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Targeting Plasminogen Activator Inhibitor‐1 Alleviates Inflammatory Responses Invoked by Sepsis or Chlorinated Lipid

Plasminogen activator inhibitor‐1 (PAI‐1) promotes leukocyte‐endothelium interactions and transmigration secondary to ischemia/reperfusion (I/R). Our previous work demonstrated that 2‐chlorohexadecanal (2‐ClHDA), derived from myeloperoxidase (MPO) produced hypochlorous acid (HOCL) targeting of plasmalogen phospholipids, may serve as a mediator of the inflammatory responses to sepsis. Given the fact that the septic inflammatory responses invoked by cecal ligation and puncture (CLP) can be reversed by an MPO inhibitor, we have postulated that sepsis‐induced inflammation may be mediated through MPO/HOCL/2‐ClHDA axis. However, the utility of drug targeting of PAI‐1 to inhibit inflammatory responses induced by CLP or 2‐ClHDA superfusion remains to be evaluated. We have begun to explore this issue by pretreating rats with PAI‐1 inhibitor, PAI‐039 (tiplaxtinin, 44 ug/kg) one hour prior to CLP or Sham surgery and then again one hour before beginning to take measurements. Six hours after surgery, inflammatory responses in four groups of Sprague‐Dawley rats (n=6) were quantified and compared on leukocyte‐endothelial cell interactions and mast cell degranulation in rat mesenteries using intravital microscopy. In other groups of rats pretreated with PAI‐039 one hour beforehand, the exposed mesenteries were superfused with 2‐ClHDA at 10 mM (a dose within the range of plasma concentrations reported for septic patients or rats) for ninety minutes, with inflammatory responses recorded at baseline, thirty, sixty and ninety minutes. The data showed that CLP or mesenteric superfusion with 2‐ClHDA induced marked increases in the numbers of rolling and firmly adherent leukocytes, and significant mast cell activation that were similar in magnitude in both models, and were prevented by pretreatment with the PAI‐1 inhibitor PAI‐039. Our results indicate that the increases in leukocyte rolling, leukocyte adhesion, and mast cell degranulation invoked by 2‐ClHDA superfusion mimicked the responses to CLP. Moreover, these proinflammatory responses appear to be dependent on PAI‐1.