Project Grant R01HL169265

ALVEOLAR MACROPHAGE SUBSET ONTOGENY AND DIFFERENTIATION DURING ARDS - PROJECT SUMMARY/ABSTRACT ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS CHARACTERIZED BY THE ACUTE ONSET OF SEVERE HYPOXEMIA ASSOCIATED WITH BILATERAL PULMONARY OPACITIES ON IMAGING THAT ARE NOT FULLY EXPLAINED BY CARDIAC DYSFUNCTION. ARDS HAS A MAJOR IMPACT ON GLOBAL HEALTH, REPRESENTING 10% OF INTENSIVE CARE UNIT ADMISSIONS, 23% OF PATIENTS SUPPORTED ON INVASIVE MECHANICAL VENTILATION, AND HAS AN ASSOCIATED MORTALITY OF 35%. DESPITE THIS BURDEN ON PUBLIC HEALTH, THERE ARE NO DISEASE-MODIFYING THERAPIES FOR ARDS THAT HAVE SHOWN EFFICACY. ALVEOLAR MACROPHAGES (AMS) ARE AN ATTRACTIVE THERAPEUTIC TARGET FOR ARDS BECAUSE THEY PLAY A CENTRAL ROLE IN ALMOST ALL ASPECTS OF ITS PATHOPHYSIOLOGY. IN ANIMAL MODELS, DIFFERENT AM "SUBSETS" CAN AUGMENT INFLAMMATION, CLEAR DEBRIS/DEAD CELLS, HALT INFLAMMATION, AND COORDINATE RESPONSES FROM OTHER CELL-TYPES (E.G. T CELLS). THESE DISTINCT AM FUNCTIONS ARE LARGELY DETERMINED BY CELL "ONTOGENY" (RESIDENT VS. RECRUITED). RESIDENT AMS (RAMS) ARE EMBRYONICALLY-DERIVED AND SELF-RENEW DURING LIFE. IN INJURY, BLOOD MONOCYTES ARE RECRUITED TO THE LUNG AND MATURE INTO MONOCYTE-DERIVED MACROPHAGES (MOMS) THAT REPLENISH DEPLETED RAMS. PRELIMINARY DATA IN THIS PROPOSAL AND PRIOR PUBLICATIONS HAS IDENTIFIED AM SUBSETS THAT ARE ASSOCIATED BETTER (E.G. CD71HIPD-L1HI, CD123HI) OR WORSE (E.G. CD163HI, CD14HI ALVEOLAR MONOCYTES) ARDS OUTCOMES. THE FUNCTIONAL ROLES OF THESE DIFFERENT AM SUBSETS IN HUMANS, AND HOW ONTOGENY CONTRIBUTES TO THEIR DEVELOPMENT AND FATE, ARE NOT KNOWN. THE PRIMARY OBJECTIVE OF THIS PROJECT IS TO DETERMINE HOW AM SUBSET ONTOGENY AND FUNCTION CONTRIBUTE TO ARDS CLINICAL OUTCOMES. AIM 1 IS A MECHANISTIC AIM THAT WILL LEVERAGE AM CHIMERISM IN LUNG TRANSPLANT RECIPIENTS TO TEST THE HYPOTHESIS THAT RECRUITED BLOOD MONOCYTES CAN MATURE INTO EITHER PROTECTIVE OR HARMFUL MOM SUBSETS. AIM 2A IS A TRANSLATIONAL AIM THAT WILL PERFORM INTRACELLULAR CYTOKINE STAINING, EFFEROCYTOSIS ASSAYS, AND AM/T CELL CO-CULTURING ON AM SUBSETS COLLECTED FROM A MULTI-CENTER COHORT OF SUBJECTS WITH ARDS TO TEST THE HYPOTHESIS THAT DIFFERENT AM SUBSETS HAVE HIGHLY DISTINCT FUNCTIONAL PROPERTIES. AIM 2B IS A CLINICAL AIM THAT WILL TEST FOR ASSOCIATIONS BETWEEN AM SUBSETS AND PATIENT-CENTERED ARDS CLINICAL OUTCOMES. THIS PROJECT LEVERAGES A MULTI-DISCIPLINARY TEAM OF EXPERTS IN ARDS, LUNG TRANSPLANT, MACROPHAGE BIOLOGY, IMMUNOLOGY, AND COMPUTATIONAL BIOLOGY. FINDINGS FROM THIS PROJECT WILL PROVIDE KEY INSIGHTS INTO ARDS PATHOBIOLOGY, FORMING A BASIS FOR FUTURE INTERVENTIONAL STUDIES TO DETERMINE HOW TO TARGET AMS IN ARDS AND OTHER INFLAMMATORY CONDITIONS OF THE LUNG.