Platelets orchestrate remote tissue damage after mesenteric ischemia-reperfusion

Abstract

<jats:p>Ischemia-reperfusion (I/R) injury is a leading cause of morbidity and mortality. A functional role for platelets in tissue damage after mesenteric I/R is largely unknown. The hypothesis that mesenteric I/R local and remote injury are platelet dependent was tested. Using a murine mesenteric I/R model, we demonstrate that platelets orchestrate remote lung tissue damage that follows mesenteric I/R injury and also contribute, albeit to a lesser degree, to local villi damage. While lung damage is delayed compared with villi damage, it increased over time and was characterized by accumulation of platelets in the pulmonary vasculature early, followed by alveolar capillaries and extravasation into the pulmonary space. Both villi and lung tissues displayed complement deposition. We demonstrate that villi and lung damage are reduced in mice made platelet deficient before I/R injury and that platelet transfusion into previously platelet-depleted mice before I/R increased both villi and lung tissue damage. Increased C3 deposition accompanied platelet sequestration in the lung, which was mostly absent in platelet-depleted mice. In contrast, C3 deposition was only minimally reduced on villi of platelet-depleted mice. Our findings position platelets alongside complement as a significant early upstream component that orchestrates remote lung tissue damage after mesenteric I/R and strongly suggest that reperfusion injury mitigating modalities should consider the contribution of platelets.</jats:p>

Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery

“…Consequently, the resulting microvascular plugging with leukocytes and activated platelets may be pivotal in the pathogenesis of postoperative AKI, 12 similarly as it has been observed in sepsis-induced kidney injury. In addition, recent evidence supports the role of platelets as potent and ubiquitously present sources of inflammatory activation, 13,14 in defining endothelial responses and neutrophil recruitment in ischemia/reperfusion injury including distant organ injury 15 and postischemic renal failure. 16 …”

Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury

“…It is not clear how natural Ig interacts with platelets or whether this interaction may be, in part, responsible for perpetuation of local or initiation of remote tissue damage following mesenteric I/R. However, our laboratory previously demonstrated that platelets may only indirectly participate in intestinal injury, but are central for the development of remote lung injury (31,32). Our group has also demonstrated increased deposition of IgM and IgA in intestine and lung after mesenteric I/R (31,49).…”

“…Platelet numbers were adjusted to 2 ϫ 10 9 /ml after counting with the Hemavet 850 (Drew Scientific, Farmington, CT), and the final volume was adjusted to 200 l for the platelet transfusion protocol. Platelets were transfused into plateletdepleted mice 10 min before the initiation of I/R injury, as described previously (20,31,32). In platelet-depleted mice, one group received platelets containing inactive Syk (treated with the Syk inhibitor, R788), and the other received normal platelets.…”

Target It All Right, But Do Not Forget the Torchbearer

“…After mesenteric IRI, platelets lodge at increasing amounts over 24 hours in the lungs and they appear to be covered with complement. 7 Although we do not know if complement deposition causes or facilitates platelet activation, it is certain that the deposited complement may facilitate remote lodging, whereas peptidoglycan activates them and causes thrombus formation. In that respect, the scFv-Crry construct prevents complement activation at the site of injury and, by not altering immunity to bacteria, limits the possibility for MDP-mediated platelet activation.…”