Involvement of preprotachykinin A gene-encoded peptides and the neurokinin 1 receptor in endotoxin-induced murine airway inflammation.
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 24 h 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-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) 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-alpha concentration were markedly diminished only in TAC1(-/-) mice. Interestingly, the concentrations of both cytokines, IL-1beta and TNF-alpha, 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.
Helyes
Zsuzsanna
Z
Department of Pharmacology and Pharmacotherapy, University of Pécs, Hungary. zsuzsanna.helyes@aok.pte.hu
Elekes
Krisztián
K
Sándor
Katalin
K
Szitter
István
I
Kereskai
László
L
Pintér
Erika
E
Kemény
Agnes
A
Szolcsányi
János
J
McLaughlin
Lynn
L
Vasiliou
Sylvia
S
Kipar
Anja
A
Zimmer
Andreas
A
Hunt
Stephen P
SP
Stewart
James P
JP
Quinn
John P
JP
D000704:Analysis of Variance; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D010993:Plethysmography, Whole Body; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013053:Spectrophotometry; D015320:Tachykinins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D014409:Tumor Necrosis Factor-alpha; C044206:preprotachykinin; D009195:Peroxidase