Faculty Bibliography

Background: Autoantibody responses have long been associated with the severity of pulmonary arterial hypertension. Previous studies in our lab have shown that a prolonged T helper 2 (Th2) response to inhaled antigen induces severe pulmonary arterial remodeling. We have also shown that urban particulate matter (PM) from air pollution exacerbates antigen induced pulmonary arterial remodeling and pulmonary hypertension. The present study was designed to identify the role of B cells (antibody producing lymphocytes) for pulmonary hypertension induced by antigen and urban PM. Methods: The respirable fraction of urban airborne PM (urban PM2.5) was collected in New York City. Mice were primed for a Th2 response with antigen adsorbed to Alum and then challenged with soluble antigen (Ovalbumin) combined with urban PM2.5 intranasally. We determined pulmonary arterial remodeling by histology, right heart hypertrophy by measuring heart weights and right ventricular systolic pressures by heart catheterization in anaesthetized, spontaneously breathing mice. Results: In contrast to wild type, Th2 primed B cell KO mice had no significantly increased right heart weights, or right heart systolic pressures in response to intranasal antigen and urban PM2.5. Reconstitution with anti-antigen antibody restored the development of pulmonary hypertension in antigen-urban PM2.5 challenged B cell KO mice. Like wild type mice, B cell KO mice had significant pulmonary arterial remodeling that was slightly increased by reconstitution with antibody. Conclusions: Our studies suggest that antigen-specific antibody is necessary for the development of pulmonary hypertension induced by the exposure to a Th2 antigen combined with urban PM2.5. Current studies are aimed at identifying mRNA and microRNA species that are differentially expressed in the right hearts of antibody reconstituted B cell KO mice that were exposed to antigen and urban PM2.5

Following a peak in asthma mortality in the late 1980s and early 1990s, we have been fortunate to see a substantial decrease in asthma deaths in recent years. Although most asthma deaths occur outside the hospital, near-fatal events are commonplace, with anywhere from 2-20% of patients with acute asthma admitted to intensive care, and 2-4% intubated for respiratory failure. Standard therapies for acute severe and near-fatal asthma include administration of systemic corticosteroids, and frequent or continuous inhaled beta agonists. Controversy remains regarding the optimal therapy of those who fail to respond to these initial treatments, those who remain at risk of acute respiratory failure, and patients requiring mechanical ventilation. There remain significant gaps in our knowledge regarding relative benefits of intravenous versus oral corticosteroids, intermittent versus continuous beta agonists, and the role of various adjunctive treatments including intravenous magnesium, systemic beta agonists, aminophylline, and helium-oxygen mixtures. Using models and radiolabeled aerosols, there is a greater understanding regarding effective administration of inhaled beta-agonists in ventilated patients. There is limited available evidence for treatment of near-fatal asthma, a fact reflected by the significant variability in asthma critical care practice. Much of the data guiding treatment in this setting has been generalized from studies of acute asthma in the ED and from general populations of hospitalized patients with acute asthma. This review will focus on pharmacologic approaches to life-threatening asthma by reviewing current guideline recommendations, reviewing the scientific basis of the guidelines, and highlighting gaps in our knowledge in treatment of refractory acute or near-fatal asthma

RATIONALE: Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003-2004 and 2006-2007), but lung function data were lacking. OBJECTIVES: To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case-control study of exposed adult residents and area workers 7-8 years post-9/11/2001. METHODS: Registrants reporting post-9/11 onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential controls. Final case-control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed. MAIN RESULTS: We identified 180 cases and 473 controls. Cases were more likely than controls to have abnormal spirometry (19% versus 11%, P<0.05), and impulse oscillometry measurements of elevated airway resistance, R5 (68% versus 27%, P<0.0001) and frequency dependence of resistance, R5-20 (36% versus 7%, P<0.0001). When spirometry was normal, cases were more likely than controls to have elevated R5 and R5-20 (62% versus 25% and 27% versus 6% respectively, both P<0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (BMI, spirometry, exposures) were analyzed using logistic regression. CONCLUSIONS: This study links persistent respiratory symptoms and oscillometric abnormalities in WTC-exposed residents and area workers. Elevated R5 and R5-20 in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms

OBJECTIVE: : To describe pathologic findings in symptomatic World Trade Center-exposed local workers, residents, and cleanup workers enrolled in a treatment program. METHODS: : Twelve patients underwent surgical lung biopsy for suspected interstitial lung disease (group 1, n = 6) or abnormal pulmonary function tests (group 2, n = 6). High-resolution computed axial tomography and pathologic findings were coded. Scanning electron microscopy with energy-dispersive x-ray spectroscopy was performed. RESULTS: : High-resolution computed axial tomography showed reticular findings (group 1) or normal or airway-related findings (group 2). Pulmonary function tests were predominantly restrictive. Interstitial fibrosis, emphysematous change, and small airway abnormalities were seen. All cases had opaque and birefringent particles within macrophages, and examined particles contained silica, aluminum silicates, titanium dioxide, talc, and metals. CONCLUSIONS: : In symptomatic World Trade Center-exposed individuals, pathologic findings suggest a common exposure resulting in alveolar loss and a diverse response to injury

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment

Introduction: Mouse RELMalpha is a member of the resistin family of adipokines and is expressed by many cell types including intestinal and airway epithelial cells, macrophages activated in the course of Th2 responses (alternatively activated macrophages), dendritic cells and white adipose tissue. This molecule is also known as Found in Inflammatory Zone (FIZZ) and Hypoxia Induced Mitogenic Factor (HIMF). The human homologue, RELMbeta, is expressed at increased levels in the pulmonary artery in pulmonary arterial hypertension and is a mitogen for human vascular smooth muscle cells. Methods: Our studies focused on the role of RELMalpha in severe pulmonary arterial remodeling induced by a T helper 2 (Th2) response to antigen. We studied wild type and RELMalpha deficient mice following immunization with Ovalbumin (OVA) complexed to Alum and exposure to soluble OVA alone or in combination with respirable urban particulate matter. The urban particulate matter (PM2.5) was collected from the air in New York City. Results: The study showed that the number of cells that stain positively for RELMalpha by immunohistochemistry was significantly correlated with the severity of pulmonary arterial remodeling. Furthermore, our studies demonstrated a significant exacerbation of pulmonary arterial remodeling in antigen primed wild type mice exposed to a combination of antigen and urban particulate matter. RELMalpha deficient mice, in contrast, failed to show the exacerbation and developed pulmonary arterial thickening to exposure with antigen and respirable urban particulate matter to a significantly smaller degree relative to wild type. The severity of inflammation and the type of the immune response in the RELMalpha deficient mice challenged with antigen or the combination of antigen and urban particulate matter was not significantly different from the responses in wild type mice. Conclusion: RELMalpha is known to have a critical role in hypoxia induced pulmonary arterial remodeling; and combustion of fossil fuels releases airborne metals that can mimic hypoxia induced cell signaling. Therefore, our data suggest the idea that hypoxia-mimetic metals contained within urban particulate matter exacerbate pulmonary arterial remodeling induced by a Th2 response to antigen via synergistic augmentation of RELMalpha expression

Rationale: Ambient pollutants upregulate cytokines involved in mucosal immune responses. We recently demonstrated that diesel exhaust particle (DEP)-treated human bronchial epithelial cells (HBEC) upregulated myeloid dendritic cell (mDC) maturation and promoted DC that support Th2 polarization via HBEC-derived thymic stromal lymphopoietin (TSLP). IL-33 is an IL-1 like cytokine that signals via a heterodimer (IL-1RL1, ST2 and IL-1R accessory protein; IL-1RAcP). Genetic variants of IL-33 and ST2 are associated with asthma. Since IL-33/ST2 signaling acts in synergy with TSLP to induce Th2 responses, we hypothesized that DEP-treated HBEC up-regulate expression and release of IL-33 and support mDC maturation. Methods: Primary culture HBEC (pHBEC) were treated with PBS (resting), PMA (5ng/ml), or DEP (3mug/cm²) and total RNA (6h) or supernatant (18h) isolated. Immature mDC isolated from peripheral blood (magnetic selection, BDCA-1) were exposed to resting or treated pHBEC (48h). mDC function was determined by the ability to support an allogeneic mixed lymphocyte reaction (aMLR) after rescue from pHBEC co-culture by FACS sorting. T cell proliferation was measured by BrdU-incorporation. Results: DEP-treated pHBEC upregulated IL-33 mRNA (2.5+/-0.5 fold induction, n=3; mean +/- SEM; p<0.05). Soluble IL-33 was undetected from resting pHBEC but was increased by DEP treatment (7.2+/-0.2pg/ml; n=3, p<0.05). mDC expressed ST2 and IL-1RacP (FACS analysis) but neither DEP nor DEP-treated pHBEC changed their expression. As previously reported, DEP-treated pHBEC upregulated mDC function (aMLR). Anti-IL-33 pAb reduced DEP-treated pHBEC-dependent functional maturation of mDC, (26+/-7% reduction; n=3; p<0.05). The reduction observed was less than that with anti-TSLP pAb (48+/-8% reduction; n=3; p<0.05). Conclusion: DEP-treated pHBEC upregulated IL-33 transcription and supernatant protein and upregulation was associated with functional mDC maturation. Our data suggest that DEP upregulated Il-33 and TSLP in pHBEC, and these may act in concert to induce mDC regulated Th2 immune-responses at mucosal sites

BACKGROUND: Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. OBJECTIVES: To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09-2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94-1.17, p = 0.33). CONCLUSIONS: Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction