Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation

Helyes, Zsuzsanna; Elekes, Krisztián; Sándor, Katalin; Szitter, István; Kereskai, László; Pintér, Erika; Kemény, Ágnes; Szolcsányi, János; McLaughlin, Lynn; Vasiliou, Sylvia; Kipar, Anja; Zimmer, Andreas; Hunt, Stephen P.; Stewart, James P.; Quinn, John P.

doi:10.1016/j.npep.2010.05.004

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Volume 44, Issue 5 , Pages 399-406, October 2010

Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation

Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
- Corresponding author. Address: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624 Pécs, Szigeti u. 12, Hungary. Tel.: +36 72 536 001/5591; fax: +36 72 536 218.
Krisztián Elekes
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
Katalin Sándor
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
István Szitter
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
László Kereskai
- Department of Pathology, University of Pécs, Hungary
Erika Pintér
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
Ágnes Kemény
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
János Szolcsányi
- Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary
Lynn McLaughlin
- School of Biomedical Sciences, Liverpool University, Liverpool, UK
Sylvia Vasiliou
- School of Biomedical Sciences, Liverpool University, Liverpool, UK
Anja Kipar
- School of Veterinary Science, University of Liverpool, UK
Andreas Zimmer
- Institute of Molecular Psychiatry, University of Bonn, Germany
Stephen P. Hunt
- Research Department of Cell and Developmental Biology, University College London, UK
James P. Stewart
- School of Infection and Host Defence, University of Liverpool, UK
John P. Quinn
- School of Biomedical Sciences, Liverpool University, Liverpool, UK

Received 5 February 2010; accepted 28 May 2010. published online 25 June 2010.

Abstract

Tachykinins encoded by the preprotachykinin A (TAC1) gene such as substance P (SP) and neurokinin A (NKA) are involved in neurogenic inflammatory processes via predominantly neurokinins 1 and 2 (NK1 and NK2) receptor activation, respectively. Endokinins and hemokinins encoded by the TAC4 gene also have remarkable selectivity and potency for the NK1 receptors and might participate in inflammatory cell functions. The aim of the present study was to investigate endotoxin-induced airway inflammation and consequent bronchial hyper-reactivity in TAC1^−/−, NK1^−/− and also in double knockout (TAC1^−/−/NK1^−/−) mice.

Sub-acute interstitial lung inflammation was evoked by intranasal Escherichia coli lipopolysaccharide (LPS) in the knockout mice and their wildtype C57BL/6 counterparts 24h before measurement. Respiratory parameters were measured with unrestrained whole body plethysmography. Bronchoconstriction was induced by inhalation of the muscarinic receptor agonist carbachol and Penh (enhanced pause) correlating with airway resistance was calculated. Lung interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) concentrations were measured with ELISA. Histological evaluation was performed and a composite morphological score was determined. Myeloperoxidase (MPO) activity in the lung was measured with spectrophotometry to quantify the number of infiltrating neutrophils/macrophages.

Airway hyper-reactivity was significantly reduced in the TAC1^−/− as well as the TAC1^−/−/NK1^−/− groups. However, LPS-induced histological inflammatory changes (perivascular/peribronchial oedema, neutrophil infiltration and goblet cell hyperplasia), MPO activity and TNF-α concentration were markedly diminished only in TAC1^−/− mice. Interestingly, the concentrations of both cytokines, IL-1β and TNF-α, were significantly greater in the NK1^−/− group.

These data clearly demonstrated on the basis of histology, MPO and cytokine measurements that TAC1 gene-derived tachykinins, SP and NKA, play a significant role in the development of endotoxin-induced murine airway inflammation, but not solely via NK1 receptor activation. However, in inflammatory bronchial hyper-responsiveness other tachykinins, such as hemokinin-1 acting through NK1 receptors also might be involved.

Keywords: Unrestrained whole body plethysmography, Enhanced pause, Myeloperoxidase activity, Interleukin-1β, Tumor necrosis factor-α, Substance P, Neurokinin A