title: Platelet-associated CD40/CD154 mediates remote tissue damage after mesenteric ischemia/reperfusion injury.
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.
authors.affiliation: Rheumatology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Lapchak
authors.forename: Antonis
authors.initials: A
authors.lastname: Ioannou
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Kannan
authors.forename: Poonam
authors.initials: P
authors.lastname: Rani
authors.forename: Jurandir J
authors.initials: JJ
authors.lastname: Dalle Lucca
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D003165:Complement System Proteins; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry / Q000379:methods; D007422:Intestines / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015427:Reperfusion Injury / Q000378:metabolism*; D013997:Time Factors
chemical_list: D019013:CD40 Antigens; D004731:Endotoxins; D023201:CD40 Ligand; D003165:Complement System Proteins