Faculty Bibliography

RATIONALE: Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function. OBJECTIVE: Define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure. METHODS: A nested case-control study of FDNY personnel with normal pre-9/11 FEV1 and who presented for subspecialty pulmonary evaluation before 3/10/2008. We correlated metabolic syndrome biomarkers obtained within six months of World Trade Center Dust exposure with subsequent FEV1. FEV1 at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV1<lower limit of normal (LLN) while controls had FEV1>/=LLN. MEASUREMENTS: Clinical data and serum sampled at the first monitoring exam within six months of 9/11/2001 assessed BMI, heart rate, serum glucose, Triglycerides/High Density Lipoprotein (HDL), Leptin, Pancreatic Polypeptide and Amylin. MAIN RESULTS: Cases and controls had significant differences in HDL<40 mg/dL with Triglycerides >/=150 mg/dL, heart rate >/=66 bpm, and Leptin >/=10,300 pg/mL. Each increased the odds of abnormal FEV1 at pulmonary evaluation by more than 2 fold, while Amylin >/=116 pg/mL decreased the odds by 84%, in a multi-biomarker model adjusting for age, race, BMI and WTC arrival time. This model had a sensitivity of 41%, a specificity of 86% and a ROC AUC of 0.77. CONCLUSION: Abnormal triglycerides and HDL, elevated heart rate and Leptin are independent risk factors of greater susceptibility to lung function impairment after 9/11/2001 while elevated Amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation

Abstract BACKGROUND:The World Trade Center (WTC) collapse produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-9/11. METHODS:In a cohort of 801 never smokers with normal pre-9/11 FEV(1), we correlated inflammatory biomarkers and complete blood counts at monitoring entry within 6 months of 9/11/2001 with a median FEV(1) at SPE (34 months, IQR 25-57). Cases of airflow obstruction had FEV(1) < LLN (100/801; 70/100 had serum) while controls had FEV(1) >/= LLN (153/801; 124/153 had serum). RESULTS:From monitoring entry to SPE, years later, FEV(1) declined 12% in cases and increased 3% in controls. Cases had elevated serum MDC, GM-CSF, G-CSF and IP-10. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) < LLN by 2.5 fold (95% CI; 1.2-5.3) and 3.0 fold (1.4-6.1) in a logistic model adjusted for exposure, BMI, age on 9/11, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI 27-51), specificity of 88% (80-93). CONCLUSIONS:Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure

Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputum-based molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers.

The development of lung cancer in humans can be divided into three steps: initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis.

Rationale: Lung cancer is the leading cause of death from all types of cancer worldwide. The high mortality rate is partly attributed to the lack of methods for early detection and identification of patients who are at risk for developing disease. Since adenocarcinoma in the lung periphery is the most common type of lung cancer and the earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the peripheral airways, we hypothesize that identifying gene expression signatures in the peripheral airways will provide the best approach for better understanding field carcinogenesis of lung adenocarcinomas. To this end, we performed gene and miRNA profiling of cells obtained from brushings of peripheral airways of smokers with and without lung adenocarcinomas. These studies will provide not only mechanistic insights into field carcinogenesis of adenocarcinoma, but more importantly, potential tools for the early detection of lung adenocarcinomas. To this end, we performed gene expression profiling of the peripheral small airway epithelium of patients with lung cancer and compared it to that of non-cancerous smokers to identify gene expression signatures of field cancerization in lung cancer. Methods: Fiberoptic bronchoscopies with brushings were used to collect peripheral airway epithelial cells from the 10^th-12^th-order bronchi in non-cancerous smokers or from the unaffected lobe of suspected lung cancer patients. Clinical samples obtained from the suspected lung cancer patients confirmed the histological diagnosis of primary lung cancer. Using Affymetrix HG-U133A Plus 2.0 microarrays, we performed gene expression profiling of over 47,000 genes using total RNA isolated from small airway epithelial cells obtained from brushings of both lung cancer patients and non-cancerous smokers. Results: Microarray analysis of the gene expression profile in the peripheral airway epithelium demonstrated several up-regulated and down-regulated genes which could represent significant alterations in lung cancer. Significantly up-regulated genes included pro-platelet basic protein, gremlin 1, aminolevulinate synthase 2, sparc/osteonectin, and wnt inhibitory factor 1 while down-regulated genes include cytochrome P450 1B1 and 2A6, mucin 2, aldedyhe dehydrognease 3A1, and glutathione peroxidase 2 (p value < 0.05). Conclusion: We had identified several up-regulated and down-regulated genes in peripheral airway epithelial cells of cancer patients which were significantly different when compared to non-cancerous smokers. Identification of the gene expression signatures in field carcinogenesis will not only provide mechanistic insights into lung cancer, but also allow us to identify novel biomarkers for the early detection of lung cancer

Introduction The lung is a common target of HIV-associated morbidity, but there are few studies of long-term pulmonary consequences of HIV infection after successful introduction of antiretroviral drugs (ARVs), particularly in developing countries with high rates of tuberculosis. Methods: A cross-sectional analysis of a prospective cohort of 152 participants with HIV infection, stable on antiretroviral therapy for at least 3 months, and without features of acute respiratory disease, was performed. Clinical and demographic information was recorded in a respiratory questionnaire, and pulmonary function tests including flow-volume loops before and after bronchodilator, body plethysmography and measurement of diffusing capacity were performed. Results: The participants were predominantly black African (81.3%) and female (53.4%); mean age was 38.4 (SD+/-8.4) years, and 32.9% had a history of tobacco smoking. The median duration of time on ART was 2.1 years (range 0.25-7.56), and the median CD₄ was 380 (range 25-1227). Forty-one percent reported a history of previous tuberculosis, and only 3 subjects previous Pneumocystis pneumonia. None were users of intravenous drugs. Respiratory symptoms were reported in 31% of participants, and any respiratory symptom (cough, phlegm, wheeze or dyspnea) was strongly associated with current smoking (OR 2.556, 95% CI 1.05-6.211, P=0.04). Irreversible airflow obstruction was present in 7%, and associated with ever smoking (OR 6.352, 95% CI 1.56-25.90, P=0.01). Impairment of diffusing capacity for carbon monoxide (DL_CO <70% predicted) was present in 57%, and associated with a history of previous tuberculosis (OR 2.01, 95% CI 1.00-4.00, P=0.47), but not with current or ever smoking. Conclusions: In this relatively young cohort of treated AIDS patients, a high proportion of whom were female, evidence of smoking-induced symptoms and airflow limitation was observed. The most common lung function abnormality, however, was an impairment in diffusing capacity, which was associated with previous tuberculosis. Further research to define structure/function relationships and the role of opportunistic infections and other risk factors is underway