Ozone Exposure Initiates a Sequential Signaling Cascade in Airways Involving Interleukin-1Beta Release, Nerve Growth Factor Secretion, and Substance P Upregulation

Previous studies demonstrated that interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF) increase synthesis of substance P (SP) in airway neurons both after ozone (O-3) exposure and by direct application. It was postulated that NGF mediates O-3-induced IL-1 beta effects on SP. The current study specifically focused on the influence of O-3 on IL-1 beta, NGF, and SP levels in mice bronchoalveolar lavage fluid (BALF) and whether these mediators may be linked in an inflammatory-neuronal cascade in vivo. The findings showed that in vivo O-3 exposure induced an increase of all three proteins in mouse BALF and that O-3-induced elevations in both NGF and SP are mediated by the inflammatory cytokine IL-1 beta. Further, inhibition of NGF reduced O-3 induced increases of SP in both the lung BALF and lung tissue, demonstrating NGF serves as a mediator of IL-1 beta effects on SP. These data indicate that IL-1 beta is an early mediator of O-3-induced rise in NGF and subsequent SP release in mice in vivo.