Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening diseases in critically ill patients that continue to increase rapidly. Disease incidence is projected to increase to 335,000 cases/year by 2030, with deaths nearly doubling to 147,000 deaths/year. Treatment of patients typically consists of supportive positive pressure ventilation, as no effective targeted therapy currently exists. Severe sepsis is the most common (33-46%) risk factor for ALI/ARDS. To enable discovery of new specific therapeutic targets and to effectively manage sepsis-induced ALI/ARDS (sepsis-ALI/ARDS), a better understanding of injury-causing pathogenic mechanisms is required.  An emerging theory of sepsis-induced ALI (sepsis-ALI) and ARDS (sepsis-ARDS) is that lung damage is due to the release of nuclear proteins from cell death such as neutrophil extracellular traps (NETs) and pyroptosis in the host response to infection. We have discovered that citrullinated histone H3 (CitH3), a subtype of histones, is a significant mediator of sepsis pathogenesis, which was previously unrecognized. Our clinical preliminary data show that CitH3, citrullinated by peptidylarginine deiminases 2 and 4 (PAD2 and PAD4), is also an important biomarker of sepsis-ARDS. The CitH3 levels in plasma and bronchoalveolar lavage (BAL) are increased only in patients with infectious ARDS but not with non-infectious ARDS. In mice, CitH3 induces macrophage pyroptosis. Our central hypothesis is that infection causes neutrophils to release NETs and CitH3, and high levels of CitH3 induce pyroptosis, resulting in the death of alveolar macrophages and epithelial cells; CitH3 is also a biomarker that can distinguish levels of severity in sepsis-ARDS and can aid clinical management. We recently generated a novel CitH3 mouse monoclonal antibody which reduces ALI and improves survival significantly in mouse sepsis models. Our project is to develop a humanized CitH3 antibody and explore the new intervention for diagnosis/ treatment of patients with sepsis-induced ALI/ARDS.  We will evaluate the mechanism and clinical significance of CitH3 in sepsis-ALI/ARDS. Accomplishment of the proposed studies will considerably advance the field by revealing the potentially crucial role that CitH3 plays in sepsis-ALI/ARDS, which may disclose novel therapeutic targets that could lead to new therapies to ameliorate sepsis-ALI/ARDS.