Abstract
Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses.
Highlights
Systemic inflammatory responses, triggered by extracorporeal circulation (ECC), are a frequent, serious problem because the triggering of inflammatory and coagulation cascades, together with endothelial damage, can lead to multiple organ injury[1]
Consistent with results we reported previously[13], ECC caused severe lung injury, which was observed as thickening of the alveolar wall, leukocyte infiltration (Fig. 2A), lower PaO2/FiO2 (Fig. 2B) and higher lung injury score than at baseline (Fig. 2C)
Since platelets can release anti-inflammatory transforming growth factor (TGF)-βwhen they interact with activated leukocytes, we examined whether the ability of platelet transfusion to increase the numbers of platelet-leukocyte aggregates (PLAs) correlated with increased production of TGF-β.platelet transfusion significantly increased TGF-βlevels, and this effect was blocked by Tirofiban (p = 0.03, Fig. 5D)
Summary
Triggered by extracorporeal circulation (ECC), are a frequent, serious problem because the triggering of inflammatory and coagulation cascades, together with endothelial damage, can lead to multiple organ injury[1]. TNF-αacts as a chemotactic signal to recruit circulating leukocytes, which accumulate inappropriately in lung tissue[2] During these processes, platelets may become activated, leading adhesive proteins on their surface, which include P-selectin and β3-integrin ( known as aIIbβ[3] or GPIIb-IIIa), to bind to leukocytes. Depleting platelets in animal models of lung injury ameliorates tissue damage[7] In contrast to their pro-inflammatory effects, platelets can exert anti-inflammatory effects. Platelet count falls under certain inflammatory conditions such as during cardiopulmonary bypass[12], and transfusion of fresh platelets can prevent bleeding after cardiopulmonary bypass These considerations led us to wonder whether and how platelets might protect against acute pulmonary dysfunction induced by a systemic inflammatory response. We examined this question using our previously characterized mouse model in which ECC leads to systemic inflammatory response, causing pulmonary dysfunction similar to that seen in humans[13]
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