title: The complex relationship between inflammation and lung function in severe asthma.
abstract: Asthma is a common respiratory disease affecting ∼300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness (AHR) remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we used the T-helper (T(H))-17 cells adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by tumor necrosis factor (TNF)-α neutralization or neutrophil depletion. Although decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved AHR to methacholine, and tissue inflammation remained elevated when compared with control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of T(H)17-related cytokines in their sputum compared with severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, whereas T-cell-driven AHR may be associated with tissue inflammation and other pulmonary factors.
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Manni
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Asthma Institute at UPMC/University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Trudeau
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Scheller
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mandalapu
authors.affiliation: Janssen Research and Development, Immunology Discovery Research, Spring House, Pennsylvania, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Elloso
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Asthma Institute at UPMC/University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Wenzel
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Alcorn
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001249:Asthma / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002648:Child; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D012720:Severity of Illness Index; D013183:Sputum / Q000276:immunology
chemical_list: D016085:Bronchoconstrictor Agents; D016207:Cytokines; D016210:Methacholine Chloride