Project Summary Candidate: Jehan Alladina, MD is a physician-scientist at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS). Her post-doctoral research interrogated type 2 (T2) immune pathways in allergic asthma. Building on that work, this proposal investigates the role of T2 immunity in acute respiratory distress syndrome (ARDS). The short-term goals of this K08 award are to provide training in murine models of acute lung injury (ALI), longitudinal statistical modeling of patient data, and translational research. Dr. Alladina’s long-term goal is to lead an independent research program on the host immune response in ARDS. Training Activities: Dr. Alladina will perform the work outlined in this proposal at MGH under the mentorship of Dr. Benjamin Medoff, an experienced mentor and expert in lung immunology; Dr. Eric Schmidt, a leading expert in animal models of ALI and sepsis; and Dr Steven Skates, an accomplished biostatistician with expertise in developing longitudinal algorithms to predict disease trajectory. Drs. David Christiani, Nuala Meyer, and Anne Sperling will serve on Dr. Alladina’s advisory committee to provide further expertise in longitudinal ARDS cohorts, molecular risk factors for ARDS, and mechanisms of lung inflammation and resolution. Dr. Alladina will also complete didactic courses in immunology, biostatistics, and translational research and will take advantage of the collaborative and rich intellectual environment at MGH and HMS. Research: ARDS is the severe consequence of inflammatory lung injury and 40% of patients have progressive disease characterized by persistent lung inflammation, fibrosis, and increased mortality. Identification of immune regulatory pathways in ARDS, and how they change over the disease trajectory, could identify biomarkers that predict outcomes and novel targets to prevent ARDS progression. Our preliminary animal and human data demonstrate that T2 immunity is induced in ALI/ARDS and that IL-33, an upstream inducer of T2 inflammation, improves survival in a murine model of influenza-induced ALI. Moreover, soluble ST2 (sST2), an endogenous inhibitor of IL-33, is associated with increased ARDS mortality and time on the ventilator. Thus, I hypothesize that increased sST2 signaling blocks T2-mediated pro-resolution and repair pathways in ARDS, leading to persistent pathological inflammation and fibrosis. To test this hypothesis, I will determine the causal role of IL-33 and its endogenous inhibitor sST2 in ALI onset and resolution. I will leverage inducible transgenic animals to manipulate IL-33 and sST2 expression early and late during ALI. I will also measure plasma and airspace IL-33, sST2, and T2 cytokine levels in ARDS patients over time, and develop hierarchical longitudinal models to differentiate as early as possible whether a patient will progress or recover. By leveraging murine models and longitudinal human data, this proposal can establish both causality and relevance to hum...