title: Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation.
abstract: Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated the role of properdin (P), a positive alternative pathway complement regulator, in allergen-induced airway inflammation. Allergen challenge stimulated P release into the airways of asthmatic patients, and P levels positively correlated with proinflammatory cytokines in human bronchoalveolar lavage (BAL). High levels of P were also detected in the BAL of OVA-sensitized and challenged but not naive mice. Compared with wild-type (WT) mice, P-deficient (P(-/-)) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab blocking of P at both sensitization and challenge phases or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of P to P(-/-) mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA-challenged P(-/-) mice were significantly lower than in wild-type mice, and intranasal coadministration of an anti-C3a mAb with P to P(-/-) mice prevented restoration of airway inflammation. These results show that P plays a key role in allergen-induced airway inflammation and represents a potential therapeutic target for human asthma.
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Blerina
authors.initials: B
authors.lastname: Ducka-Kokalari
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Imre G
authors.initials: IG
authors.lastname: Redai
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Sayaka
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Damodar
authors.initials: D
authors.lastname: Gullipalli
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, PA 19107.
authors.forename: James G
authors.initials: JG
authors.lastname: Zangrilli
authors.affiliation: Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; songwe@upenn.edu.
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015926:Complement C3a / Q000096:biosynthesis* / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011414:Properdin / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D016210:Methacholine Chloride; D011414:Properdin; D015926:Complement C3a