Higher concentration of matrix-metalloproteinase 1 (interstitial collagenase) in H. pylori-compared to NSAID-induced gastric ulcers

 

 Buy Article Permissions and Reprints

Summary

Background/Objective: Matrix metalloproteinases (MMPs) are implicated in the tissue destruction associated with inflammatory diseases. We postulated a causal involvement of MMP-1 in ulcerogenesis and quantified therefore the MMP-1 concentrations in biopsies of human gastric ulcers and the surrounding mucosa. Further, we correlated them with the individual ulcer etiology.

Methods: During upper endoscopy biopsy specimens of the ulcer and surrounding normal mucosa were taken from 45 patients with gastric ulcers of different etiology (Helicobacter pylori, NSAID-intake, both or none of these). MMP-1 concentration was measured using a MMP-1 ELISA in 35 patients, western blot was performed in the remaining 10 patients. Results: In general, median expression of MMP-1 in the ulcer tissue was significantly increased compared to the surrounding mucosa (16.8 [4.7-33.4] vs. 10.9 [2.8-17.8] ng/mg protein) (p < 0.001). Western blot analysis revealed increased concentration of the active forms of MMP-1 in ulcer tissue. Interestingly, the MMP-1 concentration was significantly higher in 15 H.p.-induced ulcers compared to 19 NSAID-induced ones: 19.3 (8.3-33.2) vs. 11.4 (4.7-33.4) ng/mg protein, p = 0.0354).

Conclusion: MMP-1-expression in the ulcer tissue depends on the ulcer etiology. However, MMP-1 does not seem to be causally involved in ulcerogenesis. In NSAID-induced ulcers the MMP-1-synthesis may be suppressed by NSAID-induced decrease of mucosal prostaglandin concentration.

Höhere Konzentration der Matrix-Metalloproteinase 1 (interstitielle Kollagenase) in H.pylori - im Vergleich zu NSAR-induzierten Magenulzera

Hintergrund und Ziele: Matrix-Metalloproteinasen (MMP) sind an der Gewebezerstörung im Rahmen entzündlicher Prozesse beteiligt. Wir postulierten eine kausale Beteiligung von MMP-1 an der Ulzerogenese und quantifizierten daher die MMP-1-Konzentrationen in Biopsien aus Magenulzera und der umgebenden Mukosa. Weiterhin korrelierten wir sie mit der individuellen Ulkusgenese.

Methoden: Während der Gastroskopie wurden von 45 Patienten mit Magenulzera verschiedener Ätiologie (Helicobacter pylori, NSAR-Einnahme, beide oder keine von diesen) Gewebeproben aus dem Ulkus und der umgebenden, normal erscheinenden Mukosa entnommen. Die MMP-1-Konzentration wurde mit einem ELISA bei 35 Patienten bestimmt, bei den übrigen 10 wurde ein Western-Blot-Test durchgeführt.

Ergebnisse: Bei Betrachtung der Gesamtgruppe war die mediane MMP-1-Expression im Ulkusgewebe im Vergleich zur Umgebung signifikant erhöht (16,8 [4] [7 33] [4] vs. 10,9 [2] [8 17] [8] ng/ml Protein, p < 0,001). Die Western-Blot-Analyse zeigte eine erhöhte Konzentration der aktiven MMP-1-Formen im Ulkusgewebe. Interessanterweise war die MMP-1-Konzentration in 15 H.-p.-induzierten Ulzera signifikant höher als bei 19 NSAR-induzierten Ulzera (19,3 [8,3-33,2] vs. 11,4 [5,0-22,4], p = 0,0354).

Schlussfolgerung: Die MMP-1-Expression im Ulkusgewebe ist abhängig von der Ulkusätiologie, MMP-1 scheint jedoch nicht kausal in die Ulzerogenese involviert zu sein. Bei NSAR-induzierten Ulzera wird die MMP-1-Synthese vermutlich durch den NSAR-bedingten Abfall der mukosalen Prostaglandinkonzentration gehemmt.

References

• 1 Matrisian L. Metalloproteinases and their inhibitors in matrix remodeling.  Trends Genet. 1990;  6 121-125
  Google Scholar
• 2 Woessner J. Matrix metalloproteinases and their inhibitors in connective tissue remodeling.  FASEB J. 1991;  5 2145-2154
  Google Scholar
• 3 Airola K, Vaalamo M, Reunala T. et al . Enhanced expression of interstitial collagenase, stromelysin-1 and urokinase plasminogen activator in lesions of dermatitis herpetiformis.  J Invest Dermatol. 1995;  105 184-189
  Google Scholar
• 4 Clark I, Powell L, Ramsey S. et al . The measurement of collagenase, tissue inhibitor of metalloproteinases (TIMP), and collagense-TIMP complex in synovial fluids from patients with osteoarthritis and rheumatoid arthritis.  Arthritis Rheum. 1993;  36 372-379
  Google Scholar
• 5 Gunja S, Morales A, Romanelli R. et al . Remodeling of human myocardial collagen in idiopathic dilated cardiomyopathy. Role of metalloproteinases and pyridinoline cross links.  Am J Pathol. 1996;  148 1639-1648
  Google Scholar
• 6 Günther U, Matthes H, Herbst H. et al . Phenotype of cells expressing matrix metalloproteinase-3 in ulcerative colitis.  Ann N Y Acad Sci. 1998;  859 237-240
  Google Scholar
• 7 Nagase H, Woessner J FJ. Matrix metalloproteinases.  J Biol Chem. 1999;  30 1491-1494
  Google Scholar
• 8 Matrisian L. The Matrix-degrading metalloproteinases.  Bio Essays. 1992;  14 455-463
  Google Scholar
• 9 Saarialho-Kere U, Vaalamo M, Puolakkainen P. et al . Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers.  Am J Pathol. 1996;  148 519-526
  Google Scholar
• 10 Yokoyama T, Otani Y, Kurihara N. et al . Expression of matrix metalloproteinases in gastric ulcer tissue and interaction between fibroblasts and Helicobacter pylori in vitro. Digestive Disease Week.  Gastroenterology. 1998;  114 G1394: (abstract)
  Google Scholar
• 11 Fujimoto N, Mouri N, Iwata K. et al . A one-step sandwich enzyme immunoessay for human matrix metalloproteinase 2 using monoclonal antibodies.  Clin Chem Acta. 1993;  221 91-103
  Google Scholar
• 12 Stallmach A, Chan C C, Ecker K W. et al . Comparable expression of matrix metalloproteinase 1 and 2 in pouchitis and ulcerative colitis.  Gut. 2000;  47 415-422
  Google Scholar
• 13 Baragi V, Qiu L, Gunja-Smith Z. et al . Role of metalloproteinases in the development and healing of acetic acid-induced gastric ulcer in rats.  Scand J Gastroenterol. 1997;  32 419-426
  Google Scholar
• 14 Noach L A, Bosma N B, Jansen J. et al . Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection.  Scand J Gastroenterol. 1994;  29 425-429
  Google Scholar
• 15 Lindholm C, Quiding-Jarbrink M, Lonroth H. et al . Local cytokine response in Helicobacter pylori-infected subjects.  Infect Immun. 1998;  66 5964-5971
  Google Scholar
• 16 Tamai K, Ishikawa H, Mauviel A. et al . Interferon-gamma coordinately upregulates matrix metalloprotease(MMP)-1 and MMP-3, but not tissue inhibitor of metalloproteases (TIMP), expression in cultured keratinocytes.  J Invest Dermatol. 1995;  104 384-390
  Google Scholar
• 17 Zhang Y, McCluskey K, Fujii K. et al . Differential regulation of monocyte matrix metalloproteinase and TIMP-1 production by TNF-alpha, granulocyte-macrophage CSF, and IL-1 beta through prostaglandin dependent and -independent mechanisms.  J Immunol. 1998;  161 3071-3076
  Google Scholar
• 18 Singer C F, Marbaix E, Lemoine P. et al . Local cytokines induce differential expression of matrix metalloproteinases but not their tissue inhibitors in human endometrial fibroblasts.  Eur J Biochem. 1999;  259 40-45
  Google Scholar
• 19 Funck R, Wilke A, Rupp H. et al . Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease.  Adv Exp Med Biol. 1997;  432 35-44
  Google Scholar
• 20 Weinreb R, Kashiwagi K, Kashiwagi F. et al . Prostaglandins increase matrix metalloproteinase release from human ciliary smooth muscle cells.  Invest Ophthalmol Vis Sci. 1997;  38 2772-2780
  Google Scholar
• 21 Zahner G, Harendza S, Müller E. et al . Prostaglandin E2 stimulates expression of matrix metalloproteinase 2 in cultured rat mesangial cells.  Kidney Int. 1997;  51 1116-1123
  Google Scholar
• 22 DiBattista J, Martel-Pelletier J, Fujimoto J. et al . Prostaglandins E2 and E1 inhibit cytokine-induced metalloproteinase expression in human synovial fibroblasts.  Lab Invest. 1994;  71 270-278
  Google Scholar
• 23 Lauhio A, Salo T, Ding Y. et al . In vivo inhibition of human neutrophil collagenase (MMP-8) activity during long-term combination therapy of doxycycline and non-steroidal anti-inflammatory drugs (NSAID) in acute reactive arthritis.  Clin Exp Immunol. 1994;  98 21-28
  Google Scholar
• 24 Werb Z, Mainardi C, Vater C. et al . Endogenous activation of latent collagenase by rheumatoid synovial cells: Evidence for a role of plasminogen activator.  N Engl J Med. 1977;  296 1017-1023
  Google Scholar
• 25 Kupper T. The activated keratinocyte: A model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses.  J Invest Dermatol. 1990;  94 (Suppl. 6) 146S-149S
  Google Scholar

Address for correspondence:

Dr. M. Menges

Department of Internal Medicine II Saarland University

66421 Homburg/Saar

Email: inmmen@med-rz.uni-sb.de