title: Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma.
abstract: Atopic asthma is a chronic allergic disease that involves T-helper type 2 (Th2)-inflammation and airway remodeling. Bronchiolar club cells (CC) and alveolar macrophages (AM) are sentinel cells of airway barrier against inhaled injuries, where allergy induces mucous metaplasia of CC and the alternative activation of AM, which compromise host defense mechanisms and amplify Th2-inflammation. As there is evidence that high levels of environmental endotoxin modulates asthma, the goal of this study was to evaluate if the activation of local host defenses by Lipopolysaccharide (LPS) previous to allergy development can contribute to preserving CC and AM protective phenotypes. Endotoxin stimulus before allergen exposition reduced hallmarks of allergic inflammation including eosinophil influx, Interleukin-4 and airway hyperreactivity, while the T-helper type 1 related cytokines IL-12 and Interferon-γ were enhanced. This response was accompanied by the preservation of the normal CC phenotype and the anti-allergic proteins Club Cell Secretory Protein (CCSP) and Surfactant-D, thereby leading to lower levels of CC metaplasia and preventing the increase of the pro-Th2 cytokine Thymic stromal lymphopoietin. In addition, classically activated alveolar macrophages expressing nitric oxide were promoted over the alternatively activated ones that expressed arginase-1. We verified that LPS induced a long-term overexpression of CCSP and the innate immune markers Toll-like receptor 4, and Tumor Necrosis Factor-α, changes that were preserved in spite of the allergen challenge. These results demonstrate that LPS pre-exposition modifies the local bronchioalveolar microenvironment by inducing natural anti-allergic mechanisms while reducing local factors that drive Th2 type responses, thus modulating allergic inflammation.
authors.affiliation: Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET and Centro de Microscopía Electrónica- Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo, Ciudad Universitaria X5000HRA, Córdoba, Argentina.
authors.forename: Luciana N
authors.initials: LN
authors.lastname: García
authors.affiliation: Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET and Centro de Microscopía Electrónica- Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo, Ciudad Universitaria X5000HRA, Córdoba, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Leimgruber
authors.affiliation: Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET and Centro de Microscopía Electrónica- Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo, Ciudad Universitaria X5000HRA, Córdoba, Argentina.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Uribe Echevarría
authors.affiliation: Fundación INFANT, Gavilan 94 C1406ABC, Capital Federal, Buenos Aires, Argentina.
authors.forename: Patricio L
authors.initials: PL
authors.lastname: Acosta
authors.affiliation: Fundación INFANT, Gavilan 94 C1406ABC, Capital Federal, Buenos Aires, Argentina.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Brahamian
authors.affiliation: Fundación INFANT, Gavilan 94 C1406ABC, Capital Federal, Buenos Aires, Argentina Department of Pediatrics, Vanderbilt University, MCN, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
authors.affiliation: Centro de Investigación en Bioquímica Clínica e Inmunología (CIBICI), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende (X5000HRA), Ciudad Universitaria, Córdoba, Argentina.
authors.forename: María S
authors.initials: MS
authors.lastname: Miró
authors.affiliation: Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET and Centro de Microscopía Electrónica- Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo, Ciudad Universitaria X5000HRA, Córdoba, Argentina.
authors.forename: Amado A
authors.initials: AA
authors.lastname: Quintar
authors.affiliation: Centro de Investigación en Bioquímica Clínica e Inmunología (CIBICI), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende (X5000HRA), Ciudad Universitaria, Córdoba, Argentina.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Sotomayor
authors.affiliation: Instituto de Investigaciones en Ciencias de la Salud (INICSA), CONICET and Centro de Microscopía Electrónica- Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Enrique Barros esq. Enfermera Gordillo, Ciudad Universitaria X5000HRA, Córdoba, Argentina cmaldon@cmefcm.uncor.edu.
authors.forename: Cristina A
authors.initials: CA
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004731:Endotoxins / Q000276:immunology / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D020545:Respiratory Mucosa / Q000166:cytology* / Q000276:immunology*; D014598:Uteroglobin / Q000378:metabolism
chemical_list: D004731:Endotoxins; D014598:Uteroglobin
keywords: Club cell; alveolar macrophage; asthma; pulmonary host defense