Am. J. Respir. Cell Mol. Biol., Vol 14, No. 1, 01 1996, 76-83.
Nitrogen dioxide exposure increases airway contractile response to histamine by decreasing histamine N-methyltransferase activity in guinea pigs
H Hoshi, K Yamauchi, K Sekizawa, Y Ohkawara, H Iijima, E Sakurai, K Maeda, S Okinaga, I Ohno, M Honma, G Tamura, Y Tanno, T Watanabe, H Sasaki and K Shirato
First Department of Internal Medicine, Tohoku University School of First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
To determine the mechanism responsible for nitrogen dioxide (NO2)- induced
airway hyperresponsiveness, we examined the effects of NO2 exposure on the
contractile response to histamine and the level of histamine
N-methyltransferase (HMT) activity, a histamine-degrading enzyme, in guinea
pig trachea in vitro. Guinea pigs were divided into seven groups. Each
group received continuous NO2 exposure (2.0 ppm) for either 2, 6, 12, 24,
48, or 96 h. The remaining group did not receive NO2 exposure (control).
HMT activity in trachea was decreased from the control value of 70.3 +/-
7.7 pmol/min/mg protein to 34.6 +/- 6.7 pmol/min/mg protein by 12 h
exposures of NO2. However, 24 and 48 h exposures of NO2 did not
significantly alter HMT activity. In contrast, HMT activity exceeded the
control value by 96 h exposures of NO2 (85.5 +/- 5.1 pmol/min/mg protein).
Twelve hour exposures of NO2 shifted the concentration-response curves to
histamine to lower concentrations and significantly reduced the median
effective concentration (EC50) of histamine (log M) from the control value
of -5.16 +/- 0.09 to -6.15 +/- 0.14 (P < 0.01). In contrast, the EC50
concentration of histamine (log M) increased from the control value of
-5.20 +/- 0.10 to -4.90 +/- 0.11 by 96 h exposures of NO2 (P < 0.05).
However, NO2 exposure did not alter the contractile response to
acetylcholine. Morphologically, tracheal epithelial cells had vacuoles
after 12 h exposures of NO2, but denudation of the epithelium did not occur
during this experiment. In situ hybridization for HMT mRNA demonstrated
that the level of HMT mRNA increased dominantly in tracheal epithelial
cells after 96 h exposures of NO2. The present results indicated that the
decrease in the level of HMT activity in the trachea was closely associated
with the increase in the airway contractile response to histamine,
suggesting that NO2- induced transient airway hyperresponsiveness to
histamine is due to the decreased capacity of histamine catabolism in
airway.
