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Title
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Anti-inflammatory effects on ischemia/reperfusion-injured lung transplants by the cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) inhibitor vildagliptin
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Author
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Abstract
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| Objectives: We showed previously that stromal cell-derived factor 1 (SDF-1) is a substrate of cluster of differentiation 26/dipeptidylpeptidase 4 (CD26/DPP4) and exerts regenerative properties on acute lung ischemia-reperfusion injury on CD26/DPP4 inhibition. Here, we extend our studies to test whether an intermediate recovery of lung transplants from ischemia/reperfusion injury by CD26/DPP4 inhibition can be achieved for up to 14 days. Methods: Syngeneic mouse lung transplantation (Tx) was performed in C57BL/6 and in CD26-/- mice by applying 18 hours of cold ischemia. Donor lungs were preconditioned with saline or the CD26/DPP4 inhibitor vildagliptin (1 mu g/mL [ 3 mu M]). In vitro, the influence of vildagliptin and SDF-1 on the macrophage cell line RAW 264.7 was tested. Transplants were analyzed up to 14 days after Tx for the expression of SDF-1, tumor necrosis factor-a (TNF-a), interleukin-10, intercellular adhesion molecule-1 (ICAM-1), immune cell infiltration, and oxygenation. Results: Cold ischemic time of 18 hours with vildagliptin preconditioning elevated lung SDF-1 levels (P = .0011) and increased interleukin-10-producing macrophages (P = .0165) compared with the control. SDF-1 reduced macrophage-derived TNF-alpha (P = .0248) in vitro. Five hours after Tx, vildagliptin significantly reduced macrophages and neutrophils (P = .0306), decreased ICAM-1 expression (P = .002), and improved transplant oxygenation (P = .0181). Seven days after Tx, grafts were preserved on CD26/DPP4-inhibition: perivascular macrophages (P = .0046) and TNF-a (P = .0013) were reduced as well as T and B cells. ICAM-1 was absent in CD26/DPP4-inhibited grafts at all time points. Conclusions: This study proves an intermediate improvement of ischemia/ reperfusion-injured lung transplants by the CD26/DPP4-inhibitor vildagliptin up to 14 days. Enhanced levels of SDF-1 induced an anti-inflammatory effect on a cellular and protein level, and render CD26/DPP4 inhibition preconditioning effective for the protection from lung ischemia/ reperfusion injury. |
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Language
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English
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Source (journal)
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The journal of thoracic and cardiovascular surgery. - St.Louis, Mo., 1959, currens
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Publication
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St.Louis, Mo.
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2017
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ISSN
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0022-5223
[print]
1097-685X
[online]
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DOI
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10.1016/J.JTCVS.2016.10.080
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Volume/pages
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153
:3
(2017)
, p. 713-724
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ISI
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000397841200052
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Pubmed ID
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27939504
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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