The counter balancing of pro- and anti-inflammatory gene transcription is crucial for normal homeostasis after septic tissue injury. Aberrant regulation of this transcriptional balance culminates in an unchecked systemic inflammation, leading to lung tissue damage and edema, respiratory failure and ultimately death. However, the exact mechanisms underlying pathological inflammation in sepsis are poorly understood, and thus the strategies to accelerate the resolution of sepsis are very limited. Studies in the proposal will test the novel hypothesis that pathogenic signaling caused by sepsis is the result of a macrophage-specific Fra-1/AP-1 restricted expression of anti- inflammatory A20, a crucial ubiquitin-editing enzyme that terminates uncontrolled activation of NF- ?B and MAP kinase signaling. Our preliminary studies, using three pre-clinical models of sepsis, showed that Fra-1 as a crucial mediator of pro-inflammatory responses in sepsis. Endotoxemia (LPS)- and pseudomonas pneumonia-induced lung injury and inflammation are markedly lower in Fra-1-deficient mice than wild-type counterparts. Fra-1-deficient mice subjected to injurious dose of i.t bacterial endotoxin (LPS), showed an accelerated resolution of lung injury compared to wild-type mice. We found increased expression of Fra-1 largely in alveolar macrophages of cadaveric lungs infected with E. coli ex vivo and in mice exposed to LPS. Importantly, mice lacking Fra-1 in myeloid cells survived longer than wild-type mice from septic shock and polymicrobial sepsis. In preliminary studies, we found reduced levels of LPS-induced NF-?B activation and an increased expression of A20 in Fra-1-deficient macrophages. A20 haplo-sufficiency in humans and in mice is associated with heightened levels of systemic inflammation. We will address the specific hypothesis that in the settings of chronic or pathological sepsis Fra-1 activation secondary to microbial insults restricts optimal A20 expression and triggers pro-inflammatory response, thereby impairing the resolution of sepsis. We will use physiological and molecular approaches and tissue-specific knockout mice and preclinical models of sepsis to test this hypothesis. The specific aims of the proposal are to: 1) Determine the role and mechanisms of macrophage-specific Fra-1 signaling in mediating sustained lung injury in pseudomonas pneumonia and sepsis, and 2) Examine the mechanisms by which Fra-1 restricts A20 transcriptional induction by microbial insults in macrophages, and determine that Fra-1 restricted A20 signaling is a causative factor of persistent lung injury in sepsis. The proposed studies will identify novel insights and targets for therapies to accelerate lung injury repair in patients with pseudomonas pneumonia and sepsis.