Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation.

Abstract

BACKGROUND:

An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far.

OBJECTIVE:

The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling.

METHODS:

Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 microg/mL) was examined by the 2',7'-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2'-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge.

RESULTS:

ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar(9),Met(11)(O(2))]-Substance P (5 nM) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar(9),Met(11)(O(2))]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P<0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P<0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P<0.01).

CONCLUSION:

Allergen challenge induces ROS in a tachykinin NK-1 receptor-dependent manner. Inhibition of the tachykinin NK-1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists.

• Authors: J Springer, D A Groneberg, Q T Dinh, D Quarcoo, E Hamelmann, R C Braun-Dullaeus, P Geppetti, S D Anker, A Fischer
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 37 Issue 12 Pg. 1788-97 (Dec 2007) ISSN: 1365-2222 [Electronic] England
• PMID: 17941913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Reactive Oxygen Species
• Receptors, Neurokinin-1

Topics

• Animals
• Cell Cycle Proteins (metabolism)
• Epithelial Cells (metabolism)
• Hypersensitivity (metabolism, pathology)
• Immunohistochemistry
• Mice
• Mice, Inbred BALB C
• Pneumonia (metabolism, pathology)
• Reactive Oxygen Species (metabolism)
• Receptors, Neurokinin-1 (metabolism)