The role of plasminogen activator inhibitor-1 in gastric mucosal protection

Susan Kenny, Islay Steele, Suzanne Lyons, Andrew R. Moore, Senthil V. Murugesan, L. Tiszlavicz, Rod Dimaline, D. Mark Pritchard, Andrea Varro, Graham J. Dockray

Research output: Contribution to journalArticle

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Abstract

Gastric mucosal health is maintained in response to potentially damaging luminal factors. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt protective mechanisms leading to bleeding and ulceration. The plasminogen activator system has been implicated in fibrinolysis following gastric ulceration, and an inhibitor of this system, plasminogen activator inhibitor (PAI)-1, is expressed in gastric epithelial cells. In Helicobacter pylori-negative patients with normal gastric histology taking aspirin or NSAIDs, we found elevated gastric PAI-1 mRNA abundance compared with controls; the increase in patients on aspirin was independent of whether they were also taking proton pump inhibitors. In the same patients, aspirin tended to lower urokinase plasminogen activator mRNA. Immunohistochemistry indicated PAI-1 localization to epithelial cells. In a model system using MKN45 or AGS-GR cells transfected with a PAI-1 promoter-luciferase reporter construct, we found no evidence for upregulation of PAI-1 expression by indomethacin, and, in fact, cyclooxygenase products such as PGE2 and PGI2 weakly stimulated expression. Increased gastric PAI-1 mRNA was also found in mice following gavage with ethanol or indomethacin, but plasma PAI-1 was unaffected. In PAI- 1-/- mice, gastric hemorrhagic lesions in response to ethanol or indomethacin were increased compared with C57BL/6 mice. In contrast, in PAI-1-H/Kβ mice in which PAI-1 is overexpressed in parietal cells, there were decreased lesions in response to ethanol and indomethacin. Thus, PAI-1 expression is increased in gastric epithelial cells in response to mucosal irritants such as aspirin and NSAIDs probably via an indirect mechanism, and PAI-1 acts as a local autoregulator to minimize mucosal damage.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume304
Issue number9
DOIs
Publication statusPublished - 2013

Fingerprint

Plasminogen Activator Inhibitor 1
Stomach
Aspirin
Indomethacin
Anti-Inflammatory Agents
Ethanol
Plasminogen Activators
Epithelial Cells
Messenger RNA
Protective Agents
Proton Pump Inhibitors
Irritants
Urokinase-Type Plasminogen Activator
Fibrinolysis
Epoprostenol
Prostaglandin-Endoperoxide Synthases
Luciferases
Inbred C57BL Mouse
Dinoprostone
Helicobacter pylori

Keywords

  • Aspirin
  • Gastric lesion
  • Hemostasis
  • Nonsteroidal anti-inflammatory drugs
  • Stomach

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

The role of plasminogen activator inhibitor-1 in gastric mucosal protection. / Kenny, Susan; Steele, Islay; Lyons, Suzanne; Moore, Andrew R.; Murugesan, Senthil V.; Tiszlavicz, L.; Dimaline, Rod; Mark Pritchard, D.; Varro, Andrea; Dockray, Graham J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 304, No. 9, 2013.

Research output: Contribution to journalArticle

Kenny, S, Steele, I, Lyons, S, Moore, AR, Murugesan, SV, Tiszlavicz, L, Dimaline, R, Mark Pritchard, D, Varro, A & Dockray, GJ 2013, 'The role of plasminogen activator inhibitor-1 in gastric mucosal protection', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 304, no. 9. https://doi.org/10.1152/ajpgi.00017.2013
Kenny, Susan ; Steele, Islay ; Lyons, Suzanne ; Moore, Andrew R. ; Murugesan, Senthil V. ; Tiszlavicz, L. ; Dimaline, Rod ; Mark Pritchard, D. ; Varro, Andrea ; Dockray, Graham J. / The role of plasminogen activator inhibitor-1 in gastric mucosal protection. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2013 ; Vol. 304, No. 9.
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