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) in rats; moreover, they determined the expression of MMP-1, MMP-3 and TIMP-1, as well as the content of hydroxyproline, activity of ceruloplasmin, and histopathological evaluation of the extent of inflammation and necrosis. They observed that curcumin decreased the expression of MMP-1, MMP-3 and TIMP-1, likely through a decrease in the concentration of their inducer TNF-α. A similar effect was observed after G. biloba; both compounds reduced extracellular degradation in IBD and decreased mucosae damage affecting the release of inflammation mediators.

 

According to the literature, the activity of gelatinases seems to be higher in IBD in comparison to liver fibrosis and CP.^[66] As mentioned above, serum MMP-9 level is correlated with the intensity of inflammation during UC. This enzyme activates several pro-inflammatory cytokines such as TNF-α, IL-1β and chemokine CXCL-8. The decrease of MMP-9 activity during the treatment with infliximab via inhibition of TNF-α is the beneficial effect of therapy.^{[71, 72]} On the other hand, the relatively low activity of metalloproteinases during liver fibrosis and CP can contribute to fibrosis development in the progress of above diseases.

 

To sum up, changes in MMPs/TIMPs balance determine the extent of mucous membrane damage in IBD.^{[82, 83]} Further, specific inhibition of MMPs and overexpression of TIMPs that can restore the balance between MMPs and their endogenous inhibitors, provide novel pharmacological perspectives.^{[84, 85]}

 

 

Among all the extracellular MMPs, the role of gelatinases in various diseases is of the highest interest for researchers. Their role in liver fibrosis is relatively best known; however, their effects on fibrosis during CP and non-specific IBDs are less clear. Another aim of the ongoing studies is to define the therapeutic implications resulting from the postulated role of MMPs in various diseases. It seems that the promising direction of research is likely to contribute to more effective treatment of gastrointestinal diseases, in which fibrosis is observed.

 

 

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