Abstract
Several innate and adaptive immune cell types participate in ischemia/reperfusion induced tissue injury. Amongst them, platelets have received little attention as contributors in the process of tissue damage after ischemia reperfusion (I/R) injury. It is currently unknown whether platelets participate through the immunologically important molecules including, CD40 and when activated, CD154 (CD40L), in the pathogenesis of I/R injury. We hypothesized that constitutive expression of CD40 and activation-induced expression of CD154 on platelets mediate local mesenteric and remote lung tissue damage after I/R injury. Wild type (WT; C57BL/6J), CD40 and CD154 deficient mice underwent mesenteric ischemia for 30 minutes followed by reperfusion for 3 hours. WT mice subjected to mesenteric I/R injury displayed both local intestinal and remote lung damage. In contrast, there was significantly less intestinal damage and no remote lung injury in CD40 and CD154 deficient mice when compared to WT mice. Platelet-depleted WT mice transfused with platelets from CD40 or CD154 deficient mice failed to reconstitute remote lung damage. In contrast, when CD40 or CD154 deficient mice were transfused with WT platelets lung tissue damage was re-established. Together, these findings suggest that multiple mechanisms are involved in local and remote tissue injury and also identify platelet-expressed CD40 and/or CD154 as mediators of remote tissue damage.
Highlights
Tissue damage following ischemia reperfusion (I/R) occurs as a consequence of deprivation of the blood flow followed by its return to the affected tissue
We test the hypothesis that platelet expression of CD40/CD154 mediates remote tissue injury after mesenteric I/R. We demonstrate that both CD40 and CD154 expression on platelets is important in remote lung tissue damage after mesenteric I/R injury
Experiments reported in this article grant platelet-expressed CD40/CD154 an important role in the expression of mesenteric I/R mediated remote lung injury
Summary
Tissue damage following ischemia reperfusion (I/R) occurs as a consequence of deprivation of the blood flow followed by its return to the affected tissue. Inhibition of complement or depletion of T or B cells has been used successfully to prevent tissue damage after I/R injury [6]. Platelets typically express a pro-inflammatory phenotype and have been shown to play an important role in the onset and progression of chronic and acute inflammatory responses in rheumatoid arthritis [8,9], systemic lupus erythematosus [10], inflammatory bowel disease [11,12],vascular inflammation in graft rejection [13] and more recently in ischemia reperfusion injury [14]. Localized inflammation may be perpetuated in the presence of both platelets and complement components
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