Enhanced systemic matrix metalloproteinase response in Helicobacter pylori gastritis

ORIGINAL ARTICLE

Enhanced systemic matrix metalloproteinase response in Helicobacterpylori gastritis

HILPI I. RAUTELIN1, AINO M. OKSANEN2, LEA I. VEIJOLA2, PENTTI I. SIPPONEN3,

TAINA I. TERVAHARTIALA4, TIMO A. SORSA4 & ANNELI LAUHIO5

1Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki

University Central Hospital Laboratory, Finland, 2Herttoniemi Hospital, City of Helsinki, Finland, 3Department of

Pathology, HUSLAB, Jorvi Hospital, Espoo, Finland, 4Department of Oral and Maxillofacial Diseases, University of

Helsinki and Helsinki University Central Hospital, Finland, and 5Division of Infectious Diseases, Department of Medicine,

Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

AbstractBackground. Helicobacter pylori causes chronic gastritis, peptic ulcer disease, and is the most important risk factor for non-cardia gastric cancer, and has been shown to upregulate matrix metalloproteinases (MMPs) in infected gastric mucosa.MMPs are proteolytic enzymes regulated by tissue inhibitors of metalloproteinases (TIMPs).Aims. We set up this study to find out whether H. pylori gastritis induces systemic MMP response.Methods. Serum samples were collected from patients undergoing gastroscopy; 26 patients had H. pylori gastritis and 18were H. pylori-negative controls with normal gastric mucosa. Serum MMP levels were analysed by enzyme-linkedimmunosorbent assay.Results. Significantly elevated serum levels of collagenase-2 (MMP-8), gelatinase B (MMP-9), neutrophil elastase (NE), andmyeloperoxidase (MPO), and reduced serum levels of gelatinase A (MMP-2) and TIMP-1 were demonstrated in patientswith H. pylori gastritis as compared to H. pylori-negative controls. No significant differences were shown in serummatrilysin-1 (MMP-7) levels.Conclusions. For the first time, we show enhanced MMP-8 response in H. pylori infection together with other neutrophildegranulation products (MMP-9, MPO, NE). Elevated circulating neutrophil degranulation product levels in serum of H.pylori-positive patients reflect accelerated proteolysis and oxidative stress, and may contribute to extraintestinal sequelae,such as cardiovascular diseases.

Key words: Gastritis, Helicobacter pylori, infection, matrix metalloproteinase

Introduction

Helicobacter pylori causes gastritis, and, although the

infection is asymptomatic in most cases, some

infected persons develop severe gastric diseases and

may be at risk for some extragastric disorders as well.

H. pylori is considered the most important single risk

factor in peptic ulcer disease and non-cardiac gastric

cancer (1). Despite the activated immune response

of the host, as shown for example by abundant

polymorphonuclear and mononuclear leukocyte in-

filtration in the gastric mucosa as well as high levels

of specific H. pylori antibodies (2), the chronic

infection persists for decades unless actively eradi-

cated (3). Neither the reasons for chronicity nor

those for the development of serious sequelae of the

infection are completely clarified.

Matrix metalloproteinases (MMPs) are geneti-

cally distinct but structurally related zinc-dependent

metalloendopeptidases, which can be classified

based on their primary structures and substrate

specificities into different groups, such as collage-

nases (MMP-1, -8, -13), gelatinases (MMP-2, -9),

stromelysins (MMP-3, -10, -11, -19), matrilysins

Correspondence: Hilpi Rautelin, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, P.O. Box 21, FI-00014 University

of Helsinki, Finland. Fax: 358 9 1912 6382. E-mail: [email protected]

(Received 25 March 2008; revised 11 September 2008; accepted 15 September 2008)

Annals of Medicine. 2009; 41: 208215

ISSN 0785-3890 print/ISSN 1365-2060 online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)DOI: 10.1080/07853890802482452

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(MMP-7, -26), membrane-type MMPs (MT-

MMPs) (MMP-14, -15, -16, -17, -24, -25), and

other MMPs (4,5). MMPs can collectively degrade

almost all components of extracellular matrix and

basement membrane, as well as process serpins,

growth factors, pro- and anti-inflammatory cyto-

kines and chemokines, as well as apoptotic signals to

modulate immune response (47). They have alsobeen shown to be important in malignant patholo-

gical processes (8). The excess activity of MMPs

leads to host damage by causing connective tissue

break-down (5,7). In host defence against bacteria,

leukocytes migrate to the site of inflammation and,

due to infectious or inflammatory stimuli, MMP-8

and MMP-9 are released and locally activated

(5,7,9). The cleavages of non-matrix cytokine and

chemokine substrates of MMP-8 and MMP-9 can

be decisive and subsequently can direct the pro- and

anti-inflammatory actions of the neutrophil-derived

MMPs (5,7,9). In this regard, MMP-8 and MMP-9

have recently been shown to modify immune re-

sponse by modulating chemokinesis and to exert

defensive and anti-inflammatory properties (5,6).

Recently the role of MMPs in immune response has

been under keen investigation in various infectious

diseases (7). The activity of MMPs is regulated by

antiproteases called tissue inhibitors of metallopro-

teinases (TIMPs) (10) and recently some specific

TIMPs, including TIMP-1, were demonstrated to

be locally upregulated in the gastric mucosa of

H. pylori patients (11). Neutrophil elastase (NE) is

a serine protease which is degranulated from azur-

ophilic granules of neutrophils when exposed to

inflammatory stimuli and microbial virulence fac-

tors. NE can degrade almost all extracellular matrix

and plasma proteins as well as activate proMMPs

and inactivate TIMP-1 (5,12,13). Degranulation of

neutrophils releases also antimicrobial substances

such as myeloperoxidase (MPO). MPO, by generat-

ing oxidants such as hypochlorous acid, is able not

only to oxidatively inactivate pathogenic microbes

but also to inactivate TIMP-1 as well as to activate

latent proMMPs (5,12,14). Thus, MPO oxidatively

and NE proteolytically can potentiate the destructive

MMP cascades.

The role of MMPs in gastrointestinal tract

diseases, such as gastric ulcer (15) and possibly

cancer (16,17), has been suggested. As gastric ulcer

and cancer are important late gastric sequelae of a

chronic H. pylori infection, the association of MMPs

with H. pylori infection has recently gained a lot of

interest (7). In fact, regarding H. pylori infection,

increased expression of MMP-2 (1822), MMP-7(19,20,23,24), and MMP-9 (1822,25,26) has beendemonstrated by cell and gastric biopsy experiments

whereas the role of MMP-8 is practically unknown

(11). The present study was set up to find out

whether H. pylori gastritis induces an enhanced

MMP-8 response and if the local gastric infection

is also reflected in a systemic MMP-2, -7, -9, TIMP-

1, NE, and MPO response by measuring circulating

levels in serum of these patients.

Methods

Patients

A total of 26 Caucasian patients (age range 4282,median 64 years; 18 females) with histologically

proven H. pylori gastritis and 18 H. pylori-negative

Caucasian patients (age range 6285, median 72years; 15 females) with macroscopically and histo-

logically proven normal gastric mucosa were in-

cluded. Both the patients and the controls were

gastroscopied at Herttoniemi Hospital in 20042005. Table I shows the underlying diseases of the

patients. The indications for and macroscopical and

histological findings of the H. pylori-positive patients

are shown in Table II. The gastroscopy indications

for the controls were the following: reflux (seven

patients), gastric pain (five patients), anaemia (three

patients), weight loss (one patient), and suspected

coeliac disease (two patients). The H. pylori-negative

controls were older than the H. pylori-positive

patients (P0.0241, Mann-Whitney test).The Ethics Committee of the Hospital District of

Helsinki and Uusimaa approved the study, and all

the participants gave their written informed consent.

Gastric histology

The gastric biopsies (two from antrum and two from

corpus) were stained with haematoxylin-eosin, Al-

cian Blue (pH 2.5)-periodic acid-Schiff, and mod-

ified Giemsa stains. Grade of gastritis (Table I) was

Key messages

. For the first time, we show enhancedMMP-8 response in Helicobacter pylori

infection together with other neutrophil

degranulation products (MMP-9, myelo-

peroxidase, neutrophil elastase).

. Elevated circulating neutrophil degranula-tion product levels in serum of H. pylori-

positive patients reflect accelerated

proteolysis and oxidative stress, and may

contribute to extraintestinal sequelae, such

as cardiovascular diseases.

H. pylori and matrix metalloproteinases 209

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assessed by one experienced pathologist according to

the updated Sydney system (27).

Serum

Serum samples were collected from patients in

context with the endoscopy and were stored at

208C until analysed. MMP-2, -7, -8, -9, NE,MPO, and TIMP-1 analyses were carried out by

enzyme-linked immunosorbent assay as earlier de-

scribed (28,29). MMP-2, MMP-7, MMP-8, MMP-

9, and TIMP-1 concentrations were determined

using commercially available enzyme-linked immu-

nosorbent assay (ELISA) kits. Biotrak ELISA sys-

tems (Amersham Biosciences UK Ltd,

Buckinghamshire, UK) were used for MMP-2,

MMP-8, and MMP-9 according to the manufac-

turers protocol. DuoSet ELISA development

Systems (R&D Systems, Minneapolis, USA) for

TIMP-1 and Quantakine MMP-7 (total) immu-

noassay for MMP-7 were used correspondingly. All

samples were analysed in duplicate. The used

MMP- and TIMP-1 ELISAs detect as informed by

the manufacturer active, pro-, complexed and frag-

mented forms of the studied MMPs and TIMP-1.

MPO and NE levels were measured according to

manufacturers instructions by commercial kits pur-

chased from Immunodiagnostic AG (Bensheim,

Germany) and Bender MedSystems mbH (Vienna,

Austria), respectively. The secondary antibody in

each kit was conjugated with horseradish peroxidase,

and tetramethyl benzidine was used as a substrate.

The absorbance was measured at 450 nm using

Labsystems Multiskan RC (Thermo Bioanalysis

Corporation, Santa FE, USA). The levels of

MMPs, TIMP-1, MPO, and NE were expressed as

ng per mL, and for calculation of MMP/TIMP-1

ratios the levels were converted to mol per L.

Serum C-reactive protein (CRP) levels (]0.3mg/L) were measured by routine methods.

Statistical analysis

Data were analysed by using GraphPad Prism

version 4.0c (GraphPad Inc., San Diego, California,

USA). Data of two groups were compared by the

Mann-Whitney test. Data are presented as median

(25%75% percentiles). Correlations were studiedusing Spearmans rank correlation test. A P-value

less than 0.05 was considered statistically significant.

Results

The serum levels of sensitive CRP did not signifi-

cantly differ (P0.5828) between the H. pylori-positive gastritis patients (median 1.0, range, B0.37.0 mg/L) and the H. pylori-negative controls with

normal gastric mucosa (median 0.95, range B0.312.0 mg/L). However, MMP-8, MMP-9, NE, and

MPO serum levels of patients with H. pylori gastritis

were significantly elevated when compared to the

serum levels of H. pylori-negative control patients

(Figure 1). The levels were 27.6 (21.239.6) versus11.3 (8.0514.5) ng of MMP-8 per mL, PB0.0001(Figure 1A), and 170 (132251) versus 112 (73.5201) ng of MMP-9 per mL, P0.0290 (Figure 1B).For NE and MPO, the corresponding levels were

169.5 (120.5225.0) versus 89.0 (69.50133.5) ngof NE per mL, P0.0004 (Figure 1C), and 81.50(60.50109.5) versus 46.50 (35.0068.00) ng ofMPO per mL, P0.0075 (Figure 1D), respectively.The serum MMP-2 levels of H. pylori gastritis

patients were significantly decreased when compared

to those of H. pylori-negative control patients (1921

(16162369) versus 2787 (20403420) ng of MMP-2 per mL, P0.004) (Figure 2A). Furthermore,serum levels of TIMP-1 were significantly lower in

H. pylori-positive patients 61.50 (52.0076.00) thanin H. pylori-negative controls 78.00 (61.0085.50)ng per mL, P0.0463 (Figure 2B). In addition, theMMP-8/TIMP-1 and MMP-9/TIMP-1 ratios for H.

pylori-positive patients were significantly higher than

those for H. pylori-negative controls (PB0.0001 and

Table I. Underlying diseases of the Helicobacter pylori-positive

patients and the H. pylori-negative controls. No statistically

significant differences in the presence of any of the underlying

diseases were found between the two groups.

Number of patients with

underlying diseases

Underlying disease

H. pylori-

positive

patients

(n26)

H. pylori-

negative

controls

(n18)

Hypertension 7 8

Coronary artery disease 4 3

Atrial fibrillation 1 1

Hypercholesterolaemia 4 3

Diabetes type I 0 1

Diabetes type II, no complications 0 2

Diabetes type II, nephropathy 0 1

Bronchial asthma 3 4

Epilepsy 1 0

Sarcoidosis 1 0

Osteoarthritis 2 3

Rheumatoid arthritis 0 1

Osteoporosis 3 4

Migraine 1 0

Hiatal hernia, Barretts oesophagus 0 1

Crohns disease 0 1

Diverticular disease and irritable colon 2 2

Prostatic hyperplasia 2 1

210 H. I. Rautelin et al.

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P0.0047, respectively). On the contrary, serumlevels of MMP-7 between H. pylori-positive

and -negative subjects did not significantly differ

(P0.242). MMP-7 levels correlated with acuteinflammation (r0.47, P0.016, scores for antrumand corpus together), but the levels of other bio-

markers tested did not correlate either with acute or

chronic or total inflammation scored either sepa-

rately for antrum and corpus or both together.

Among the H. pylori-negative control patients, the

levels of MMP-7 (r0.67, P0.0022), MMP-9(r0.47, P0.0480), and TIMP-1 (r0.55,P0.0185) correlated with increasing age.

Discussion

We found significantly elevated serum levels of

neutrophilic degranulation markers MMP-8,

MMP-9, NE, and MPO in patients with H. pylori

gastritis as compared to H. pylori-negative controls

with macroscopically and histologically normal gas-

tric mucosa. In addition, significantly decreased

levels of serum MMP-2 and TIMP-1 were detected

in H. pylori gastritis patients when compared to

H. pylori-negative controls. These findings indicate,

for the first time, that H. pylori infection is associated

with an enhanced MMP-8 response. The finding

strongly suggests enhanced neutrophil degranulation

further supported by elevated serum levels of NE

and MPO in H. pylori-positive patients as compared

to H. pylori-negative controls. Elevated MPO may

indeed potentiate the oxidative activation of both

MMP-8 and MMP-9 as well as oxidatively inactivate

TIMP-1 (12,14). Enhanced levels of MMP-8 and

MPO indicate increased degranulation of specific

granules of neutrophils. NE, a serine protease, can

also accelerate MMP-cascades by activating latent

proMMPs and inactivating TIMP-1 (5,12). The

lower serum levels of TIMP-1 and higher MMP-8/

TIMP-1 ratios in H. pylori gastritis patients as

compared to H. pylori-negative individuals suggest

that the proteolytic activity of MMP-8 may be

relatively unopposed by TIMP-1 in chronic H. pylori

gastritis or that the higher TIMP-1 levels in controls

were due to the older age.

Earlier studies have shown an increased produc-

tion of MMP-9, another MMP from C-particles or

tertiary granules of neutrophils (5,12), in H. pylori-

infected gastric and other cells (18,2022,25,26,30)

Table II. Characteristics of Helicobacter pylori-positive gastroscopied patients.

No Sex Age (y)

Indication for

endoscopy Erosions and ulcers

Chronica inflammation

antrum/corpus

Acuteb inflammation

antrum/corpus

1 F 56 coeliac disease? 3/2 1/1

2 M 68 dyspepsia 3/3 2/2

3 F 43 coeliac disease? 2/2 1/1

4 F 43 reflux 2/1 1/1

5 F 49 H. pylori resistance 3/2 1/1

6 F 79 anaemia 2/1 3/1

7 F 65 dyspepsia 3/2 2/2

8 F 64 reflux 2/2 1/1

9 F 80 reflux 3/2 1/1

10 F 57 dyspepsia gastric ulcer 2/2 2/2


12 M 77 weight loss 2/2 1/1


14 M 71 reflux 2/1 1/0

15 M 82 anaemia fewc erosions 2/2 0/2



18 F 70 H. pylori resistance 1/1 0/0

19 M 54 reflux 2/1 2/2

20 F 54 dyspepsia few erosions 1/0 1/0

21 F 50 reflux 2/1 3/1



24 M 71 reflux 2/2 1/1



aChronic (plasma cell/lymphocytic) inflammation was scored (0none, 1mild, 2moderate, 3severe) separately for antrum andcorpus.bAcute (granulocytic) inflammation was scored (0none, 1mild, 2moderate, 3severe) separately for antrum and corpus.c15 macroscopical minimal erosions in the gastric mucosa.


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and in gastric biopsies from H. pylori-positive

patients (18,25). In the present study, we could

confirm and further extend the association of H.

pylori infection with elevated MMP-9 production,

and we could show, for the first time, also a systemic

elevation of MMP-9 in serum of patients with

chronic H. pylori gastritis. In addition to MMP-9,

we also assayed the serum levels of MMP-2, both of

which can degrade type IV collagen abundant in

basement membranes. Earlier studies have demon-

strated in H. pylori infection that local expression of

MMP-2 in gastric biopsies or in infected cell lines is

upregulated (1822) or there is no effect at all(25,31). In the present study, the serum MMP-2

levels were found to be lower in H. pylori-positive

patients as compared to H. pylori-negative subjects

Figure 2. Serum matrix metalloproteinase (MMP)-2 (A) and tissue inhibitor of metalloproteinase (TIMP)-1 (B) levels of 26 Helicobacter

pylori gastritis patients and 18 H. pylori-negative controls with normal gastric mucosa. Data of two groups compared by the Mann-Whitney

test. The horizontal line indicates median.

Figure 1. Serum levels of neutrophilic degranulation markers matrix metalloproteinase (MMP)-8 (A), MMP-9 (B), neutrophil elastase

(NE) (C), and myeloperoxidase (MPO) (D) of 26 Helicobacter pylori gastritis patients and 18 H. pylori-negative controls with normal gastric

mucosa. Data of two groups compared by the Mann-Whitney test. The horizontal line indicates median.


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with normal gastric mucosa. Recently McQuibban et

al. (32) showed that MMP-2 cleaved monocyte

chemoattractant protein-3, which resulted in chemo-

kine antagonism and reduced inflammation. In our

study, the systemic downregulation of MMP-2 in

H. pylori infection may reflect, at least to some extent,

enhanced inflammation against H. pylori infection.

MMP-7 expression levels have been shown to be

enhanced in H. pylori-infected cell lines or in gastric

biopsies (19,20,23,24), and MMP-7 has been found

to be capable of activating MMP-8 (33). However,

in the present study, the serum levels of MMP-7 did

not significantly differ between H. pylori-positive

patients and controls with normal gastric mucosa.

Although it is generally considered that H. pylori

has no proven role in extraintestinal sequelae, except

probably for unexplained iron deficiency anaemia

and idiopathic thrombocytopenic purpura (1), a

recent meta-analysis indicated an association be-

tween more virulent CagA-positive (positive for

protein coded by cytotoxin-associated gene) H. pylori

infection and ischaemic heart disease (34). H. pylori

(18,19,30) and especially CagA-positive strains

(20,22,25) have been shown to upregulate MMP-9

production. Furthermore, according to a recent

finding, successful therapy, in contrast to unsuccess-

ful treatment, of H. pylori infection results in down-

regulation of MMP-9 in gastric biopsies taken from

patients after therapy (35). There is increasing

evidence supporting an association of MMPs, espe-

cially MMP-9, with the pathogenesis of cardiovas-

cular diseases (36). Recent studies have shown that

circulating MMP-8 and MMP-9 concentrations

together with an elevated MMP-8/TIMP-1 ratio

were significantly associated with cardiovascular

disease deaths, indicating that elevated circulating

MMP-8, MMP-9 and MMP-8/TIMP-1 can be

regarded as important prognostic factors in patients

with cardiovascular diseases (3739). We found inthis study that chronic H. pylori infection, lasting for

decades unless eradicated, induces a systemic host

response by increasing the serum levels of two

functionally distinct MMPs, a collagenase MMP-8

and a gelatinase MMP-9, both of which may have a

role in cardiovascular diseases (3739). In addition,serum MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios

were significantly elevated. Overall, this suggests

that, by increasing MMP-8 and MMP-9 (together

with other tissue-destructive neutrophil degranula-

tion products, MPO and NE) in systemic circulation

where the activity is only moderately opposed by low

levels of TIMP-1, chronic H. pylori infection may

predispose to cardiovascular diseases. This may be

especially possible in combination with elevated

levels of sensitive serum CRP. Nevertheless, in our

study, there was no significant difference in the

serum CRP levels between the H. pylori-positive

and -negative subjects.

The reasons why only a small number of H.

pylori-infected individuals develop serious gastric

and extragastric sequelae are not known, but bacter-

ial, host, and environmental factors are thought to be

involved (1). MMPs are enzymes which influence

the host immune response in infectious diseases (7)

and contribute to the pathogenesis of gastric ulcers

(15) and possibly cancer (16,17,40). Recently in a

work by Hellmig and co-workers, patients with

certain genetic variants of MMP-9 had a higher

risk for gastric ulcers than others (15). Furthermore,

elevated plasma levels of MMP-9 have been demon-

strated in patients with gastric cancer (41). In the

present study, none of the Helicobacter-positive

gastritis patients had duodenal ulcer but three of

them had gastric ulcer. The MMP-9 levels of these

three gastric ulcer patients were clearly above the

median of all patients, and close or above the 75%

percentile value (data not shown). In addition to

MMP-9, the efficient collagen-degrading protease

MMP-8 has recently been suggested to have a role in

gastrointestinal diseases such as gastric cancer (40).

Thus, it is not surprising that elevated levels of

MMP-8, mostly originating from neutrophils, were

detected in H. pylori gastritis in the present study.

MMP-8 expression and levels are mainly regulated

by selective release of the contents of specific

granules upon neutrophil degranulation (5,7,12).

Prepacked and presynthesized MMP-8 is released

by triggered neutrophils without significant de novo

synthesis (12). This also concerns two other neu-

trophilic degranulation products studied, i.e. MPO

and NE. Therefore, the systemic elevated level of

MMP-8 (and that of MPO and NE) in H. pylori

infection as shown in the present study is not

eventually reflected by local gastric production of

MMP-8 mRNA (11).

Our main interest was to see if local H. pylori

gastritis could associate with a systemic MMP

response as demonstrated by circulating serum

MMP and neutrophilic degranulation product

(MPO and NE) levels, and thus it was crucial to

include a control group with endoscopically verified

normal gastric mucosa. Our control patients were all

referred to upper endoscopy for various reasons and

could have other diseases or infectious processes

than H. pylori that may increase the MMP levels.

However, no significant differences were detected

either in the presence of underlying diseases or in the

serum CRP levels between the H. pylori-positive

gastritis patients and the controls.


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In conclusion, in H. pylori gastritis the serum

levels of MMP-8, MMP-9, MMP-8/TIMP-1,

MMP-9/TIMP-1, MPO, and NE are elevated, but

those of MMP-2 and TIMP-1 decreased as com-

pared to the serum levels in H. pylori-negative

individuals with healthy gastric mucosa. Our results

for the first time suggest the association of H. pylori

infection with a systematically enhanced neutrophil-

derived proteolytic and oxidative response which

may contribute to extraintestinal sequelae, such as

cardiovascular diseases. Our novel findings raise the

question whether we should search and treat H.

pylori infection more actively, not only because of

abnormalities in the gastrointestinal tract but also

considering extraintestinal sequelae.

Acknowledgements

This study was in part presented at the XXthInternational Workshop on Helicobacter and Re-lated Bacteria in Chronic Digestive Inflammation,European Helicobacter Study Group, Istanbul, Tur-key, 2022 September 2007.

This work has been supported by grants from the

Academy of Finland and Helsinki University Central

Hospital Research (EVO) Funds.

Declaration of interest: Dr Pentti Sipponen has

served as a speaker, a consultant, and an advisory

board member for Biohit Plc (a company that

produces laboratory pipettes and develops and

markets laboratory tests), and as a speaker for

meetings and congresses of many pharmaceutical

companies. In the last 10 years, he has not received

any funds from any companies or organizations,

except the funding from the University Hospital.

Dr Sipponen owns stocks and shares in Biohit Plc,

including some other companies on the stock-

market in Helsinki. Dr Sipponen does not own any

personal patents.

The other authors have no competing interests.

The authors alone are responsible for the content

and writing of the paper.

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Enhanced systemic matrix metalloproteinase response in Helicobacter pylori gastritis

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