Susan He

Bio: Susan He is an academic researcher. The author has contributed to research in topics: Neuroscience & Respiratory disease. The author has an hindex of 2, co-authored 3 publications receiving 569 citations.

A Chitinase-like Protein in the Lung and Circulation of Patients with Severe Asthma

Abstract: Background The evolutionarily conserved 18-glycosyl-hydrolase family contains true chitinases and chitinase-like proteins that lack enzymatic activity. Acidic mammalian chitinase has recently been associated with animal models of asthma. The related chitinase-like protein, YKL-40 (also called human cartilage glycoprotein 39 [HCgp-39] and chitinase 3–like 1), can be readily measured in the serum. However, its relationship to asthma has not been evaluated. Methods We quantified serum YKL-40 levels in three cohorts of patients with asthma — one recruited from the patient population at Yale University, one from the University of Paris, and one from the University of Wisconsin — as well as in controls from the surrounding communities. In the Paris cohort, immunohistochemical analysis and morphometric quantitation were used to evaluate the locus of expression of YKL-40 in the lung. The clinical characteristics of the patients with high serum or lung YKL-40 levels were also evaluated. Results Serum YKL-40 levels...

Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure.

Abstract: Interleukin (IL)-13, a key mediator of Th2-mediated immunity, contributes to the pathogenesis of asthma and other pulmonary diseases via its ability to generate fibrosis, mucus metaplasia, eosinophilic inflammation, and airway hyperresponsiveness. In these studies, we compared surfactant accumulation in wild-type mice and mice in which IL-13 was overexpressed in the lung. When compared with littermate controls, transgenic animals showed alveolar type II cell hypertrophy under light and electron microscopy. Over time, their alveoli also filled with surfactant in a pulmonary alveolar proteinosis pattern. At the same time, prominent interstitial fibrosis occurs. Bronchoalveolar lavage fluid from these mice had a three- to sixfold increase in surfactant phospholipids. Surfactant proteins (SP)-A, -B, and -C showed two- to threefold increases, whereas SP-D increased 70-fold. These results indicate that IL-13 is a potent stimulator of surfactant phospholipid and surfactant accumulation in the lung. IL-13 may therefore play a central role in the broad range of chronic pulmonary conditions in which fibrosis, type II cell hypertrophy, and surfactant accumulation occur.

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice

Abstract: Initiating drug use during adolescence increases the risk of developing addiction and psychiatric disorders later in life, with long-term outcomes varying according to sex and exact timing of use. Even though most individuals begin experimenting with drugs of abuse in adolescence, to date, the cellular and molecular underpinnings explaining differential sensitivity to detrimental drug effects remain unknown. The Netrin-1/DCC guidance cue system plays a critical role in the adolescent development of mesocorticolimbic dopamine circuitry, segregating the cortical and limbic pathways. Adolescent experiences, including exposure to drugs of abuse, can regulate Dcc expression in male mice, placing Netrin-1/DCC signaling as a potential molecular link between experience and enduring changes to circuitry and behavior. Here we show that exposure to a recreational-like regimen of amphetamine (AMPH) in adolescence induces sex- and age-specific alterations in Dcc expression in the ventral tegmental area. Female mice are protected against the deleterious long-term effects of AMPH-induced Dcc regulation by compensatory changes in the expression of its binding partner, Netrin-1. AMPH induces targeting errors in mesolimbic dopamine axons and triggers their ectopic growth to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to its enduring cognitive effects. Upregulating DCC receptor expression in dopamine neurons in adolescent males using a neuron-optimized CRISPR/dCas9 Activation System induces female-like protection against the persistent effects of AMPH in early adolescence on inhibitory control. Netrin-1/DCC signaling is therefore a molecular switch which can be differentially regulated in response to the same experience as function of age and sex of the individual, leading to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

The cytokine network in asthma and chronic obstructive pulmonary disease

Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.

Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury.

Abstract: The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated. Acidic mammalian chitinase (AMCase) inhibits chitin-induced innate inflammation; augments chitin-free, allergen-induced Th2 inflammation; and mediates effector functions of IL-13. The CLPs BRP-39/YKL-40 (also termed chitinase 3-like 1) inhibit oxidant-induced lung injury, augments adaptive Th2 immunity, regulates apoptosis, stimulates alternative macrophage activation, and contributes to fibrosis and wound healing. In accord with these findings, levels of YKL-40 in the lung and serum are increased in asthma and other inflammatory and remodeling disorders and often correlate with disease severity. Our understanding of the roles of C/CLPs in inflammation, tissue remodeling, and tissue injury in health and disease is reviewed below.

Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.

Abstract: Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by T H 2 cytokines in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (Feno), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV 1 , 60% of predicted value; mean Asthma Control Questionnaire [ACQ] score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, Feno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting T H 2 inflammation.

Interleukin-4- and Interleukin-13-Mediated Alternatively Activated Macrophages: Roles in Homeostasis and Disease

Abstract: The macrophage, a versatile cell type prominently involved in host defense and immunity, assumes a distinct state of alternative activation in the context of polarized type 2 immune responses such as allergic inflammation and helminth infection. This alternatively activated phenotype is induced by the canonical type 2 cytokines interleukin (IL)-4 and IL-13, which mediate expression of several characteristic markers along with a dramatic shift in macrophage metabolic pathways that influence surrounding cells and tissues. We discuss recent advances in the understanding of IL-4- and IL-13-mediated alternatively activated macrophages and type 2 immune responses; such advances have led to an expanded appreciation for functions of these cells beyond immunity, including maintenance of physiologic homeostasis and tissue repair.