{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/127488"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/127488","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Pathogenic roles of Pseudomonas aeruginosa-derived volatile organic compounds in airway mucus hypersecretion: Molecular mechanisms and immune modulation","abstract":"This Dissertation was approved for publication on 2024-12-04 at 14:52.","abstract_html":"This Dissertation was approved for publication on 2024-12-04 at 14:52.","abstract_has_math":false,"creators":["Kuo, Hsuan (Shanny)"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"VMS - Pathobiology","degree_department":null,"school":null,"contributors":["Lau, Gee W.","Nanjappa, Som G.","Witola, William H.","Vieson, Miranda D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-12-04","date_published":"2024-12-04","updated_at":"2026-07-22T22:25:04Z","subjects":["Mucus Hypersecretion","Pseudomonas Aeruginosa","Volatile Organic Compounds","Aryl Hydrocarbon Receptor"],"languages":["en","eng"],"rights":["Copyright 2024 Hsuan Kuo"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/127488","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Lau, Gee W.","Nanjappa, Som G.","Witola, William H.","Vieson, Miranda D."]},{"key":"dc:creator","label":"Author","values":["Kuo, Hsuan (Shanny)"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-12-04","2024-12"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["VMS - Pathobiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Mucus Hypersecretion","Pseudomonas Aeruginosa","Volatile Organic Compounds","Aryl Hydrocarbon Receptor"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 Hsuan Kuo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/127488"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["This Dissertation was approved for publication on 2024-12-04 at 14:52.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21477 on 2025-03-28 at 14:55:36","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","The student, Hsuan Kuo, accepted the attached license on 2024-12-03 at 14:39.","The student, Hsuan Kuo, submitted this Dissertation for approval on 2024-12-03 at 14:58.","Pseudomonas aeruginosa (PA) is a major bacterial pathogen that infects chronically diseased human lungs, such as those affected by cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Key pathological features include dysregulated airway goblet cell metaplasia, mucus hypersecretion, and impaired clearance. PA is metabolically versatile and secretes a plethora of secondary metabolites, many of which exhibit host-modulatory effects that contribute to disease pathogenesis. However, the role of volatile organic compounds (VOCs) in airway mucus dysregulation remains unclear. We hypothesize that VOCs could induce goblet cell metaplasia (GCM) and mucus hypersecretion by activating the aryl hydrocarbon receptor (AhR), which has recently emerged as a regulator of mucosal barrier function. Additionally, we postulate that VOCs could modulate airway proinflammatory immune responses that drive GCM and mucus hypersecretion. To test these hypotheses, we investigated the impact of several dominant VOCs (e.g., 1-undecene, 2-nonanone, 2-aminoacetophenone, 1-dodecene), which are present in the breath of CF and COPD patients, on GCM and the expression of major mucus glycoproteins MUC5AC and MUC5B. We utilized air-liquid interface 3D cultures of human bronchial epithelial cells and a mouse model of chronic VOC exposure. Both individual and cocktail VOCs at concentrations found in patient breath and in bacterial culture headspace significantly increased the expression of MUC5B and MUC5AC, while downregulating FOXA2, a key regulator of airway mucus homeostasis. VOC exposure elevated AhR expression, and pretreatment with an AhR inhibitor restored FOXA2 expression, thereby reducing excessive mucin production. Flow cytometry analysis of immune cells from bronchoalveolar lavage fluids and homogenized lungs of VOC-exposed mice revealed a predominance of iNOS+ M1 macrophages, neutrophils, and Thy1.2+ cells, with most Thy1.2+ cells secreting IL-17A. Selective depletion of either macrophages or neutrophils decreased mucin production and restored FOXA2 expression in the airways following VOC exposure. Similarly, IL-17a-/- mice showed reduced mucin production and restored FOXA2 activity after VOC exposure. These studies suggest that PA-derived VOCs induce mucus hypersecretion via AhR signaling and the polarization of the airways towards proinflammatory responses mediated by M1 macrophages, neutrophils, and type 17 cells, which act to promote mucus overproduction. Thus, the PA VOCs disrupt GCM homeostasis and modulate host immune responses to drive excessive mucus secretion in diseased airways during PA infection."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Pathogenic roles of Pseudomonas aeruginosa-derived volatile organic compounds in airway mucus hypersecretion: Molecular mechanisms and immune modulation"]}]}],"canonical_facts":{"dc:contributor":["Lau, Gee W.","Nanjappa, Som G.","Witola, William H.","Vieson, Miranda D."],"dc:creator":["Kuo, Hsuan (Shanny)"],"dc:date":["2024-12-04","2024-12"],"dc:description":["This Dissertation was approved for publication on 2024-12-04 at 14:52.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21477 on 2025-03-28 at 14:55:36","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-12-01","The student, Hsuan Kuo, accepted the attached license on 2024-12-03 at 14:39.","The student, Hsuan Kuo, submitted this Dissertation for approval on 2024-12-03 at 14:58.","Pseudomonas aeruginosa (PA) is a major bacterial pathogen that infects chronically diseased human lungs, such as those affected by cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Key pathological features include dysregulated airway goblet cell metaplasia, mucus hypersecretion, and impaired clearance. PA is metabolically versatile and secretes a plethora of secondary metabolites, many of which exhibit host-modulatory effects that contribute to disease pathogenesis. However, the role of volatile organic compounds (VOCs) in airway mucus dysregulation remains unclear. We hypothesize that VOCs could induce goblet cell metaplasia (GCM) and mucus hypersecretion by activating the aryl hydrocarbon receptor (AhR), which has recently emerged as a regulator of mucosal barrier function. Additionally, we postulate that VOCs could modulate airway proinflammatory immune responses that drive GCM and mucus hypersecretion. To test these hypotheses, we investigated the impact of several dominant VOCs (e.g., 1-undecene, 2-nonanone, 2-aminoacetophenone, 1-dodecene), which are present in the breath of CF and COPD patients, on GCM and the expression of major mucus glycoproteins MUC5AC and MUC5B. We utilized air-liquid interface 3D cultures of human bronchial epithelial cells and a mouse model of chronic VOC exposure. Both individual and cocktail VOCs at concentrations found in patient breath and in bacterial culture headspace significantly increased the expression of MUC5B and MUC5AC, while downregulating FOXA2, a key regulator of airway mucus homeostasis. VOC exposure elevated AhR expression, and pretreatment with an AhR inhibitor restored FOXA2 expression, thereby reducing excessive mucin production. Flow cytometry analysis of immune cells from bronchoalveolar lavage fluids and homogenized lungs of VOC-exposed mice revealed a predominance of iNOS+ M1 macrophages, neutrophils, and Thy1.2+ cells, with most Thy1.2+ cells secreting IL-17A. Selective depletion of either macrophages or neutrophils decreased mucin production and restored FOXA2 expression in the airways following VOC exposure. Similarly, IL-17a-/- mice showed reduced mucin production and restored FOXA2 activity after VOC exposure. These studies suggest that PA-derived VOCs induce mucus hypersecretion via AhR signaling and the polarization of the airways towards proinflammatory responses mediated by M1 macrophages, neutrophils, and type 17 cells, which act to promote mucus overproduction. Thus, the PA VOCs disrupt GCM homeostasis and modulate host immune responses to drive excessive mucus secretion in diseased airways during PA infection."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/127488"],"dc:language":["en","eng"],"dc:rights":["Copyright 2024 Hsuan Kuo"],"dc:subject":["Mucus Hypersecretion","Pseudomonas Aeruginosa","Volatile Organic Compounds","Aryl Hydrocarbon Receptor"],"dc:title":["Pathogenic roles of Pseudomonas aeruginosa-derived volatile organic compounds in airway mucus hypersecretion: Molecular mechanisms and immune modulation"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["VMS - Pathobiology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:04Z"}