Antagonistic Effects Of Ozone (O3) Exposure and Glucocorticoid Treatment On Airway Hyperresponsiveness (AHR) and Surfactant Protein D (SP-D) Production In Mice

S U N D A Y 559 Bronchial Mast Cell Markers and Clinical Asthma Severity In Steroid Refractory Asthmatics Dr. Mandeep Hundal, MD, Dr. Katherine N. Cahill, MD, Robert Pedicini, Allison Crosby-Thompson, Stefanie Dutile, Usha Govindarajulu, PhD, Dr. Kartik Shenoy, MD, Dr. Mark Dransfield, Dr. Emily DiMango, Dr. Serpil C. Erzurum, MD, Dr. Mario Castro, MD, MPH, Dr. Nizar N. Jarjour, MD, Dr. Howard Katz, PhD, Dr. Joshua A. Boyce, MD, FAAAAI, Dr. Elliot Israel, MD, FAAAAI; Brigham and Women’s Hospital, Boston, MA, Brigham and Women’s Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA, Temple University School of Medicine, University of Alabama School of Medicine, AL, Columbia University, New York, NY, Department of Pathobiology, Cleveland Clinic, Washington University School of Medicine, St. Louis, MO, University of Wisconsin School of Medicine and Public Health, Madison, WI. RATIONALE: Mast cells are thought to play a significant role in asthma and are resistant to corticosteroid effects. Bronchial mast cells express chymase, tryptase and the c-kit receptor. We investigated the relationship between these mast cell markers and clinical asthma severity measurements in patients with steroid refractory asthma. METHODS: We recruited adult asthmatics with severe asthma symptoms (ACQ>1.5) on continuous treatment with high-dose inhaled corticosteroids (ICS) and at least one additional controller therapy. All subjects had confirmed airway hyperresponsiveness with methacholine challenge (PC20< 10 mg/ml). Endobronchial biopsies were obtained from these subjects (n527) andmast cells were immunostained for tryptase and chymase. Bronchoalveolar lavage (BAL) fluid (n528) was processed and c-kit mRNAwas measured in the BAL cell pellet using qPCR. RESULTS: Intramucosal chymase positive mast cell numbers show a positive correlation with log PC20 (r50.45, p50.02); suggesting decreasing methacholine hyperresponsiveness with increasing chymase positive mast cells. Intramucosal tryptase positive mast cell counts did not show any significant association with log PC20. FEV1/FVC ratio had a negative correlation with c-kit mRNA in the BAL cell pellet (r5-0.37, p50.05). CONCLUSIONS: Increased c-kit mRNA in BAL is related to worsening airway obstruction suggestingmast cell activity contributes to poor asthma control in steroid unresponsive asthmatics. It has been previously reported that chymase positive mast cells in severe asthma correlate with better lung function. The negative correlation between chymase positive mast cells and airway hyperresponsiveness in our study supports a unique pathobiological role for this mast cell phenotype in severe asthmatics.