Aims: 

We have established that the preprotachykinin A gene-encoded substance P and neurokinin A expressed predominantly in sensory neurons play an important role in airway inflammation via neurokinin 1 and 2 receptor activation, respectively. Hemokinin-1 (HK-1) derived from the TAC4 gene is also a potent agonist at the NK1 receptors and likely to participate in inflammation. Therefore, we investigated endotoxin-induced airway inflammation and consequent hyperreactivity in TAC4 gene-deleted (TAC4^-/-) mice compared to the C57BL/6 wildtype counterparts.

Methods: 

Acute pneumonitis was evoked by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h after LPS administration. Semiquantitative histopathological evaluation of the lung was performed based on perivascular oedema, neutrophil accummulation, infiltration of activated macrophages and goblet cell hyperplasia. Myeloperoxidase (MPO) activity of the lung homogenates was measured with spectrophotometry and interleukin-1b (IL-1b) concentration with ELISA.

Results: 

LPS administration resulted in bronchial hyperresponsiveness and increased concentrations of IL-1b in the lungs that did not differ significantly in wildtype and TAC4^-/- mice. The typical LPS-induced inflammatory changes and the semiquantitative histopathological scores were significantly diminished in the TAC4^-/- group. In agreement with the histological results, MPO activity correlating with the number of accumulated granulocytes and macrophages was also significantly reduced in TAC4^-/- animals. Despite the decreased intensity of the inflammatory reaction, in the lung of LPS-treated TAC4^-/- mice large, follicle-like lymphoid structures were observed in association with the bronchi and vessels.

Conclusion: 

TAC4 gene-encoded HK-1 is involved in the formation of characteristic inflammatory changes of acute pneumonitis, but it does not influence bronchial hyperresponsiveness. Furthermore, HK-1 seems to have a specific regulatory role on lymphocyte functions, but elucidation of its precise mechanisms needs further investigations.

Support: 

OTKA K72592, K73044, ETT 03-380/2009, SROP-4.2.1.B-10/2/KONV-2010-0002