No description available.

No description available.

No description available.

No description available.

Asthma is a chronic condition characterized by variable airflow obstruction, bronchial hyper-responsiveness, airway inflammation and remodeling. In spite of tremendous advances, the regulatory mechanisms controlling these pathological features have not yet been completely addressed. From an immunological perspective, type 2 inflammation and eosinophilic infiltration are the most striking hallmarks of asthma. At physiological level, structural changes such as increase in smooth muscle mass take the center stage which is usually associated with clinical measures of asthma. There might be some regulatory mediators capable of tuning airway inflammation and remodeling under homeostatic conditions but abrogated in asthmatic conditions. Semaphorin 3E (Sema3E) is an axon guidance molecule that is ubiquitously expressed and plays diverse roles in structural and inflammatory cells such as regulation of cell migration, proliferation and angiogenesis. However, its role in clinical and experimental asthma remains unclear. In this thesis, I have set out to uncover the expression and function of Sema3E in allergic asthma. It is generally hypothesized that Sema3E is down-regulated in allergic asthma which orchestrates the function of inflammatory (dendritic cells and neutrophils) and structural (airway smooth muscle) cells. Replenishment of Sema3E, which is suppressed under asthmatic conditions, could confer protection against allergic asthma by modulation of cellular functions. I began by comparing the expression of Sema3E between allergic asthmatics and healthy subjects. A remarkable down-regulation of Sema3E under asthmatic patients was observed which was further confirmed in a mouse model of the disease. Decreased expression of Sema3E was specifically demonstrated on bronchial epithelial cells obtained from asthmatic patients at both mRNA and protein levels. To address the function of Sema3E in allergic asthma in vivo, I extended my studies to mouse models of the disease and demonstrated that Sema3e gene deletion results in exacerbated allergic asthma pathology induced by allergen exposure. To investigate the translational relevance of my findings, I performed treatment of an asthmatic mouse model with exogenous Sema3E in which its intranasal administration attenuated airway inflammation, remodeling and hyper-responsiveness. The mechanism underlying Sema3E’s role in pathogenesis of allergic asthma was extensively studied indicating a crucial role of this mediator in modulation of dendritic cells and neutrophils functions. Our data demonstrated that both dendritic cells and neutrophils express the Sema3E high affinity receptor, PlexinD1, which makes them responsive to Sema3E treatment. Then, I studied expression and function of PlexinD1 on human airway smooth muscle (ASM) cells. I found that PlexinD1 surface expression was reduced on ASM cells from asthmatic patients. Treatment of ASM cells with Sema3E inhibited their proliferation and migration as the characteristic feature of airway remodeling. Suppression of Rac1 GTPase activity and phosphorylation of Akt/PI3K and ERK/MAPK were found as signaling mechanisms underlying Sema3E’s inhibitory effects. Together, these findings show that Sema3E thereby appears as a novel regulatory mediator, upstream of pro-allergic events, suggestive of a new approach to attenuate allergic asthma deficits. / May 2016

Background: Fraction of exhaled nitric oxide (FENO) is a promising non-invasive index of airway inflammation that may be used to assess respiratory effects of air pollution. We evaluated FENO as a measure of airway inflammation after controlled exposure to diesel exhaust or ozone. Methods: Healthy volunteers were exposed to either diesel exhaust (particle concentration 300 mu g/m(3)) and filtered air for one hour, or ozone (300 ppb) and filtered air for 75 minutes. FENO was measured in duplicate at expiratory flow rates of 10, 50, 100 and 270 mL/s before, 6 and 24 hours after each exposure. Results: Exposure to diesel exhaust increased FENO at 6 hours compared with air at expiratory flow rates of 10 mL/s (p = 0.01) and at 50 mL/s (p = 0.011), but FENO did not differ significantly at higher flow rates. Increases in FENO following diesel exhaust were attenuated at 24 hours. Ozone did not affect FENO at any flow rate or time point. Conclusions: Exposure to diesel exhaust, but not ozone, increased FENO concentrations in healthy subjects. Differences in the induction of airway inflammation may explain divergent responses to diesel exhaust and ozone, with implications for the use of FENO as an index of exposure to air pollution.

Background The mechanism by which allergies trigger asthma occurs through the interaction of antigen, IgE and the FcεR1 receptor on mast cells resulting in the release of mediators that exert their effects on various surrounding tissues causing bronchoconstriction, plasma exudation and mucus hypersecretion. The response is usually maximal within 30 minutes and resolves spontaneously within two hours. At least half of the individuals who exhibit this so called early response also manifest a late response which is a subsequent episode of bronchoconstriction that is usually maximal around six hours following exposure and involves airway inflammation. Montelukast has proven efficacious in the management of asthma and desloratadine is effective in the treatment of allergic rhinitis and chronic idiopathic urticaria. Since the early response involves the actions of multiple mediators, including histamine and the leukotrienes, the question of whether concurrent mediator blockade would be superior to either agent alone was raised. Additionally, the recent evidence supporting anti-inflammatory activity for these agents suggested potential efficacy against the late airway response. Methods Two double-blind, randomized, placebo-controlled, 4-way crossover allergen inhalation challenge investigations were conducted in twenty (10 per investigation) mild atopic asthmatics. The early response investigation involved the administration of either 5 mg desloratadine, 10 mg montelukast, the combination , or placebo (Vitamin B1) at 26 hours and 2 hours prior to allergen inhalation. The late response investigation involved single dose administration of each agent, alone or in combination, 2 hours prior to allergen inhalation. Measurements of changes in airway responsiveness and inflammation were also conducted. Results The early response was significantly inhibited by montelukast and the combination. Desloratadine did not differ from placebo. The late response was significantly decreased by desloratadine and montelukast and completely blocked with the combination. Desloratadine decreased sputum eosinophils at 7 hours, montelukast at 24 hours, and the combination at both time points. Airway responsiveness to methacholine trended lower with montelukast and the combination. Montelukast was the only treatment to significantly decrease exhaled nitric oxide levels. Conclusion The combination of desloratadine and montelukast provides inhibition that is superior to both monotherapies on the early and the late airway responses to inhaled allergen in people with mild atopic asthma.

Background The mechanism by which allergies trigger asthma occurs through the interaction of antigen, IgE and the FcεR1 receptor on mast cells resulting in the release of mediators that exert their effects on various surrounding tissues causing bronchoconstriction, plasma exudation and mucus hypersecretion. The response is usually maximal within 30 minutes and resolves spontaneously within two hours. At least half of the individuals who exhibit this so called early response also manifest a late response which is a subsequent episode of bronchoconstriction that is usually maximal around six hours following exposure and involves airway inflammation. Montelukast has proven efficacious in the management of asthma and desloratadine is effective in the treatment of allergic rhinitis and chronic idiopathic urticaria. Since the early response involves the actions of multiple mediators, including histamine and the leukotrienes, the question of whether concurrent mediator blockade would be superior to either agent alone was raised. Additionally, the recent evidence supporting anti-inflammatory activity for these agents suggested potential efficacy against the late airway response. Methods Two double-blind, randomized, placebo-controlled, 4-way crossover allergen inhalation challenge investigations were conducted in twenty (10 per investigation) mild atopic asthmatics. The early response investigation involved the administration of either 5 mg desloratadine, 10 mg montelukast, the combination , or placebo (Vitamin B1) at 26 hours and 2 hours prior to allergen inhalation. The late response investigation involved single dose administration of each agent, alone or in combination, 2 hours prior to allergen inhalation. Measurements of changes in airway responsiveness and inflammation were also conducted. Results The early response was significantly inhibited by montelukast and the combination. Desloratadine did not differ from placebo. The late response was significantly decreased by desloratadine and montelukast and completely blocked with the combination. Desloratadine decreased sputum eosinophils at 7 hours, montelukast at 24 hours, and the combination at both time points. Airway responsiveness to methacholine trended lower with montelukast and the combination. Montelukast was the only treatment to significantly decrease exhaled nitric oxide levels. Conclusion The combination of desloratadine and montelukast provides inhibition that is superior to both monotherapies on the early and the late airway responses to inhaled allergen in people with mild atopic asthma.

Indiana University-Purdue University Indianapolis (IUPUI) / Airway inflammation is the most common and important component of respiratory diseases, such as influenza and asthma. Severe influenza A virus infection typically triggers detrimental lung inflammation with massive immune cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor known for its function in bone formation and spermatogenesis, in regulating antiviral immune responses and immunopathology. Nmp4-deficient mice are protected from influenza induced immunopathology and body weight loss. While having no effects on viral clearance or CD8/CD4 T cell or humoral immune responses, Nmp4 deficiency in either lung structural cells or hematopoietic cells significantly reduces the recruitment of neutrophils and monocytes to the lungs. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes Ccl2 and Cxcl1 and upregulates their expression in mouse lung epithelial cells and macrophages. These chemokines attract monocytes and neutrophils to the airway, resulting in exaggerated airway inflammation and collateral lung damage. Another transcription factor forkhead box P3 (FOXP3) is critical for the development of regulatory T cells (Tregs) that function to control immune responses. Unlike human FOXP3 gene that encodes two major isoforms, a full length (FOXP3-FL) isoform and a short isoform lacking the exon 2 region (FOXP3-ΔE2), mouse Foxp3 gene only encodes Foxp3-FL isoform. We generate Foxp3-ΔE2 mice to study its function and find that Tregs expressing the Foxp3-ΔE2 isoform have intrinsic defects, thus allowing intensified adaptive immune responses without changes in innate immunity against influenza infection. In a model of chronic asthma, mice expressing only the Foxp3-ΔE2 isoform have significantly increased allergic airway inflammation and elevated production of allergen-specific IgE compared with mice expression the Foxp3-FL isoform. Mechanistically, Tregs expressing the Foxp3-ΔE2 isoform are less stable and prone to trans-differentiation into effector Th9-like cells, which are closely associated with the pathogenesis of asthma. These data suggest that the two Foxp3 isoforms have different functions in regulating airway immune responses. Overall, we have defined the important roles of both transcription factors NMP4 and FOXP3 in regulating airway inflammation. / 2022-08-17

Master of Science / Department of Kinesiology / Craig A. Harms / Obesity and asthma often coexist in the same people. Both are characterized by the presence of low-grade systemic inflammation. A high-fat diet may contribute to concurrent development of both conditions by promoting a pro-inflammatory postprandial environment leading to a transient accumulation of blood lipids (postprandial lipemia; PPL) and acute airway inflammation. Previous results from our lab have shown an ~20% increase in airway inflammation two hours after consuming a high-fat meal (HFM) that was significantly associated with increased plasma triglycerides. While acute exercise has been shown to attenuate PPL, it is unknown whether these protective effects will translate to reduced airway inflammation after a high-fat meal. PURPOSE: To determine the effects of an acute bout of exercise on airway inflammation after a HFM. We tested the hypothesis that an acute bout of exercise 12 hours before a high-fat meal would protect against subsequent airway inflammation in healthy men and would be related to the decreased PPL and systemic inflammatory markers. METHODS: In a randomized cross-over study, 12 healthy college-aged men consumed a HFM (1g fat/1kg body weight) 12 hours following exercise (EX; 60 min at 60% VO2max) or without exercise (CON). Exhaled nitric oxide (eNO; measure of airway inflammation), blood lipid profiles (venous sample; total cholesterol, HDL, LDL, triglycerides, glucose), inflammatory markers (hsCRP, TNF-[alpha], IL-6) and pulmonary function tests (PFT) (forced expiratory volume in 1-s,forced vital capacity, forced expiratory flow at 25-75% of vital capacity) were measured pre-HFM, two hours, and four hours post-HFM. RESULTS: Baseline eNO was not different (p>0.05) between trials. eNO increased (p<0.05) post HFM at two hours in the both CON and EX conditions. eNO between trials was not different (p>0.05). Triglycerides were significantly increased two and four hours post HFM but were not different (p>0.05) between conditions. There was no relationship (p>0.05) between eNO and triglycerides or systemic inflammatory markers for any time point in either condition. Pulmonary function did not differ (p>0.05) between any condition. CONCLUSION: These results demonstrate that an acute bout of moderate intensity exercise 12 hours before a HFM does not attenuate postprandial airway inflammation or lipemia in healthy college-aged men.