Nedocromil sodium reduces cigarette smoke-induced bronchoconstrictor hyperresponsiveness to substance P in the guinea-pig

Abstract

Acute exposure to cigarette smoke provokes airway hyperresponsiveness to substance P and inactivates neutral endopeptidase (NEP). To determine whether nedocromil sodium can prevent cigarette smoke-induced hyperresponsiveness to substance P, we studied two groups of anaesthetized guinea-pigs. One group of guinea-pigs was pretreated with aerosolized 0.9% NaCl solution (90 breaths), the other group was pretreated with aerosolized nedocromil sodium (10(-4) M, 90 breaths). In each animal, pretreatment was followed by either exposure to the smoke of one cigarette or exposure to air. After acute exposure to cigarette smoke or to air, we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P. In the absence of nedocromil sodium, the bronchoconstrictor responses to substance P were greater in cigarette smoke-exposed guinea-pigs than in air-exposed animals. Aerosolized nedocromil sodium had no effect on the response to substance P in air-exposed animals, but it reduced cigarette smoke-induced hyperresponsiveness to substance P. The preventive effect on cigarette smoke-induced hyperresponsiveness to substance P was observed at concentrations of aerosolized nedocromil sodium of 3 x 10(-5), 10(-4), and 3 x 10(-4) M. In vitro, cigarette smoke solution inhibited NEP activity from lung membrane preparations, but this inhibitory effect was not modified by nedocromil sodium (10(-4) M). We conclude that aerosolized nedocromil sodium reduces cigarette smoke-induced airway hyperresponsiveness to substance P in vivo. This action of nedocromil sodium is not due to a protective effect on cigarette smoke-induced inactivation of NEP in vitro.

Pre-protachykinin-A mRNA is increased in the airway epithelium of smokers with chronic bronchitis

“…In view of the fact that epithelial cells produce NEP, it has been speculated that airway epithelial cell dysfunction or loss consequent to inflammation may lead to a nett decrease in NEP activity and hence a potentiation of tachykinin effects. Thus far, in vivo studies of airway responsiveness in humans with asthma have failed to support this hypothesis 34 and there are no reports specifically addressing the issue of NEP activity in patients with chronic bronchitis, although cigarette smoke has been shown to decrease NEP in animal models 35,36 . We did not find any change in NEP mRNA in airway epithelium from our subjects with chronic bronchitis, although we did find changes suggesting that airway inflammation was indeed present (increases in IL‐8 and ICAM‐1 mRNA).…”

Asthma mechanisms, determinants of severity and treatment: the role of nedocromil sodium Report of a workshop held in Whistler, British Columbia, Canada, 18–19 May 1995

“…In one study |122], nedocromil sodium inhibited the cigarette smoke induced increase in total number of cells recovered in BAL fiuid, suggesting that nedocromil sodium could also be inhibiting infiammatory mechanisms. The inhibitory effect of nedocromil sodium does not appear to be secondary to prevention of NEP inactivation by cigarette smoke [121].…”

Neurogenic Inflammation and Sensitivity to Environmental Chemicals

“…Human recombinant NEP suppresses neurogenic inflammation (18)(19)(20). Exogenous substances that inhibit NEP include cigarette smoke (21), respiratory viruses (22)(23)(24)(25), and the volatile organic chemical toluene diisocyanate (26).…”