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

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

American journal of physiology. Gastrointestinal and liver physiology 2013 May 01

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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.

Citation

Susan Kenny, Islay Steele, Suzanne Lyons, Andrew R Moore, Senthil V Murugesan, Laszlo Tiszlavicz, Rod Dimaline, D Mark Pritchard, Andrea Varro, Graham J Dockray. The role of plasminogen activator inhibitor-1 in gastric mucosal protection. American journal of physiology. Gastrointestinal and liver physiology. 2013 May 01;304(9):G814-22