Platelets inhibit apoptotic lung epithelial cell death and protect mice against infection-induced lung injury. Blood Adv 2019 Feb 12;3(3):432-445
Date
02/09/2019Pubmed ID
30733303Pubmed Central ID
PMC6373758DOI
10.1182/bloodadvances.2018026286Scopus ID
2-s2.0-85061225330 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar-capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar-capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic Mpl -/- mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary Pseudomonas aeruginosa (PA) infection; barrier disruption was attenuated by platelet reconstitution. Although PA infection was associated with a brisk neutrophil influx, depletion of airspace neutrophils failed to substantially mitigate PA-triggered alveolar barrier disruption in Mpl -/- mice. Rather, PA cell-free supernatant was sufficient to induce lung epithelial cell apoptosis in vitro and in vivo and alveolar barrier disruption in both platelet-depleted mice and Mpl -/- mice in vivo. Cell-free supernatant from PA with genetic deletion of the type 2 secretion system, but not the type 3 secretion system, mitigated lung epithelial cell death in vitro and lung injury in Mpl -/- mice. Moreover, platelet releasates reduced poly (ADP ribose) polymerase cleavage and lung injury in Mpl -/- mice, and boiling of platelet releasates, but not apyrase treatment, abrogated PA supernatant-induced lung epithelial cell cytotoxicity in vitro. These findings indicate that while neutrophil airspace influx does not potentiate infectious lung injury in the thrombocytopenic host, platelets and their factors protect against severe pulmonary complications from pathogen-secreted virulence factors that promote host cell death even in the absence of overt infection.
Author List
Bain W, Olonisakin T, Yu M, Qu Y, Hulver M, Xiong Z, Li H, Pilewski J, Mallampalli RK, Nouraie M, Ray A, Ray P, Cheng Z, Shanks RMQ, St Croix C, Silverstein RL, Lee JSAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Blood Platelets
Cell Death
Epithelial Cells
Lung Injury
Mice
Thrombocytopenia
