Role of substance P and neurokinin A in toluene diisocyanate-induced increased airway responsiveness in rabbits

Abstract

The aim of the present study was to examine the role of neuropeptides, especially substance P (SP) and neurokinin A (NKA), in toluene diisocyanate (TDI)-induced airway hyperresponsiveness (AHR) to acetylcholine aerosols. Thirty parts per billion of TDI in air administered over 4 hours caused a significant increase in the airway constrictive response to acetylcholine (ACH) aerosols in rabbits (DeltaRI: 245 +/- 30%, p < 0.005) without altering basic values of respiratory, cardiovascular or blood gas parameters. Inhalation of the aerosolized neuropeptides SP and NKA resulted in a similar increase in airway responsiveness (AR) to ACH as exposure to 30 ppb TDI. To determine whether neuropeptides contribute to TDI-induced AHR, we studied their effects after systemic treatment with capsaicin as well as after infusion of specific synthetic antagonists for SP and NK2 (NKA) receptors. CAPS treatment performed on 4 consecutive days as well as antagonists' infusion only moderately (p > 0.05) decreased airway responses to ACH. CAPS application prevented the TDI-induced increase in AR to ACH in all rabbits. The increase in airway resistance to ACH did not significantly change after TDI exposure (98 +/- 22% of the control response before TDI, p > 0.05). Simultaneous infusion of specific synthetic SP and NK2 receptor antagonists also abolished the TDI-induced increase in airway responses to ACH in all animals investigated (p > 0.05). The results of this study demonstrate that neuropeptides, especially the tachykinins SP and NKA, are important mediators in TDI-induced AHR in rabbits.

Rats Repeatedly Exposed to Toluene Diisocyanate Exhibit Immune Reactivity against Methyl Isocyanate-Protein Conjugates

“…From these results we conclude that MIC and TDI share some properties in terms of respiratory toxicity. Previously it was reported that TDI-induced airway hyperreactivity is dependent on tachykinins [38], suggesting a plausible mechanism for induction of immediate bronchoconstriction by diisocyanates [25, 39, 40]. Moreover, a connection between release of tachykinins, immunoglobulin production, leukocyte recruitment and activation has been established in earlier studies [41, 42], indicating that diisocyanate-induced respiratory toxicity could trigger the subsequent immune response.…”

Toluylendiisocyanate [MAK Value Documentation in German language, 1999]

“…Hierzu liegen zahlreiche -auch mechanistische -Untersuchungen an Kaninchen und Meerschweinchen sowie in vitro vor, auf die hier nicht näher eingegangen wird. Auf eine Übersichtsarbeit (Raulf-Heimsoth und Baur 1998) und einige neuere Untersuchungen hierzu (Gagniere et al 1996(Gagniere et al , 1997Lastbom et al 1996;Mapp et al 1996;Marek et al 1996) sei verwiesen.…”

Acute exposure to hair bleach causes airway hyperresponsiveness in a rabbit model

“…A detailed description of the rabbit model and the statistical data analysis has been presented in previous papers [12,13]. Male and female white New Zealand rabbits of the same breed and of similar age and body weight (3.5-4.0 kg) were anaesthetized with 20-30 mg·kg -1 thiopentobarbital sodium (Trapanal®; Byk Gulden, Konstanz, Germany) after premedication with 25 mg·kg -1 ketamine hydrochloride (Ketanest®; Parke-Davis, Berlin, Germany) and 5 mg· kg -1 xylazin (Rompun®; Bayer, Leverkusen, Germany) and placed in a supine position.…”

“…The particles had a diameter of 0.5-5.5 µm. During the challenge tests, animals inhaled for 1 min with a mean of 1.1±0.3 L from the ACh aerosol [12], which corresponded to a total dose of 0.05 and 0.5 mg ACh, respectively (0.2% and 2.0% solution).…”