James E. Abbott

© 2015, Springer-Verlag Berlin Heidelberg and ESICM. Objective: Thombomodulin is an activator of protein C and a biomarker for endothelial injury. We hypothesized that elevated plasma levels would be associated with clinical outcomes and polymorphisms in the TM gene would be associated with plasma levels. Patients: We studied 449 patients enrolled in the Fluid and Catheter Treatment Trial for whom both plasma and DNA were available. We used logistic regression and receiver operator curves to test for associations between soluble TM and mortality at 60 days. Measurements and results: Plasma sTM levels were higher in non-survivors than survivors at baseline [median 147 vs. 89 ng/mL, p < 0.0001] and on day 3 after study enrollment [205 vs. 127, p < 0.0001]. The odds of death increased by 2.4, and by 2.8 for every log increase in baseline and day 3 sTM levels, respectively, after adjustment for age, race, gender, severity of illness, fluid management strategy, baseline creatinine, and non-pulmonary sepsis as the primary cause of ARDS. By ROC analysis, plasma sTM levels discriminated between non-survivors and survivors [AUC = 72 % vs. AUC = 54 % for severity based on Berlin criteria). Addition of sTM improved discrimination based on APACHE III from 77 to 80 %. sTM levels at baseline were not statistically different among subjects stratified by genotypes of tag SNPs in the TM gene. Conclusions: Higher plasma sTM levels are associated with increased mortality in ARDS. The lack of association between the sTM levels and genetic variants suggests that the increased levels of sTM may reflect severity of endothelial damage rather than genetic heterogeneity. These findings underscore the importance of endothelial injury in ARDS pathogenesis and suggest that, in combination with clinical markers, sTM could contribute to risk stratification.

Copyright © 2015 by The American Association of Immunologists, Inc. Previous studies demonstrated that bone marrow-derived mesenchymal stem cells reduce the severity of acute lung injury in animal models and in an ex vivo perfused human lung model. However, the mechanisms by which MSCs reduce lung injury are not well understood. In the present study, we tested the hypothesis that human MSCs promote the resolution of acute lung injury in part through the effects of a specialized proresolving mediator lipoxin A4. Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA 4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA 4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury in mice led to improved survival, and blocking the LXA 4 receptor with WRW4, a LXA 4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA 4 alone improved survival in mice, and it also significantly decreased the production of TNF-α and MIP-2 in bronchoalveolar lavage fluid. In summary, these experiments demonstrated two novel findings: human MSCs promote the resolution of lung injury in mice in part through the proresolving lipid mediator LXA 4, and LXA 4 itself should be considered as a therapeutic for acute respiratory distress syndrome.