Project Grant R03HL171347

PROTECTIVE ROLE OF B CELLS IN HYPEROXIC LUNG INJURY - HIGH CONCENTRATIONS OF INSPIRED OXYGEN ARE NECESSARY DURING TREATMENT OF CRITICALLY ILL PATIENTS WITH IMPAIRED LUNG FUNCTION, SUCH AS THOSE WITH ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). HOWEVER, STUDIES IN ANIMAL MODELS SHOW THAT HYPEROXIA MAY FURTHER EXACERBATE PULMONARY INFLAMMATION AND COMPOUND LUNG INJURY. FOUR-DAY EXPOSURE OF C57BL/6 MICE TO FIO2>90% LEADS TO DIFFUSE ALVEOLAR DAMAGE AND IMMUNE CELL INFILTRATION OF THE LUNGS, INCLUSIVE OF NKT CELLS AND NEUTROPHILS. WE RECENTLY DISCOVERED THAT EXPERIMENTAL HYPEROXIA IS ASSOCIATED WITH PROFOUND LOSS OF PULMONARY B CELLS. SUCH B CELL DEPLETION HAS ALSO BEEN REPORTED IN PATIENTS WITH ARDS. WE NOW SHOW THAT ADOPTIVE TRANSFER OF NAIVE B CELLS DURING HYPEROXIC EXPOSURE NOT ONLY ADDRESSES THE B CELL DEPLETION BUT ALSO LIMITS NEUTROPHIL INFILTRATION AND DECREASES THE SEVERITY OF LUNG INJURY. OUR CENTRAL HYPOTHESIS FOR THIS NOVEL LINE OF INVESTIGATION IS THAT HYPEROXIA IMPACTS PULMONARY B CELL NUMBERS AND/OR REGULATORY FUNCTIONS PROVOKING INFLAMMATION. THE COROLLARY IS THAT THIS PROCESS CAN BE REVERSED, AND LUNG INJURY MITIGATED BY ADMINISTRATION OF NAIVE B CELLS. WE PROPOSE THAT STRATEGIES PRESERVING OR AUGMENTING B CELL NUMBERS IN THE LUNGS COULD PROMOTE IMMUNE REGULATION AND MITIGATE INFILTRATION WITH INFLAMMATORY CELL SUBSETS (E.G., NKT CELLS, NEUTROPHILS) DURING HYPEROXIA. IN AIM 1, WE WILL CHARACTERIZE THE DYNAMICS OF B CELL RESPONSES DURING HYPEROXIA AND EXAMINE THE PROTECTIVE IMPACTS OF B CELL SUPPLEMENTATION. WE WILL ALSO TEST WHETHER PROTECTIVE EFFECTS OF EXOGENOUS B CELLS ARE MEDIATED BY IL-10 OR OTHER FACTORS. IN AIM 2, WE WILL STUDY MECHANISTIC INTERACTIONS BETWEEN PROTECTIVE B CELLS AND PATHOGENIC NKT CELLS DURING HYPEROXIA AS MEDIATED VIA THE AUTOTAXIN- LYSOPHOSPHATIDIC ACID PATHWAY. WE WILL TEST WHETHER DELETION OF NKT CELLS OR INHIBITION OF AUTOTAXIN FUNCTIONS IMPROVE B CELL NUMBERS IN THE LUNGS AND/OR OTHERWISE ENHANCE PROTECTIVE EFFECTS OF ADOPTIVE B CELL IMMUNOTHERAPY. THIS R03 AWARD WILL PROVIDE NEW DATA ON THE REGULATORY ROLE OF B CELLS IN HYPEROXIC LUNG INJURY AND ENSURE ESSENTIAL SUPPORT TO PI DR. HANIDZIAR ON HIS PATH TO BECOME AN INDEPENDENT, R01 FUNDED INVESTIGATOR.