Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig. Possible role of free radicals.

Abstract

We examined the effects of acute exposure to cigarette smoke on the airway responses to substance P in anesthetized guinea pigs and on the activity of airway neutral endopeptidase (NEP). After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon. In the absence of phosphoramidon the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea pigs than in air-exposed animals. Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals. In the presence of phosphoramidon, bronchoconstrictor responses to substance P in animals exposed to air or to cigarette smoke were not different. Aerosols of SOD delivered before cigarette smoke exposures dramatically reduced smoke-induced hyperresponsiveness to substance P, whereas heat-inactivated SOD had no effect on smoke-induced hyperresponsiveness to substance P. Cigarette smoke solution inhibited NEP activity from tracheal homogenate in a concentration-dependent fashion, an inhibitory effect that was mostly due to the gas phase of the smoke, but not to nicotine. The mild chemical oxidant N-chlorosuccinimide mimicked the concentration-dependent inhibitory effect of smoke solution on airway NEP activity. We conclude that cigarette smoke causes enhanced airway responsiveness to substance P in vivo by inactivating airway NEP. We suggest that cigarette smoke-induced inhibition of airway NEP is due to effects of free radicals.

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

“…Neuropeptides from sensory nerve fibers, such as substance P, can elicit "neurogenic inflammation" (12), mainly linked to neutrophilic inflammation and vascular leakage, possibly contributing to bronchoconstriction (13,14). Cigarette smoke elicits nonspecific AHR to substance P in guinea pigs, which is of unclear significance to asthma in humans (15).…”

Epidemiologic evidence for asthma and exposure to air toxics: linkages between occupational, indoor, and community air pollution research.

“…Airborne irritants could also indirectly enhance neuroinflammation by inhibition of neutral endopeptidase (NEP). NEP degrades tachykinins and its levels are decreased following exposure to oxidants (27), cigarette smoke (28), and an agent responsible for a form of occupational asthma, toluene diisocyanate (TDI) (29).…”

Tachykinin activation of human monocytes from patients with interstitial lung disease, healthy smokers or healthy volunteers

“…34 Cigarette smoke induces the surface expression of cell adhesion molecules such as ICAM-1, ELAM-1 and VCAM-1 and favours transendothelial migration of MO. 35 In rodents, tobacco smoke enhances airway responsiveness to SP, mainly by inactivating neutral endopepeptidase, 36 stimulating primary afferent sensory nerves and releasing tachykinins in the lung. 37,38 However, according to our results, MO from healthy smokers present a reduced sensitivity to NK 1 and NK 2 receptor stimulation (as compared to MO from volunteers or ILD patients), as evidenced by the higher ED 50 values: we have no definite explanation for this fact, but some attempts can be afforded.…”