Survivors of acute respiratory distress syndrome (ARDS) manifest pulmonary and neurological sequelae, as clearly documented during the COVID-19 pandemic. The goal of this project is to ameliorate both pulmonary and brain neuronal injury in ARDS and mitigate against long-term complications. Using a mouse model of hyperoxic lung injury, we recently discovered that hyperoxia leads to a surprisingly profound depletion of pulmonary B cells, with regulatory and memory B cell subsets being particularly vulnerable. B cell depletion has also been reported in patients with ARDS. We aim to modulate inflammatory responses in ARDS by administering B cells that would ameliorate this deficit and restore immune regulation. We now show that systemic administration of naïve B cells has significant anti-inflammatory and tissue-protective effects in hyperoxic lung injury and that a fraction of these B cells traffic to the lungs. Our central hypothesis is that adoptively transferred naïve B cells provide multiorgan protection in hyperoxia-associated ARDS; we propose that this is achieved by trafficking to the sites of tissue injury to restore immune regulation and suppress inflammatory responses in IL-10 and/or adenosine-dependent manner. In Aim 1, we will study the efficiency of B cell homing to the lungs and brain and characterize the phenotype(s) of B cells that home in these inflamed sites. In Aim 2, we will identify the immunomodulatory effects of adoptively transferred B cells in the lungs and brain and study their dependence on B cell-derived non-Ig factors including IL-10 and adenosine. In Aim 3, we will determine the effects of syngeneic and allogeneic B cell therapy on long-term pulmonary and neurologic outcomes. Understanding long-term outcomes after allogeneic B cell therapy will be critical for future translation of this therapy into clinical practice. The results of these proposed experimental studies will direct our further research into B cell therapy for ARDS. Our studies may have substantive translational impacts, in identifying novel therapeutic targets for treating patients with this highly significant and increasingly common clinical problem.