Histamine stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase.

Abstract

Oxidative stress has been implicated in the pathogenesis of bronchial asthma. Besides granulocytes, the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma-related oxidative stress. Histamine is a major inflammatory mediator present in large quantities in asthmatic airways. Whether histamine triggers epithelium-derived oxidative stress is unknown. We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine. We found that air-liquid interface cultures of primary human bronchial epithelial cells (BECs) and an immortalized BEC model (Cdk4/hTERT HBEC) produce H2O2 in response to histamine. The main source of airway epithelial H2O2 is an NADPH dual oxidase, Duox1. Out of the four histamine receptors (H1R-H4R), H1R has the highest expression in BECs and mediates the H2O2-producing effects of histamine. IL-4 induces Duox1 gene and protein expression levels and enhances histamine-induced H2O2 production by epithelial cells. Using HEK-293 cells expressing Duox1 or Duox2 and endogenous H1R, histamine triggers an immediate intracellular calcium signal and H2O2 release. Overexpression of H1R further increases the oxidative output of Duox-expressing HEK-293 cells. Our observations show that BECs respond to histamine with Duox-mediated H2O2 production. These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways, suggesting novel therapeutic targets for treating asthmatic airway disease.

• Authors: Balázs Rada, Howard E Boudreau, Jonathan J Park, Thomas L Leto
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 50 Issue 1 Pg. 125-34 (Jan 2014) ISSN: 1535-4989 [Electronic] United States
• PMID: 23962049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Receptors, Histamine H1
• Interleukin-4
• Histamine
• Hydrogen Peroxide
• Dual Oxidases
• NADPH Oxidases
• DUOX1 protein, human
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• TERT protein, human
• Telomerase

Topics

• Bronchi (metabolism)
• Cells, Cultured
• Cyclin-Dependent Kinase 4 (metabolism)
• Cytokines (metabolism)
• Dual Oxidases
• Epithelial Cells (metabolism)
• HEK293 Cells
• Histamine (metabolism)
• Humans
• Hydrogen Peroxide (metabolism)
• Interleukin-4 (metabolism)
• NADPH Oxidases (metabolism)
• Receptors, Histamine H1 (metabolism)
• Telomerase (metabolism)
• Th2 Cells (metabolism)