ABSTRACT
UNLABELLED: Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2×10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. SIGNIFICANCE: This article describes the cases of two patients with severe refractory adult respiratory syndrome (ARDS) who failed to improve after both standard life support measures, including mechanical ventilation, and additional measures, including extracorporeal ventilation (i.e., in a heart-lung machine). Unlike acute forms of ARDS (such in the current NIH-sponsored study of mesenchymal stromal cells in ARDS), recovery does not generally occur in such patients.
Subject(s)
Mesenchymal Stem Cell Transplantation , Severe Acute Respiratory Syndrome/therapy , Adult , Allografts , Catheterization, Central Venous , Cells, Cultured , Combined Modality Therapy , Compassionate Use Trials , Epithelium/pathology , Extracellular Vesicles , Extracorporeal Membrane Oxygenation , Histocompatibility , Humans , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/therapy , Living Donors , Lung/pathology , Lymphocyte Culture Test, Mixed , Male , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/chemistry , MicroRNAs/blood , Middle Aged , Myeloid Cells/immunology , Proteome , Salvage Therapy , Severe Acute Respiratory Syndrome/complicationsABSTRACT
UNLABELLED: To better understand the pathogenesis of postoperative atrial fibrillation (AF), the mode of onset of AF after coronary artery bypass grafting was analyzed with respect to the autonomic balance, the heart rate (HR), and the presence of arrhythmias preceding the onset of sustained AF. METHOD: Holter recordings of 24 hours, obtained from the first postoperative morning until clinically documented sustained AF, were analyzed in 29 untreated patients and in 13 patients treated with thoracic epidural anesthesia (TEA), who all developed AF after coronary artery bypass grafting. The presence of arrhythmias, the HR, and the autonomic balance, assessed by heart rate variability in the frequency domain, were analyzed at predefined time intervals within the 3-hour period before AF onset. Supraventricular premature beats (SPBs) and ventricular premature beats triggering the onset of AF were also evaluated. RESULT: An SPB triggering the onset of AF can be identified in 21 (72.4%) of 29 untreated patients and in 12 (100%) of 12 TEA-treated patients in whom the recordings permitted such an analysis. The heart rate variability components analyzed during 5-minute periods for 30 minutes before AF onset did not differ significantly from those at corresponding times at the first postoperative day in either patient group. The HR during the 8 beats immediately before AF onset was lower in TEA-treated than in untreated patients. CONCLUSION: The finding of an SPB at the onset of postoperative AF in most of the patients and irrespective of changes in HR supports the hypothesis that postoperative AF is primarily triggered by latent focal atrial activity. The autonomic tone did not seem to be of major importance in the population studied.
