The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung dis- eases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in pro- motingwound healing,proliferation,andinhibiting apoptosis. Usingthe bleomycininducedfibrosis model, the protective effects of early or late MSC administration were examined. The role for he- patocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC condi- tioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apo- ptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1 b , reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGFasHGFknockdown MSC were unable toprotect againstfibrosisinvivo.Thesefindingsdelineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease.