Purpose: Lung transplantation faces two unresolved challenges: the inadequate number of transplantable donor organs and the low survival rate in recipients who do receive a graft. Consequently, the waitlist mortality rate is high, and the 5-year survival for recipients remains less than 50%. Nevertheless, research in this field has yet to identify a therapy that addresses either problem. As mesenchymal stromal (stem) cells (MSCs) emerge as a promising tool in other lung-related diseases. Mesenchymal stromal cells administered during ex vivo lung perfusion (EVLP) and post transplantation at two timepoints were studied under the hypothesis that the therapy could improve damaged lungs and reduce the incidence of PGD.

Methods: Acute respiratory distress syndrome (ARDS) was induced using E. coli-derived lipopolysaccharide in donor pigs, and confirmed via blood gas values, chest x-ray and histology. Harvested lungs were placed on EVLP for 4 hours, and the left lungs were transplanted. Recipients were followed and closely monitored over 3 days. At the 3: rd day a right pneumectomy was done and the transplanted left lung alone was evaluated over 4 hours. The treatment group consisted of six donor lungs which received intravascular doses of MSCs during EVLP and at 2 timepoints following transplantation. 6 lungs were maintained as a non-treated group which underwent the same protocol.

Results: Histological assessment based on blinded lung injury scoring of 7 parameters demonstrated that the treated lungs were significantly less injured both after EVLP and after transplantation than the non-treated ones and significantly less than biopsies taken at the time of confirmed ARDS. Assessment of lung functionality through the PaO2/FiO2 ratio showed that treated recipients had ratios significantly increased compared at the time of confirmed ARDS and to the transplanted non-treated recipients. All six of the treated group were PGD grade 0 on the third day of follow-up, while the non-treated group consisted of one grade 2 and five grade 3 recipients. Cell counts of leukocytes were comparable in plasma at the induction of ARDS and in the perfusate during EVLP, however, lymphocytes were significantly decreased in the treated group relative to the non-treated during the first day following transplantation.

Conclusion: Repeated mesenchymal stromal cell therapy at both EVLP and early during the post-transplantation period enabled repair of lungs with ARDS and decreased the incidence of PGD.  The amelioration of lung function by MSCs shows potential clinical use to increase the donor lung pool for lung transplantation and reduce PGD.