Faculty Bibliography

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.

Pulmonary Hypertension is a condition that causes decreased quality of life and early mortality. The pulmonary hypertension phenotype includes severe pulmonary vascular remodeling, increased right ventricular pressure, molecular changes in the right heart, and in many cases also dysfunction of the immune response. The experimental ease by which severe vascular remodeling with mild changes in the right heart can be generated in animal models of an exacerbated, prolonged immune response in the lungs suggests the participation of pre-programmed molecular pathways and networks. Search of the literature suggests the hypothesis that the diverse ancient macro- and micro-biome of the vasculature evolutionary fine-tuned the host's immune response and also growth factor receptor signaling (epidermal growth factor receptor, transforming growth factor beta-family) to induce pulmonary arterial remodeling with mild pulmonary hypertension. The factors (protein, sugar, cytokines) produced by the parasites, pattern recognition molecules stimulated by the co-infectants of the parasites with bacteria and virus (bacteriophages) fine-tuned the host's immune response in a way that ensured the symbiosis of the parasites and the host. On the host-part the response needed to: A) Avoid fatal hemorrhage, this likely necessitated vascular remodeling with thickening of the vascular wall while preserving elasticity. B) Allow free blood flow through the arteries thus avoiding large increases in the right heart pressures, to preserve heart function. C) Optimal immune response to restrict parasite and bacterial loads while avoiding immune-pathology. D) This response pattern likely also made it necessary to maintain in the host population genetic diversity of response genes that were critical modulators of the host-microbial communication. It follows that a balanced molecular dialogue between the microbiome and the host stabilizes a symbiotic relationship with mild clinical signs in the host. The imbalance of this molecular dialogue is likely the basis for the switch to an infectious disease that causes severe pulmonary hypertension in the host. The molecular understanding of these responses is expected to significantly increase our ability to manage clinical pulmonary hypertension associated with a dysfunctional immune response, e.g. in autoimmunity

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.

Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen- and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule alpha. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13- and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13- and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response-induced pulmonary hypertension.

Pulmonary Hypertension is characterized by pulmonary arterial remodeling and increased pressure in the pulmonary circulation. It is often associated with inflammation in the lungs and can lead to right heart failure. Our work shows that urban ambient pollution exacerbates the experimental pulmonary hypertension phenotype just like other types of inflammatory lung conditions. We aimed to identify microRNAs (miRNAs) that are differentially expressed in our mouse model. In addition, we examined plasma samples from individuals occupationally exposed to high levels of air pollution or cigarette smoke, and from controls. Our study is the first to show significantly de-regulated expression of three microRNA species (miR-135a, miR-21, miR-204) in the lungs of mice that were exposed to antigen and particulate matter and developed pulmonary hypertension. De-regulated levels of miR-21 and miR-204 have been reported in human pulmonary hypertension and in experimental pulmonary hypertension. MiR-135a is targeting STAT6 and upregulated expression has been reported in experimental asthma. Using human samples, our study showed that plasma levels of miR-21 and miR-135a, but not levels of miR-204, clustered individuals with high dose exposures and individuals with low dose environmental exposures. Current studies are aimed at identifying the cytokines that control these miRNAs' expression. The long range goal is to identify miRNAs that indicate an at-risk state of the pulmonary vasculature

Particulates from air pollution are implicated in causing or exacerbating respiratory and systemic cardiovascular diseases and are thought to be among the leading causes of morbidity and mortality. However, the contribution of ambient particulate matter to diseases affecting the pulmonary circulation, the right heart, and especially pulmonary hypertension is much less documented. Our own work and that of other groups has demonstrated that prolonged exposure to antigens via the airways can cause severe pulmonary arterial remodeling. In addition, vascular changes have been well documented in a typical disease of the airways, asthma. These experimental and clinical findings link responses in the airways with responses in the lung's vasculature. It follows that particulate air pollution could cause, or exacerbate, diseases in the pulmonary circulation and associated pulmonary hypertension. This perspective details the literature for support of this concept. Data regarding the health effects of particulate matter from air pollution on the lung's vasculature, with emphasis on the lung's inflammatory responses to particulate matter deposition and pulmonary hypertension, are discussed. A deeper understanding of the health implications of exposure to ambient particulate matter will improve our knowledge of how to improve the management of lung diseases, including diseases of the pulmonary circulation. As man-made ambient particulate air pollution is typically linked to economic growth, a better understanding of the health effects of exposure to particulate air pollution is expected to integrate the global goal of achieving healthy living for all.