Dual oxidase regulates neutrophil recruitment in allergic airways

Sandra Chang, Angela Linderholm, Lisa Franzi, Nicholas Kenyon, Helmut Grasberger, Richart W Harper

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Enhanced reactive oxygen species production in allergic airways is well described and correlates with increased airway contractions, inflammatory cell infiltration, goblet cell metaplasia, and mucus hypersecretion. There is also an abundance of interleukin-4/interleukin-13 (IL-4/IL-13)- or interleukin-5- secreting cells that are thought to be central to the pathogenesis of allergic asthma. We postulated that the dual oxidases (DUOX1 and DUOX2), members of the nicotinamide adenine dinucleotide phosphate oxidase family that release hydrogen peroxide (H2O2) in the respiratory tract, are critical proteins in the pathogenesis of allergic airways. DUOX activity is regulated by cytokines, including IL-4 and IL-13, and DUOX-mediated H2O 2 influences several important features of allergic asthma: mucin production, IL-8 secretion, and wound healing. The objective of this study was to establish the contribution of DUOXs to the development of allergic asthma in a murine model. To accomplish this goal, we utilized a DUOXA-deficient mouse model (Duoxa-/-) that lacked maturation factors for both DUOX1 and DUOX2. Our results are the first to demonstrate evidence of DUOX protein and DUOX functional activity in murine airway epithelium. We also demonstrate that DUOXA maturation factors are required for airway-specific H2O 2 production and localization of DUOX to cilia of fully differentiated airway epithelial cells. We compared wild-type and Duoxa -/- mice in an ovalbumin exposure model to determine the role of DUOX in allergic asthma. In comparison to DUOX-intact mice, Duoxa-/- mice had reduced mucous cell metaplasia and lower levels of TH2 cytokine levels in bronchoalveolar fluid. In addition, increased airway resistance in response to methacholine was observed in Duoxa+/+ mice, as expected, but was absent in Duoxa-/- mice. Surprisingly, Duoxa-/- mice had decreased influx of neutrophils in bronchoalveolar fluid and lung tissue sections associated with a lower level of the chemotactic cytokine IL-6. These findings suggest that DUOX-derived H2O2 has an important role in signaling neutrophils into allergic airways.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalFree Radical Biology and Medicine
Volume65
DOIs
StatePublished - 2013

Fingerprint

Neutrophil Infiltration
Oxidoreductases
Interleukin-13
Asthma
Interleukin-4
Metaplasia
Neutrophils
Cytokines
Airway Resistance
Goblet Cells
Methacholine Chloride
Cilia
Interleukin-5
Ovalbumin
Mucins
Mucus
Fluids
Interleukin-8
NADP
Chemokines

Keywords

  • Asthma
  • Dual oxidase
  • DUOX
  • Free radicals
  • Lung
  • Murine
  • Neutrophil

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Dual oxidase regulates neutrophil recruitment in allergic airways. / Chang, Sandra; Linderholm, Angela; Franzi, Lisa; Kenyon, Nicholas; Grasberger, Helmut; Harper, Richart W.

In: Free Radical Biology and Medicine, Vol. 65, 2013, p. 38-46.

Research output: Contribution to journalArticle

Chang, Sandra ; Linderholm, Angela ; Franzi, Lisa ; Kenyon, Nicholas ; Grasberger, Helmut ; Harper, Richart W. / Dual oxidase regulates neutrophil recruitment in allergic airways. In: Free Radical Biology and Medicine. 2013 ; Vol. 65. pp. 38-46.
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AB - Enhanced reactive oxygen species production in allergic airways is well described and correlates with increased airway contractions, inflammatory cell infiltration, goblet cell metaplasia, and mucus hypersecretion. There is also an abundance of interleukin-4/interleukin-13 (IL-4/IL-13)- or interleukin-5- secreting cells that are thought to be central to the pathogenesis of allergic asthma. We postulated that the dual oxidases (DUOX1 and DUOX2), members of the nicotinamide adenine dinucleotide phosphate oxidase family that release hydrogen peroxide (H2O2) in the respiratory tract, are critical proteins in the pathogenesis of allergic airways. DUOX activity is regulated by cytokines, including IL-4 and IL-13, and DUOX-mediated H2O 2 influences several important features of allergic asthma: mucin production, IL-8 secretion, and wound healing. The objective of this study was to establish the contribution of DUOXs to the development of allergic asthma in a murine model. To accomplish this goal, we utilized a DUOXA-deficient mouse model (Duoxa-/-) that lacked maturation factors for both DUOX1 and DUOX2. Our results are the first to demonstrate evidence of DUOX protein and DUOX functional activity in murine airway epithelium. We also demonstrate that DUOXA maturation factors are required for airway-specific H2O 2 production and localization of DUOX to cilia of fully differentiated airway epithelial cells. We compared wild-type and Duoxa -/- mice in an ovalbumin exposure model to determine the role of DUOX in allergic asthma. In comparison to DUOX-intact mice, Duoxa-/- mice had reduced mucous cell metaplasia and lower levels of TH2 cytokine levels in bronchoalveolar fluid. In addition, increased airway resistance in response to methacholine was observed in Duoxa+/+ mice, as expected, but was absent in Duoxa-/- mice. Surprisingly, Duoxa-/- mice had decreased influx of neutrophils in bronchoalveolar fluid and lung tissue sections associated with a lower level of the chemotactic cytokine IL-6. These findings suggest that DUOX-derived H2O2 has an important role in signaling neutrophils into allergic airways.

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