The incidence of acute respiratory distress syndrome (ARDS) has risen exponentially in the post-SARS-CoV-2 pandemic era. Current treatments for this disease are broad-spectrum, and lack the specificity required to treat this highly-complex disease. Mesenchymal stromal cells (MSCs) are an immunomodulatory and pro-reparative cell-type, that are a prominent interest in the field of regenerative medicine. These cells can interact with other cells to dampen their inflammatory effects, while also secreting paracrine factors that can aid in immune modulation and repair. In the context of inflammatory disease, MSCs have been trialled, tested and proven to have an exquisite safety profile in the context of many diseases; including ARDS. However, they have not been therapeutically efficacious in the treatment of ARDS. Given that resident stromal cells within the lung are known to be defective within the diseased lung microenvironment, this project sought to identify the impact that elements of the ARDS patient microenvironment could have on MSC therapeutic efficacy in a pre-clinical model of acute lung inflammation. It was shown that general inflammation, by TNFɑ, could enhance MSC modulation of neutrophils; a key driver of ARDS. This study further highlighted the impact of differential inflammatory profiles of ARDS patients on MSC therapeutic efficacy. This firstof- its-kind patient stratification study highlighted that MSCs exposed to a highly-inflammatory ARDS microenvironment could enhance lung epithelium barrier function in a VEGFdependent manner, but the same effect was not seen from MSCs exposed to lower levels of inflammation. It was also identified that free fatty acids within the ARDS microenvironment could enhance MSC pro-reparative capacity in an ANGPTL4-dependent manner, through activation of the PPARβ/� nuclear receptor. This research largely contributes to the field of cell-therapy, by promoting a need to investigate the environment in which the cells are placed, and identifying the key mechanisms required for therapeutic effect in the inflammatory lung.