title: Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4.
abstract: Previous studies demonstrated that bone marrow-derived mesenchymal stem (stromal) cells (MSCs) 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 (LXA4). Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury (ALI) in mice led to improved survival (48 h), and blocking the LXA4 receptor with WRW4, a LXA4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA4 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 LXA4, and LXA4 itself should be considered as a therapeutic for acute respiratory distress syndrome.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143; xiaohui.fang@ucsf.edu.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Jason
authors.initials: J
authors.lastname: Abbott
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Linda
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Colby
authors.affiliation: Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94143; and.
authors.forename: Jae Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Pulmonary and Critical Care Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143; Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94143; and Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008070:Lipopolysaccharides / Q000276:immunology; D044045:Lipoxins / Q000276:immunology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors*; D044067:Receptors, Lipoxin / Q000037:antagonists & inhibitors*; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000628:therapy; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; C105101:FPR2 protein, human; D008070:Lipopolysaccharides; D044045:Lipoxins; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide