Molecular and cellular mechanisms responsible for beneficial effects of MSCs in the therapy of COPD. Reduced emphysematous changes and alveolar damage, accompanied with increased FEVs, were noticed in MSC-treated COPD animals. MSC-dependent downregulation of the COX2/PGE2 pathway in inflammatory M1 macrophages occurs via the p38 MAPKs and ERK pathways and resulted in macrophage polarization toward an anti-inflammatory M2 phenotype. Transplantation of MSCs significantly improved the lung architecture of COPD animals by decreasing the production of macrophage-derived MMP-2, MMP-9, and MMP-12. Additionally, transplanted MSCs either directly (through the differentiation into ATII-like cells) or indirectly (by inducing proliferation and differentiation of lung resident (CD45-/CD31-/Sca-1+) stem cells) regenerated injured lungs.