Faculty Bibliography

BACKGROUND: Noninvasive sputum sampling has enabled the identification of biomarkers in asthmatic patients. Studies of discrete cell populations in sputum can enhance measurements compared with whole sputum in which changes in rare cells and cell-cell interactions can be masked. OBJECTIVE: We sought to enrich for sputum-derived human bronchial epithelial cells (sHBECs) and sputum-derived myeloid type 1 dendritic cells (sDCs) to describe transcriptional coexpression of targets associated with a type 2 immune response. METHODS: A case-control study was conducted with patients with mild asthma (asthmatic cases) and healthy control subjects. Induced sputum was obtained for simultaneous enrichment of sHBECs and sDCs by using flow cytometry. Quantitative PCR was used to measure mRNA for sHBEC thymic stromal lymphopoietin (TSLP), IL33, POSTN, and IL25 and downstream targets in sDCs (OX40 ligand [OX40L], CCL17, PPP1R14A, CD1E, CD1b, CD80, and CD86). RESULTS: Final analyses for the study sample were based on 11 control subjects and 13 asthmatic cases. Expression of TSLP, IL33, and POSTN mRNA was increased in sHBECs in asthmatic cases (P = .001, P = .05, and P = .04, respectively). Expression of sDC OX40L and CCL17 mRNA was increased in asthmatic cases (P = .003 and P = .0001, respectively). sHBEC TSLP mRNA expression was strongly associated with sDC OX40L mRNA expression (R = 0.65, P = .001) and less strongly with sDC CCL17 mRNA expression. sHBEC IL33 mRNA expression was associated with sDC OX40L mRNA expression (R = 0.42, P = .04) but not sDC CCL17 mRNA expression. CONCLUSIONS: Noninvasive sampling and enrichment of select cell populations from sputum can further our understanding of cell-cell interactions in asthmatic patients with the potential to enhance endotyping of asthmatic patients.

BACKGROUND: Destruction of the World Trade Center (WTC) towers on September 11, 2001, released massive dust, gas, and fumes with environmental exposures for community members. Many community members have lower respiratory symptoms (LRSs) that began after September 11, 2001, and remain persistent. We evaluated whether systemic inflammation measured by C-reactive protein was associated with WTC dust exposures, persistent LRS, and lung function. METHODS: Community members self-referred for the treatment of symptoms related to September 11, 2001. C-reactive protein and lung function measurements, including spirometry and forced oscillation tests (impulse oscillometry system), were included as routine analyses in patients (2007 to 2012). RESULTS: Increased C-reactive protein levels were associated with the type of WTC dust exposure, LRS, reduced spirometry, and increased forced oscillation measurements (n = 724). CONCLUSIONS: Ongoing systemic inflammation measured years after the event was associated with WTC dust exposures, persistent LRS, and abnormal lung function in a community cohort. These findings have implications for treatment and surveillance.

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung's normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well-phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC-exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after WTC exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1 below the lower limit of normal known as WTC-Lung Injury (WTC-LI). We utilized a nested case-cohort control design of previously healthy never smokers who sought subspecialty pulmonary evaluation to explore predictive biomarkers of WTC-LI. We have identified biomarkers of inflammation, metabolic derangement, protease/antiprotease balance, and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services.

This review discusses biomarkers that are being researched for their usefulness to phenotype chronic inflammatory lung diseases that cause remodeling of the lung's architecture. The review focuses on asthma, chronic obstructive pulmonary disease (COPD), and pulmonary hypertension. Bio-markers of environmental exposure and specific classes of biomarkers (noncoding RNA, metabolism, vitamin, coagulation, and microbiome related) are also discussed. Examples of biomarkers that are in clinical use, biomarkers that are under development, and biomarkers that are still in the research phase are discussed. We chose to present examples of the research in biomarker development by diseases, because asthma, COPD, and pulmonary hypertension are distinct entities, although they clearly share processes of inflammation and remodeling.

Air pollution is known to exacerbate chronic inflammatory conditions of the lungs including pulmonary hypertension, cardiovascular diseases and autoimmune diseases. Directly pathogenic antibodies bind pro-inflammatory cell receptors and cause or exacerbate inflammation. In contrast, anti-inflammatory antibody isotypes (e.g. mouse immunoglobulin G1, IgG1) bind inhibitory cell receptors and can inhibit inflammation. Our previous studies showed that co-exposure to antigen and urban ambient particulate matter (PM2.5) induced severe pulmonary arterial thickening and increased right ventricular systolic pressures in mice via T-cell produced cytokines, Interleukin (IL)-13 and IL-17A. The aim of the current study was to understand how B cell and antibody responses integrate into this T cell cytokine network for the pulmonary hypertension phenotype. Special focus was on antigen-specific IgG1 that is the predominant antibody in the experimental response to antigen and urban ambient PM2.5. Wild type and B cell-deficient mice were primed with antigen and then challenged with antigen and urban particulate matter and injected with antibodies as appropriate. Our data surprisingly showed that B cells were necessary for the development of increased right ventricular pressures and molecular changes in the right heart in response to sensitization and intranasal challenge with antigen and PM2.5. Further, our studies showed that both, the increase in right ventricular systolic pressure and right ventricular molecular changes were restored by reconstituting the B cell KO mice with antigen specific IgG1. In addition, our studies identified a critical, non-redundant role of B cells for the IL-17A-directed inflammation in response to exposure with antigen and PM2.5, which was not corrected with antigen-specific IgG1. In contrast, IL-13-directed inflammatory markers, as well as severe pulmonary arterial remodeling induced by challenge with antigen and PM2.5 were similar in B cell-deficient and wild type mice. Our studies have identified B cells and antigen specific IgG1 as potential therapeutic targets for pulmonary hypertension associated with immune dysfunction and environmental exposures.