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Platelets inhibit apoptotic lung epithelial cell death and protect mice against infection-induced lung injury

William Bain, Tolani Olonisakin, Minting Yu, Yanyan Qu, Mei Hulver, Zeyu Xiong, Huihua Li, Joseph Pilewski, Rama K. Mallampalli, Mehdi Nouraie, Anuradha Ray, Prabir Ray, Zhenyu Cheng, Robert M. Q. Shanks, Claudette St. Croix, Roy L. Silverstein and Janet S. Lee

Key Points

  • Platelets protect against lung injury from pathogen-secreted factors that promote host cell death even in the absence of overt infection.

  • Neutrophil airspace influx does not potentiate lung injury caused by pathogens in the susceptible host with thrombocytopenia.

Abstract

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.

  • Submitted September 21, 2018.
  • Accepted January 9, 2019.
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