title: Neutrophilic inflammation in severe asthma.
abstract: Neutrophils may play an important role in the pathogenesis of severe asthma. Their infiltration into the airway is increased. Interleukin (IL)-8 is involved in this process, and is actually upregulated in the airways of patients. We have observed that in the absence of eosinophil chemoattractants, neutrophils stimulated by IL-8 augment eosinophil trans-basement membrane migration by releasing superoxide anion, matrix metalloproteinase, leukotriene B(4) and platelet-activating factor. These findings suggest that IL-8-stimulated neutrophils could lead eosinophils to accumulate in the airways of asthmatic patients, which might be a mechanism for corticosteroid resistance in severe asthma. However, the mechanisms of IL-8 upregulation in the airway are not completely understood. Several studies suggest that IL-17 (or T helper 17 cells; Th17) is involved in the IL-8 upregulation observed in severe asthma. We clarified that dopamine induces Th17 differentiation through dopamine D1-like receptor (D1-like-R), and that the D1-like-R antagonist attenuates Th17-mediated diseases like experimental autoimmune encephalomyelitis. Furthermore, we demonstrated that a D1-like-R antagonist significantly suppressed ovalbumin (OVA)-induced neutrophilic airway inflammation in OVA T cell receptor-transgenic DO11.10 mice through inhibiting Th17-mediated immune responses. Therefore, dopamine D1-like-R antagonists could become useful for treating Th17-mediated neutrophil-dominant severe asthma. As inhaled corticosteroids are known to be less effective for controlling neutrophilic inflammation, a more effective therapeutic strategy for neutrophil-dominant asthma should still be elucidated.
authors.affiliation: Department of Respiratory Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan. nakagomek-tky@umin.ac.jp
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakagome
authors.forename: Sho
authors.initials: S
authors.lastname: Matsushita
authors.forename: Makoto
authors.initials: M
authors.lastname: Nagata
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D002465:Cell Movement; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D009504:Neutrophils / Q000502:physiology*; D011014:Pneumonia / Q000276:immunology*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D058504:Th17 Cells / Q000276:immunology
chemical_list: D016209:Interleukin-8; D017447:Receptors, Dopamine D1