Location of Pulmonary Mast Cells Predicts Asthma Outcomes

Pulmonary mast cells (MC) have been associated with asthma pathogenesis. We have previously shown differences in MC phenotype by location in the lung (submucosa and epithelium) [Balzar, AJRCCM, 2011]. Little is known regarding the relative importance of luminal MCs to asthma. We hypothesized that distal/luminal MCs would better predict more severe clinical outcomes than proximal/epithelial MCs. In 102 University of Pittsburgh asthmatics enrolled in NHLBI trials, bronchial epithelial brushings, bronchoalveolar (BAL) cells and fluid were obtained at bronchoscopy. Expression of the MC protease, tryptase mRNA was determined by qRT-PCR. Using the median tryptase mRNA values for epithelial brushings and BAL cells, subjects were classified as proximal and distal MC “Hi” or “Lo.” Regression analysis was performed to assess the effect of MC “Hi” on the outcomes of history of recent exacerbation, baseline FEV1% predicted and FEV1/FVC. Distal MCHi asthma significantly predicted exacerbation [OR=3.6, p=0.004], while proximal MCHi asthma did not [OR=1.7, p=0.2]. Distal MCHi asthma negatively associated with baseline FEV1% predicted [Beta= -12.5, p=0.006, R2=0.07] and baseline FEV1/FVC [Beta= -0.06, p=0.019, R2=0.05]. This relationship was not seen with proximal MCHi asthma [p for FEV1% predicted=0.6, p for FEV1/FVC=0.8]. In matched samples from asthmatic subjects, the distal/BAL cell MC signature better predicted asthma exacerbation, lower FEV1%predicted and decreased FEV1/FVC than the proximal/epithelial MC signature. In asthma, this suggests an important difference in MC function based on the location in the lung. Use of distal MC biomarkers should better identify more clinically severe asthma.