Universität zu Köln

Wittwer, Thorsten, Rahmanian, Parwis, Choi, Yeong-Hoon, Zeriouh, Mohamed, Karavidic, Samira, Neef, Klaus, Christmann, Astrid, Piatkowski, Tanja, Schnapper, Anke, Ochs, Matthias, Muehlfeld, Christian and Wahlers, Thorsten (2014). Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation. J. Cardiothorac. Surg., 9. LONDON: BMC. ISSN 1749-8090

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Abstract

Background: Lung transplantation (LTx) is still limited by organ shortage. To expand the donor pool, lung retrieval from non-heart-beating donors (NHBD) was introduced into clinical practice recently. However, primary graft dysfunction with inactivation of endogenous surfactant due to ischemia/reperfusion-injury is a major cause of early mortality. Furthermore, donor-derived human mesenchymal stem cell (hMSC) expansion and fibrotic differentiation in the allograft results in bronchiolitis obliterans syndrome (BOS), a leading cause of post-LTx long-term mortality. Therefore, pretreatment of NHBD with recipient-specific bone-marrow-(BM)-derived hMSC might have the potential to both improve the postischemic allograft function and influence the long-term development of BOS by the numerous paracrine, immunomodulating and tissue-remodeling properties especially on type-II-pneumocytes of hMSC. Methods: Asystolic pigs (n = 5/group) were ventilated for 3 h of warm ischemia (groups 2-4). 50x106 mesenchymal-stem-cells (MSC) were administered in the pulmonary artery (group 3) or nebulized endobronchially (group 4) before lung preservation. Following left-lung-transplantation, grafts were reperfused, pulmonary-vascular-resistance (PVR), oxygenation and dynamic-lung-compliance (DLC) were monitored and compared to control-lungs (group 2) and sham-controls (group 1). To prove and localize hMSC in the lung, cryosections were counter-stained. Intra-alveolar edema was determined stereologically. Statistics comprised ANOVA with repeated measurements. Results: Oxygenation (p = 0.001) and PVR (p = 0.009) following endovascular application of hMSC were significantly inferior compared to Sham controls, whereas DLC was significantly higher in endobronchially pretreated lungs (p = 0.045) with overall sham-comparable outcome regarding oxygenation and PVR. Stereology revealed low intrapulmonary edema in all groups (p > 0.05). In cryosections of both unreperfused and reperfused grafts, hMSC were localized in vessels of alveolar septa (endovascular application) and alveolar lumen (endobronchial application), respectively. Conclusions: Preischemic deposition of hMSC in donor lungs is feasible and effective, and endobronchial application is associated with significantly better DLC as compared to sham controls. In contrast, transvascular hMSC delivery results in inferior oxygenation and PVR. In the long term perspective, due to immunomodulatory, paracrine and tissue-remodeling effects on epithelial and endothelial restitution, an endobronchial NHBD allograft-pretreatment with autologous mesenchymal-stem-cells to attenuate limiting bronchiolitis-obliterans-syndrome in the long-term perspective might be promising in clinical lung transplantation. Subsequent work with chronic experiments is initiated to further elucidate this important field.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wittwer, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahmanian, Parwis UNSPECIFIED UNSPECIFIED UNSPECIFIED Choi, Yeong-Hoon UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeriouh, Mohamed UNSPECIFIED UNSPECIFIED UNSPECIFIED Karavidic, Samira UNSPECIFIED UNSPECIFIED UNSPECIFIED Neef, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Christmann, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Piatkowski, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Schnapper, Anke UNSPECIFIED UNSPECIFIED UNSPECIFIED Ochs, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Muehlfeld, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wahlers, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-428997
DOI:	10.1186/s13019-014-0151-3
Journal or Publication Title:	J. Cardiothorac. Surg.
Volume:	9
Date:	2014
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1749-8090
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RESTRICTIVE ALLOGRAFT SYNDROME; ENDOTHELIAL GROWTH-FACTOR; EXTENDED CRITERIA DONORS; EXOGENOUS SURFACTANT; BONE-MARROW; ISCHEMIA/REPERFUSION INJURY; INTRAALVEOLAR SURFACTANT; EXPERIMENTAL-ISCHEMIA; POSTISCHEMIC FUNCTION; EDEMA FORMATION Multiple languages Cardiac & Cardiovascular Systems; Surgery Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42899