Tissue adaptation to damage 4303

Abstract Description Living organisms effectively manage a wide array of stressors to ensure their survival and optimal function. While a majority of research has focused on cellular stress responses, tissue-level stress responses remain poorly defined. Stressors can lead to tissue damage causing inflammatory diseases. However, repeated exposure to stressors can lead to improved resilience. Mechanisms behind these tissue adaptations to stress are not well understood. To address that, we developed a model where animals were exposed to the proteolytic toxin LasB in the lungs either once or three times. We discovered that single LasB exposure resulted in lung damage, red blood cell infiltration, and reduced lung function. In contrast, repeated exposure to LasB resulted in reduced lung damage, improved lung function, and protection from subsequent bacterial and viral infections. Using genetic animal models, sequencing, and pharmacological approaches, we determined that this adaptation is dependent on sensing of oxidative heme, comprising the tissue-level oxidative stress response. Lung alveolar macrophages are the main sensors of oxidative stress. Upon heme sensing, they induce expression of an antioxidant gene program, including heme oxygenase 1 (Hmox1). Hmox1 catabolizes heme, resulting in the accumulation of bilirubin that can relay cytoprotective responses to neighboring cells. This study provides a framework for understanding tissue remodeling and the development of memory to tissue damage. Funding Sources Yale Brown-Coxe Fellowship, LSRF-HHMI Fellowship, FASI Topic Categories Mucosal and Regional Immunology (MUC)