Faculty Bibliography

RATIONALE: Obesity is characterized by increased systemic and pulmonary blood volumes (pulmonary vascular congestion). Concomitant abnormal alveolar membrane diffusion suggests subclinical interstitial edema. In this setting, functional abnormalities should encompass the entire distal lung including the airways. OBJECTIVES: We hypothesize that in obesity: 1) pulmonary vascular congestion will affect the distal lung unit with concordant alveolar membrane and distal airway abnormalities; and 2) the degree of pulmonary congestion and membrane dysfunction will relate to the cardiac response. METHODS: 54 non-smoking obese subjects underwent spirometry, impulse oscillometry (IOS), diffusion capacity (DLCO) with partition into membrane diffusion (DM) and capillary blood volume (VC), and cardiac MRI (n = 24). Alveolar-capillary membrane efficiency was assessed by calculation of DM/VC. MEASUREMENTS AND MAIN RESULTS: Mean age was 45+/-12 years; mean BMI was 44.8+/-7 kg/m2. Vital capacity was 88+/-13% predicted with reduction in functional residual capacity (58+/-12% predicted). Despite normal DLCO (98+/-18% predicted), VC was elevated (135+/-31% predicted) while DM averaged 94+/-22% predicted. DM/VC varied from 0.4 to 1.4 with high values reflecting recruitment of alveolar membrane and low values indicating alveolar membrane dysfunction. The most abnormal IOS (R5 and X5) occurred in subjects with lowest DM/VC (r2 = 0.31, p<0.001; r2 = 0.34, p<0.001). Cardiac output and index (cardiac output / body surface area) were directly related to DM/VC (r2 = 0.41, p<0.001; r2 = 0.19, p = 0.03). Subjects with lower DM/VC demonstrated a cardiac output that remained in the normal range despite presence of obesity. CONCLUSIONS: Global dysfunction of the distal lung (alveolar membrane and distal airway) is associated with pulmonary vascular congestion and failure to achieve the high output state of obesity. Pulmonary vascular congestion and consequent fluid transudation and/or alterations in the structure of the alveolar capillary membrane may be considered often unrecognized causes of airway dysfunction in obesity.

Background: Rheumatoid arthritis (RA) is a complex, autoimmune disease in which several genetic and environmental factors play a role. Recent data suggest that the gut and oral microbiome might potentially contribute to an aberrant systemic immune response characteristic of RA. Among recently studied microbiota, both P. gingivalis in the oral cavity1 and P. copri2 in the gut have been implicated. Imaging abnormalities seen in RA patients and also in at-risk individuals for the development of disease3 along with the presence of autoantibodies in the airways4 implicates the lung as yet another site of autoimmunity generation in RA. Objectives: To test whether the RA lung microbiome contains distinct taxonomic features that associate with local and/or systemic autoimmunity Methods: Bronchoalveolar lavage (BAL) samples from 20 subjects with RA and 10 with sarcoidosis were obtained by research bronchoscopy. 16S rDNA sequencing was performed to define microbiota composition. Levels of arginine/citrulline were measured in BAL fluid using GC-MS for all samples. Autoantibodies, including anti-CCP, RF and ACPAs were also measured in RA subjects in BAL and serum. Statistical analysis was performed using wilcoxon test and Spearman correlation. Results: There were no differences in demographic or clinical characteristics (including smoking status) between the groups. 16S sequencing data show similar alpha and beta diversity based on UniFrac between groups. Taxonomic comparison between RA and sarcoidosis was performed using LEfSe, which revealed several significant differences (LDA score>2). While RA BAL samples were enriched with Sphingobacteria, sarcoidosis BAL was enriched with Bacteroidia, Rhizobiales, Nitrospirales, and Campylobacter. GC-MS showed similar levels of arginine and citrulline in BAL for the sarcoidosis and RA groups. Raoultella and Barnesiella correlated with CCP2 levels in BAL (rho=0.49 and 0.47; p-value=0.026 and 0.032 respectively). Serum levels of CCP-IgA had a negative correlation with Massilia and Tannerella (rho= -0.63 and 0.53; p-value 0.003 and 0.016, respectively), and a positive correlation with Vagococcus and Lactobacillus (rho=0.59 and 0.54; p-value 0.006 and 0.014, respectively). Unclas-Lactobacillales also had a positive correlation with serum levels of RF-IgA (rho=0.71; p-value <0.001). Serum levels of anti-CCP2 antibodies had a negative correlation with Escherichia and Bdellovibrio (rho=-0.47 and 0.45, p-value=0.03 and 0.04 respectively), and a positive correlation with Porphyromonas, Rahnella and Chryseobacterium (rho=0.46, 0.46 and 0.45; p-value=0.03, 0.03 and 0.04 respectively). Conclusions: Despite the relatively small number of samples analyzed, several taxonomic differences were noted between RA and Sarcoidosis. Correlations between relative abundance of specific taxa in BAL with serum autoantibodies (i.e., anti-CCP) support an association between the lung microbiome and the host immune phenotype in RA. Further evaluation of functional aspects of this microbiome may provide further insights into its possible contribution to RA

Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets.