Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections

Abstract

Neuropeptides such as substance P are implicated in inflammation mediated by sensory nerves (neurogenic inflammation), but the roles in disease of these peptides and the peptidases that degrade them are not understood. It is well established that inflammation is a prominent feature of several airway diseases, including viral infections, asthma, bronchitis, and cystic fibrosis. These diseases are characterized by cough, airway edema, and abnormal secretory and bronchoconstrictor responses, all of which can be elicited by substance P. The effects of substance P and other peptides that may be involved in inflammation are decreased by endogenous neutral endopeptidase (NEP; also called enkephalinase, EC 3.4.24.11), which is a peptidase that degrades substance P and other peptides. In the present study, we report that rats with histories of infections caused by common respiratory tract pathogens (parainfluenza virus type 1, rat corona-virus, and Mycoplasma pulmonis) not only have greater susceptibility to neurogenic inflammatory responses than do pathogen-free rats but also have a lower activity of NEP in the trachea. This reduction in NEP activity may cause the increased susceptibility to neurogenic inflammation by allowing higher concentrations of substance P to reach tachykinin receptors in the trachea. Thus decreased NEP activity may exacerbate some of the pathological responses in animals with respiratory tract infections.

Effects of aerosolised substance P on lung resistance in guinea‐pigs: a comparison between inhibition of neutral endopeptidase and angiotensin‐converting enzyme

“…Support for this reasoning is given by studies showing that viral infections enhance the contractile responses to SP in guinea-pig bronchi (Saban et al, 1987) and ferret trachea (Jacoby et al, 1988). Furthermore, histories of infections in rats have been associated with a decreased activity of NEP and an enhanced SP-induced vascular leakage in the trachea (Borson et al, 1989).…”

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

“…The results imply that there is continuous release of tachykinins and kinins and that NEP maintains low basal levels of these peptides. These findings are of possible clinical interest, since NEP is down-regulated in inflamed tissues, which may contribute to uncontrolled inflammation [40,41].…”

Inflammation-Induced Plasticity of the Afferent Innervation of the Airways

“…Similarly, respiratory infections of rodents with Sendai virus (parainfluenza type 1) can potentiate substance P-induced increases in airways blood flow (78) and enhance tachykinergic nerve-mediated contraction of airway smooth muscle (79). These effects appear to be at least partially due to decreased activity of neutral endopeptidase, a protease normally present in the airways, which degrades tachykinins (80)(81)(82).…”