Lung megakaryocytes and lung megakaryocyte-derived platelets contribute to lung injury

About This Grant

Platelets are key cells involved in coagulation and have been recognized as effector immune cells with significant contributions to infectious and inflammatory syndromes. While capable to de novo protein synthesis, platelets are anucleate and must have mRNA invested into them by a parent megakaryocyte prior to being released into circulation. We have previously shown that bone megakaryocytes alter the transcriptome of circulating platelets in a mouse model of sepsis. My NHLBI K08 focused on the role of FcγRIIA, a low affinity IgG immune receptor, impacted platelets function in sepsis. We have found that FCGR2A transcript was one of the most differentially expressed transcripts in platelets from patients with sepsis. I aimed to interrogate how FcγRIIA upregulation impacted platelet function and increased sepsis-induced mortality. After my K award was initiated the COVID-19 pandemic shuttered all research with the exception of those studies that were directly related to COVID-19. I quickly pivoted my research towards investigating the impact of acute COVID-19 infection on the platelet transcriptome and alterations in platelet function. During the COVID-19 pandemic we found that the platelet transcriptome was significantly altered in those patients with acute hypoxemic respiratory failure. Furthermore, we found that platelets and neutrophil extracellular traps (NETs) were found in small lung vessel of patients deceased from COVID-19. We found plasma markers of NETs were significantly correlated with severity of respiratory failure and mortality. Suggesting that immunothrombosis is a significant contributor to hypoxemic respiratory failure. Sepsis is the most common cause of acute hypoxemic respiratory failure, termed acute respiratory distress syndrome (ARDS). ARDS is a common cause of ICU admission that continues to carry significant morbidity and mortality. Moreover, others have shown that megakaryocytes are found in both the lung and the spleen and produce platelets that express markers suggesting an immune phenotype. We hypothesized that the population of megakaryocytes found in the lung will contribute to lung injury. We have found that lung megakaryocytes are present and produce platelets in a murine model of LPS- induced acute lung injury. We aim to study how both the lung megakaryocyte and lung megakaryocyte-derived platelet increase both early and late-stage lung injury.