title: MyD88 in lung resident cells governs airway inflammatory and pulmonary function responses to organic dust treatment.
abstract: Inhalation of organic dusts within agriculture environments contributes to the development and/or severity of airway diseases, including asthma and chronic bronchitis. MyD88 KO (knockout) mice are nearly completely protected against the inflammatory and bronchoconstriction effects induced by acute organic dust extract (ODE) treatments. However, the contribution of MyD88 in lung epithelial cell responses remains unclear. In the present study, we first addressed whether ODE-induced changes in epithelial cell responses were MyD88-dependent by quantitating ciliary beat frequency and cell migration following wounding by electric cell-substrate impedance sensing. We demonstrate that the normative ciliary beat slowing response to ODE is delayed in MyD88 KO tracheal epithelial cells as compared to wild type (WT) control. Similarly, the normative ODE-induced slowing of cell migration in response to wound repair was aberrant in MyD88 KO cells. Next, we created MyD88 bone marrow chimera mice to investigate the relative contribution of MyD88-dependent signaling in lung resident (predominately epithelial cells) versus hematopoietic cells. Importantly, we demonstrate that ODE-induced airway hyperresponsiveness is MyD88-dependent in lung resident cells, whereas MyD88 action in hematopoietic cells is mainly responsible for ODE-induced TNF-α release. MyD88 signaling in lung resident and hematopoietic cells are necessary for ODE-induced IL-6 and neutrophil chemoattractant (CXCL1 and CXCL2) release and neutrophil influx. Collectively, these findings underscore an important role for MyD88 in lung resident cells for regulating ciliary motility, wound repair and inflammatory responses to ODE, and moreover, show that airway hyperresponsiveness appears uncoupled from airway inflammatory consequences to organic dust challenge in terms of MyD88 involvement.
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA. japoole@unmc.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Poole
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.|Department of Environmental, Agricultural & Occupational Health, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.|VA Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wyatt
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.|Department of Environmental, Agricultural & Occupational Health, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Romberger
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Staab
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Simet
authors.affiliation: High Plains Intermountain Center for Agricultural Health and Safety, Department of Environmental and Radiological Health Sciences, Colorado State University, Ft. Collins, CO, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Reynolds
authors.affiliation: Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Sisson
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE, 68198-5990, USA.
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016026:Bone Marrow Transplantation; D016084:Bronchoconstriction / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002923:Cilia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004391:Dust; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006799:Housing, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020556:Neutrophil Infiltration / Q000187:drug effects; D009930:Organic Chemicals / Q000633:toxicity*; D010641:Phenotype; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013997:Time Factors
chemical_list: D016207:Cytokines; D004391:Dust; D018836:Inflammation Mediators; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009930:Organic Chemicals; D017493:Leukocyte Common Antigens