Epidemiological studies have demonstrated an association between different levels of air pollution and various health outcomes including mortality, exacerbation of asthma, chronic bronchitis, respiratory tract infections, ischaemic heart disease and stroke. Of the motor vehicle generated air pollutants, diesel exhaust particles account for a highly significant percentage of the particles emitted in many towns and cities. This review is therefore focused on the health effects of diesel exhaust, and especially the particular matter components.Acute effects of diesel exhaust exposure include irritation of the nose and eyes, lung function changes, respiratory changes, headache, fatigue and nausea. Chronic exposures are associated with cough, sputum production and lung function decrements. In addition to symptoms, exposure studies in healthy humans have documented a number of profound inflammatory changes in the airways, notably, before changes in pulmonary function can be detected. It is likely that such effects may be even more detrimental in asthmatics and other subjects with compromised pulmonary function.There are also observations supporting the hypothesis that diesel exhaust is one important factor contributing to the allergy pandemic. For example, in many experimental systems, diesel exhaust particles can be shown to act as adjuvants to allergen and hence increase the sensitization response.Much of the research on adverse effects of diesel exhaust, bothin vivoandin vitro, has however been conducted in animals. Questions remain concerning the relevance of exposure levels and whether findings in such models can be extrapolated into humans. It is therefore imperative to further assess acute and chronic effects of diesel exhaust in mechanistic studies with careful consideration of exposure levels. Whenever possible and ethically justified, studies should be carried out in humans.

Intravital microscopy and determination of in vivo histamine release revealed that the cyclooxygenase inhibitor indomethacin reduced antigen-induced vasodilation while enhancing plasma extravasation, leukocyte accumulation, and histamine release in cheek pouches of immunized hamsters. Topical application of prostaglandin E2 (PGE2, 30 nM) totally reversed the indomethacin-induced potentiation of the inflammatory reaction to antigen challenge and suppressed both the histamine release and plasma leakage also in the absence of indomethacin. On the other hand, PGE2, which per se caused vasodilation, markedly potentiated the postcapillary leakage of plasma induced by histamine or leukotriene C4, as well as the leukocyte activation and subsequent plasma extravasation evoked by leukotriene B4. Taken together, the data indicate that PGE2 reduced the antigen response by suppression of mediator release from the numerous mast cells present in the cheek pouch. Moreover, the PGE2-sensitive potentiation by indomethacin of the antigen response suggests that endogenous vasodilating prostaglandins (possibly PGE2) predominantly were antiinflammatory.The potent vasodilator prostaglandin E2 (PGE2) is released at sites of inflammation, causes a wheal and flare reaction when injected into skin, and enhances the effects of pain-and edema-producing stimuli (cf. ref. 1). Moreover, nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the fatty acid cyclooxygenase, which catalyzes the initial steps in the biosynthesis of PGE2 from arachidonic acid (cf. ref. 1). Hence, PGE2 is considered to be an inflammatory mediator. Nevertheless, PGE2 and related compounds also exhibit antiinflammatory activities (2-8), and NSAIDs sometimes augment inflammation (9, 10). These conflicting observations complicate understanding of the functional role of PGE2 in inflammation.In the present study, intravital microscopy of the hamster cheek pouch was used to characterize the influence of PGE2 and the prototype of NSAIDs, indomethacin, on microcirculatory dynamics during acute mast cell-dependent inflammation evoked by antigen challenge. Supported also by in vivo measurements of antigen-induced histamine release from the cheek pouch and analysis of the microvascular interactions between exogenous inflammatory mediators and PGE2, we conclude that endogenous cyclooxygenase products predominantly inhibit acute allergic inflammation via local suppression of inflammatory mediator release.MATERIALS AND METHODS Drugs and Chemicals. Leukotrienes B4 and C4 (LTB4, LTC4) were provided by J. Rokach (Merck Frosst Labs, Pointe Claire, PQ) and PGE2 by J. Pike (Upjohn). Arachidonic acid was from Nu Chek Prep. Stock solutions of LTB4, PGE2, and arachidonic acid were stored at -20°C in ethanol, and LTC4 was stored similarly in ethanol/water, 1:1. Concentrations and purity of the icosanoids were checked before use by appropriate methods (UV spectrometry, reverse-phase HPLC, and thin-layer chromatography). Acetylcholine chloride, fluorescein isothiocyanate-conjugated dextr...

Adenosine potentiated anaphylactic histamine release from isolated rat mast cells in a dose-dependent manner between 10(-8) and 10(-5) M. Adenosine was found to be present during a normal incubation of mast cells, but the concentration was low (2 x 10(-8) M). In rat plasma the concentration was 1.5 x 10(-7) M. The effect of 10(-5) M adenosine was dose-dependently inhibited by theophylline. 50% inhibition was found at 3 x 10(-5) M theophylline. Cyclic nucleotide phosphodiesterase inhibition required much higher concentrations (IC50 approximately 10(-3) M). It is suggested that some of the anti-allergic actions of theophylline (clinical concentration range: 10(-5) M) does not involve cyclic nucleotides but may be due to inhibition of the effects of endogenous adenosine.

Rat peritoneal mast cells were exposed to the neurohormone and basic opioid peptide beta-endorphin. beta-Endorphin induced a dose-dependent release of histamine from the mast cells. A significant histamine release was found at 5 mumol/l of beta-endorphin and maximal release (35% of total) at 20 mumol/l. The histamine release process was very rapid and terminated within 30 s at 37 C, and in this sense is very similar to the histamine release induced by compound 48/80 or neurotensin. The histamine release was temperature-dependent showing an optimum release around 30 C, and it was independent of available extracellular calcium, but was inhibited in the presence of high extracellular calcium concentrations. Naloxone, only in very high concentrations (10 mmol/l), inhibited the release, and the very same concentration also inhibited the neurotensin - as well as the compound 48/80-induced histamine release. Cromoglycate and benzalkoniumchloride, a 48/80 antagonist, both produced a progressive dose-dependent inhibition of beta-endorphin-, neurotensin- as well as compound 48/80-induced histamine release. Taken together, the findings indicate that the opioid peptide beta-endorphin induces a selective, energy-dependent release of histamine from peritoneal rat mast cells. The pattern of release has much in common with that of compound 48/80 and other basic peptides, such as neurotensin and substance P. In addition this pattern of release is similar to that induced by dynorphin.