Xian Fang

© 2015 by The American Association of Immunologists, Inc. Acute respiratory distress syndrome is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific abTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific αβTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of αβTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RβVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that abTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease.

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.

Background Despite advances in supportive care, moderate-severe acute respiratory distress syndrome is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem cells as a novel intravenous therapy for the early treatment of ARDS. Methods This article describes the study design and challenges encountered during the implementation and phase 1 component of the START trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned. Results This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU. Conclusions Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses. Trial registration Clinical Trials Registration: NCT01775774 and NCT02097641. © 2014 Liu et al.; licensee Springer.