Role of maresin 1 in the resolution of lung inflammation

Brigham And Women'S Hospital, Boston MA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) affects more than 125,000 patients in the US annually, and carries significant morbidity and mortality rates approaching 40%. Despite increased understanding of the initiating events leading to ARDS, therapies directed at these mechanisms have failed to improve the lives of patients with this devastating disease. Unintended bystander lung tissue injury and dysfunction from dysregulated acute inflammation are the hallmarks of ARDS. In health, acute inflammatory responses are terminated by specialized pro-resolving mediators (SPMs) that restrain the inflammatory response and signal for resolution. A new family of docosahexaenoic acid-derived SPMs from macrophages was recently uncovered in murine peritonitis and coined maresins (i.e., macrophage mediators in resolving inflammation). In work in progress, we have identified a new intra-vascular biosynthetic pathway for maresin 1 (MaR1) early after acute lung injury (ALI) that is pivotal to controlling lung inflammation and protecting lung function. Of note, at a later time point after ALI, MaR1 is produced via a different biosynthetic route that involves lung tissue macrophages. We hypothesize that MaR1 activates resolution pathways that are critical in ARDS. To investigate this hypothesis, we have proposed the following specific aims: 1) to determine restoration of lung function by MaR1 after ALI using established and innovative methods; 2) to determine the role of MaR1 on monocyte recruitment for resolution of acute lung injury; 3) to examine the role of MaR1 in macrophage programming, and the macrophage subsets that serve as the cellular source of MaR1 during resolution of acute lung inflammation. We will use a clinically relevant murine model of ARDS for discovery and mechanistic experiments, and validate these findings in human samples from a Registry of Critical Illness. Under the guidance of his mentor Dr. Bruce D. Levy, the principal investigator has developed a five-year training program that includes tailored didactic activities, and mechanisms to ensure continued mentoring and supervision, to develop the skills necessary to become a successful physician-scientist in the field of pulmonary and critical care medicine. The candidate's training will be overseen by an advisory committee with expertise related to key areas of this proposal including ALI, resolution of inflammation, monocyte/macrophage biology, and functional imaging. The proposed career development plan will establish scientific foundations and provide the additional training necessary to achieve the principal investigator's ultimate goal of becoming an independent investigator studying the biologic basis for resolution of ARDS.