Ultrafine particles affect the balance of endogenous pro- and anti-inflammatory lipid mediators in the lung:<em> In-vitro</em> and <em>in-vivo </em>studies.

BACKGROUND: Exposure to ultrafine particles exerts diverse harmful effects including aggravation ofpulmonary diseases like asthma. Recently we demonstrated in a mouse model for allergicairway inflammation that particle-derived oxidative stress plays a crucial role duringaugmentation of allergen-induced lung inflammation by ultrafine carbon particle (UfCP)inhalation. The mechanisms how particle inhalation might change the inflammatory balancein the lungs, leading to accelerated inflammatory reactions, remain unclear. Lipid mediators,known to be immediately generated in response to tissue injury, might be strong candidatesfor priming this particle-triggered change of the inflammatory balance. METHODS: We hypothesize that inhalation of UfCP may disturb the balance of pro- and antiinflammatorylipid mediators in: i) a model for acute allergic pulmonary inflammation,exposing mice for 24 h before allergen challenge to UfCP inhalation (51.7 nm, 507 &igrave;g/m3),and ii) an in-vitro model with primary rat alveolar macrophages (AM) incubated with UfCP(10 &igrave;g/1 x 106 cells/ml) for 1 h. Lungs and AM were analysed for pro- and anti-inflammatorylipid mediators, namely leukotriene B4 (LTB4), prostaglandin E2 (PGE2), 15(S)-hydroxyeicosatetraenoicacid (15(S)-HETE), lipoxin A4 (LXA4) and oxidative stress marker 8-isoprostane by enzyme immunoassays and immunohistochemistry. RESULTS: In non-sensitized mice UfCP exposure induced a light non-significant increase of all lipidmediators. Similarly but significantly in rat AM all lipid mediators were induced alreadywithin 1 h of UfCP stimulation. Also sensitized and challenge mice exposed to filtered airshowed a partially significant increase in all lipid mediators. In sensitized and challengedmice UfCP exposure induced highest significant levels of all lipid mediators in the lungstogether with the peak of allergic airway inflammation on day 7 after UfCP inhalation. Thelevels of LTB4, 8-isoprostane and PGE2 were significantly increased also one day after UfCPexposure. Immunohistochemistry localized highest concentrations of PGE2 especially in AMone day after UfCP exposure. CONCLUSION: Our results suggest that UfCP exposure affects the balance between pro- and antiinflammatorylipid mediators. In allergic mice, where the endogenous balance of pro- andanti-inflammatory mediators is already altered, UfCP exposure aggravates the inflammationand the increase in anti-inflammatory, pro-resolving lipid mediators is insufficient tocounterbalance the extensive inflammatory response. This may be a contributing mechanismthat explains the increased susceptibility of asthmatic patients towards particle exposure