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.