Exposure to ozone induces airway hyperresponsiveness (AHR) mediated partly by SP released from nerve terminals of intrinsic airway neurons. Our recent studies showed that IL-1, an important multifunctional proinflammatory cytokine, increases synthesis and release of SP from intrinsic airway neurons. The purpose of this study is to investigate the possible involvement of endogenous IL-1 in modulating neural responses associated with ozone-enhanced airway responsiveness. Ferrets were exposed to 2 ppm ozone or filtered air for 3 hrs. IL-1 in the bronchoalveolar lavage (BAL) fluid was significantly increased in ozone-exposed animals and responses of tracheal smooth muscle to methacholine (MCh) and electrical field stimulation (EFS) were elevated significantly. Both the SP nerve fiber density in tracheal smooth muscle and the number of SP-containing neurons in airway ganglia were significantly increased following ozone exposure. Pretreatment with IL-1 receptor antagonist (IL-1 Ra) significantly diminished ozone-enhanced airway responses to EFS as well as ozone-increased SP in the airway. To selectively investigate intrinsic airway neurons, segments of ferret trachea were maintained in culture conditions for 24 hrs to eliminate extrinsic contributions from sensory nerves. The segments were then exposed to 2 ppm ozone in vitro for 3 hrs. The changes of ozone-induced airway responses to MCh and EFS, and the SP levels in airway neurons paralleled those observed with in vivo ozone exposure. The ozone-enhanced airway responses and neuronal SP levels were inhibited by pretreatment with IL-1 Ra. These findings show that IL-1 is released during ozone exposure enhances airway responsiveness by modulating SP expression in airway neurons.
Previous studies demonstrated that interleukin-1β (IL-1β) and nerve growth factor (NGF) increase synthesis of substance P (SP) in airway neurons both after ozone (O3) exposure and by direct application. It was postulated that NGF mediates O3-induced IL-1β effects on SP. The current study specifically focused on the influence of O3 on IL-1β, 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 O3 exposure induced an increase of all three proteins in mouse BALF and that O3-induced elevations in both NGF and SP are mediated by the inflammatory cytokine IL-1β. Further, inhibition of NGF reduced O3 induced increases of SP in both the lung BALF and lung tissue, demonstrating NGF serves as a mediator of IL-1β effects on SP. These data indicate that IL-1β is an early mediator of O3-induced rise in NGF and subsequent SP release in mice in vivo.
Our previous studies showed that both IL‐1 and NGF increase synthesis of substance P (SP) in airway neurons after either direct application or ozone exposure. We hypothesize that NGF mediates IL‐1 effects on SP, similar to the pathway described for sympathetic neurons in culture. The current study specifically focuses on the effect of IL‐1 on NGF levels in mice BALF. Three different experimental groups of adult mice were exposed to 2 ppm ozone for three hours while a control group was exposed to filtered air. The three experimental groups were 1) intratracheal (i.t.) instillation of IL‐1 receptor antagonist (IL‐1Ra) before ozone exposure; 2) i.t. instillation of saline before exposure; and 3) ozone exposure with no i.t. instillation. The following day, BALF was collected and NGF concentration was determined using Enzyme‐Linked ImmunoSorbent Assay (ELISA). The results showed ozone exposure alone or after saline instillation significantly increased the NGF level (3230 ng/ml ± 1039 and 2710 ng/ml ± 773 respectively) compared with the filtered air control group (1426 ng/ml ± 694). Pretreatment with IL‐1Ra attenuated the ozone‐induced increase in NGF levels (1045 ng/ml ± 51 units). These data indicate that IL‐1 regulates the ozone‐induced increase in NGF release in mice. Funded by NIH HL 35812.
Our previous studies showed that both IL‐1 and NGF increase synthesis of substance P (SP) in airway neurons after either direct application or ozone exposure. We hypothesize that NGF mediates IL‐1 effects on SP, similar to the pathway described for sympathetic neurons in culture. The current study specifically focuses on the effect of IL‐1 on NGF levels in mice BALF. Three different experimental groups of adult mice were exposed to 2 ppm ozone for three hours while a control group was exposed to filtered air. The three experimental groups were 1) intratracheal (i.t.) instillation of IL‐1 receptor antagonist (IL‐1Ra) before ozone exposure; 2) i.t. instillation of saline before exposure; and 3) ozone exposure with no i.t. instillation. The following day, BALF was collected and NGF concentration was determined using Enzyme‐Linked ImmunoSorbent Assay (ELISA). The results showed ozone exposure alone or after saline instillation significantly increased the NGF level (3230 ng/ml ± 1039 and 2710 ng/ml ± 773 respectively) compared with the filtered air control group (1426 ng/ml ± 694). Pretreatment with IL‐1Ra attenuated the ozone‐induced increase in NGF levels (1045 ng/ml ± 51 units). These data indicate that IL‐1 regulates the ozone‐induced increase in NGF release in mice. Funded by NIH HL 35812.
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