Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS

Katherine D Wick, Aleksandra Leligdowicz, Hanjing Zhuo, Lorraine B Ware, Michael A Matthay, Katherine D Wick, Aleksandra Leligdowicz, Hanjing Zhuo, Lorraine B Ware, Michael A Matthay

Abstract

BACKGROUNDWhether airspace biomarkers add value to plasma biomarkers in studying acute respiratory distress syndrome (ARDS) is not well understood. Mesenchymal stromal cells (MSCs) are an investigational therapy for ARDS, and airspace biomarkers may provide mechanistic evidence for MSCs' impact in patients with ARDS.METHODSWe carried out a nested cohort study within a phase 2a safety trial of treatment with allogeneic MSCs for moderate-to-severe ARDS. Nonbronchoscopic bronchoalveolar lavage and plasma samples were collected 48 hours after study drug infusion. Airspace and plasma biomarker concentrations were compared between the MSC (n = 17) and placebo (n = 10) treatment arms, and correlation between the two compartments was tested. Airspace biomarkers were also tested for associations with clinical and radiographic outcomes.RESULTSCompared with placebo, MSC treatment significantly reduced airspace total protein, angiopoietin-2 (Ang-2), IL-6, and soluble TNF receptor-1 concentrations. Plasma biomarkers did not differ between groups. Each 10-fold increase in airspace Ang-2 was independently associated with 6.7 fewer days alive and free of mechanical ventilation (95% CI, -12.3 to -1.0, P = 0.023), and each 10-fold increase in airspace receptor for advanced glycation end-products (RAGE) was independently associated with a 6.6-point increase in day 3 radiographic assessment of lung edema score (95% CI, 2.4 to 10.8, P = 0.004).CONCLUSIONMSCs reduced biological evidence of lung injury in patients with ARDS. Biomarkers from the airspaces provide additional value for studying pathogenesis, treatment effects, and outcomes in ARDS.TRIAL REGISTRATIONClinicalTrials.gov NCT02097641.FUNDINGNational Heart, Lung, and Blood Institute.

Keywords: Cytokines; Endothelial cells; Pulmonology; Respiration; Stem cells.

Conflict of interest statement

Conflict of interest: MAM declares research grant support from Roche-Genentech for ARDS observational studies and consulting income from Citius Pharmaceuticals for ARDS. LBW declares research contracts from Genentech and CSL Behring.Role of funding source: The funder of the study had no role in study design, data collection, data analysis, or data interpretation.

Figures

Figure 1. Study design.
Figure 1. Study design.
Figure 2. Airspace samples were collected 48…
Figure 2. Airspace samples were collected 48 hours after treatment with either placebo or MSCs.
Concentrations were not normally distributed after log10 transformation. Comparisons were made by Mann-Whitney U test on untransformed data. Horizontal lines and boxes represent median and IQR.
Figure 3. Airspace Ang-2 concentration in placebo…
Figure 3. Airspace Ang-2 concentration in placebo and MSC groups.
Airspace samples were collected 48 hours after treatment with either placebo or MSCs. Concentrations were normally distributed after log10 transformation. Comparisons were made by unpaired t test on transformed data. Horizontal lines and boxes represent median and IQR.
Figure 4. Airspace inflammatory biomarker concentrations in…
Figure 4. Airspace inflammatory biomarker concentrations in placebo and MSC groups.
Airspace samples were collected 48 hours after treatment with either placebo or MSCs. Horizontal lines and boxes represent median and IQR. (A) IL-6. Concentrations were normally distributed after log10 transformation. Comparisons were made by unpaired t test on transformed data. (B) sTNFR-1. Concentrations were not normally distributed after log10 transformation. Comparisons were made by Mann-Whitney U test on untransformed data.
Figure 5. Correlation between airspace total protein…
Figure 5. Correlation between airspace total protein and Ang-2 measured at 48 hours.
Correlation coefficient depicts Spearman’s rho (ρ). Comparisons were made by Spearman’s rank correlation.

References

    1. Matthay MA, et al. Phenotypes and personalized medicine in the acute respiratory distress syndrome. Intensive Care Med. 2020;46(12):2136–2152. doi: 10.1007/s00134-020-06296-9.
    1. Calfee CS, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018;6(9):691–698. doi: 10.1016/S2213-2600(18)30177-2.
    1. Kor DJ, et al. Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department: the LIPS-A randomized clinical trial. JAMA. 2016;315(22):2406–2414. doi: 10.1001/jama.2016.6330.
    1. National Heart Lung Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network, et al. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184(5):561–568. doi: 10.1164/rccm.201012-2090OC.
    1. Liu KD, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med. 2008;178(6):618–623. doi: 10.1164/rccm.200803-419OC.
    1. Limaye AP, et al. Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA. 2017;318(8):731–740. doi: 10.1001/jama.2017.10569.
    1. Stapleton RD, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med. 2011;39(7):1655–1662. doi: 10.1097/CCM.0b013e318218669d.
    1. Uchida T, et al. Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury. Am J Respir Crit Care Med. 2006;173(9):1008–1015. doi: 10.1164/rccm.200509-1477OC.
    1. Tsangaris I, et al. Angiopoietin-2 levels as predictors of outcome in mechanically ventilated patients with acute respiratory distress syndrome. Dis Markers. 2017;2017:6758721.
    1. Stapleton RD, et al. Bronchoalveolar fluid and plasma inflammatory biomarkers in contemporary ARDS patients. Biomarkers. 2019;24(4):352–359. doi: 10.1080/1354750X.2019.1581840.
    1. Matthay MA, et al. The acute respiratory distress syndrome. J Clin Invest. 2012;122(8):2731–2740. doi: 10.1172/JCI60331.
    1. Morrison TJ, et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196(10):1275–1286. doi: 10.1164/rccm.201701-0170OC.
    1. Park J, et al. Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E. coli pneumonia. Thorax. 2019;74(1):43–50. doi: 10.1136/thoraxjnl-2018-211576.
    1. Lee JW, et al. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A. 2009;106(38):16357–16362. doi: 10.1073/pnas.0907996106.
    1. Silva JD, et al. MSC extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS. Eur Respir J. doi: 10.1183/13993003.02978-2020. [published online December 17, 2020].
    1. Asmussen S, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014;69(9):819–825. doi: 10.1136/thoraxjnl-2013-204980.
    1. Matthay MA, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019;7(2):154–162. doi: 10.1016/S2213-2600(18)30418-1.
    1. Abreu SC, et al. Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells. Am J Physiol Lung Cell Mol Physiol. 2020;319(6):L908–L925. doi: 10.1152/ajplung.00218.2020.
    1. Abreu SC, et al. Lung inflammatory environments differentially alter mesenchymal stromal cell behavior. Am J Physiol Lung Cell Mol Physiol. 2019;317(6):L823–L831. doi: 10.1152/ajplung.00263.2019.
    1. Islam D, et al. Identification and modulation of microenvironment is crucial for effective mesenchymal stromal cell therapy in acute lung injury. Am J Respir Crit Care Med. 2019;199(10):1214–1224. doi: 10.1164/rccm.201802-0356OC.
    1. Zhu YG, et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32(1):116–125. doi: 10.1002/stem.1504.
    1. Krasnodembskaya A, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229–2238. doi: 10.1002/stem.544.
    1. Clark JG, et al. Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med. 1995;122(1):17–23. doi: 10.7326/0003-4819-122-1-199501010-00003.
    1. Meduri GU, et al. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest. 1995;108(5):1303–1314. doi: 10.1378/chest.108.5.1303.
    1. Agrawal A, et al. Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials. Am J Physiol Lung Cell Mol Physiol. 2012;303(8):L634–L639. doi: 10.1152/ajplung.00195.2012.
    1. Lee JW, et al. Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med. 2013;187(7):751–760. doi: 10.1164/rccm.201206-0990OC.
    1. Laffey JG, Matthay MA. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value. Am J Respir Crit Care Med. 2017;196(3):266–273. doi: 10.1164/rccm.201701-0107CP.
    1. Fang X, et al. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem. 2010;285(34):26211–26222. doi: 10.1074/jbc.M110.119917.
    1. McAuley DF, et al. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Physiol Lung Cell Mol Physiol. 2014;306(9):L809–L815. doi: 10.1152/ajplung.00358.2013.
    1. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–1822. doi: 10.1182/blood-2004-04-1559.
    1. Pati S, et al. Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock. PLoS One. 2011;6(9):e25171. doi: 10.1371/journal.pone.0025171.
    1. Shyamsundar M, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med. 2014;189(12):1520–1529. doi: 10.1164/rccm.201310-1892OC.
    1. Hendrickson CM, et al. Higher mini-BAL total protein concentration in early ARDS predicts faster resolution of lung injury measured by more ventilator-free days. Am J Physiol Lung Cell Mol Physiol. 2017;312(5):L579–L585. doi: 10.1152/ajplung.00381.2016.
    1. Nakos G, et al. Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Alterations in leukocytes, proteins, PAF and surfactant components. Intensive Care Med. 1998;24(4):296–303. doi: 10.1007/s001340050571.
    1. Schrepfer S, et al. Stem cell transplantation: the lung barrier. Transplant Proc. 2007;39(2):573–576. doi: 10.1016/j.transproceed.2006.12.019.
    1. Fischer UM, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–692. doi: 10.1089/scd.2008.0253.
    1. Sinha P, et al. Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. Lancet Respir Med. 2020;8(3):247–257. doi: 10.1016/S2213-2600(19)30369-8.
    1. Fiedler U, et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood. 2004;103(11):4150–4156. doi: 10.1182/blood-2003-10-3685.
    1. Calfee CS, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest. 2015;147(6):1539–1548. doi: 10.1378/chest.14-2454.
    1. Hendrickson CM, Matthay MA. Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS. Pulm Circ. 2018;8(2):2045894018769876.
    1. Jabaudon M, et al. Receptor for advanced glycation end-products and ARDS prediction: a multicentre observational study. Sci Rep. 2018;8(1):2603. doi: 10.1038/s41598-018-20994-x.
    1. Agrawal A, et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med. 2013;187(7):736–742. doi: 10.1164/rccm.201208-1460OC.
    1. Jabaudon M, et al. Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data. Intensive Care Med. 2018;44(9):1388–1399. doi: 10.1007/s00134-018-5327-1.
    1. Zinter MS, et al. Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality. Am J Physiol Lung Cell Mol Physiol. 2016;310(3):L224–L231. doi: 10.1152/ajplung.00336.2015.
    1. Calfee CS, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611–620. doi: 10.1016/S2213-2600(14)70097-9.
    1. Delucchi K, et al. Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax. 2018;73(5):439–445. doi: 10.1136/thoraxjnl-2017-211090.
    1. Warren MA, et al. Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Thorax. 2018;73(9):840–846. doi: 10.1136/thoraxjnl-2017-211280.
    1. Liu KD, et al. Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes. Crit Care Med. 2011;39(12):2665–2671. doi: 10.1097/CCM.0b013e318228234b.
    1. Bernard GR, et al. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med. 1994;20(3):225–232.

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