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.

Isolation of sensitized rat mast cells by density gradient centrifugation in Ficoll decreases the histamine release obtained when they are subsequently exposed to antigen. The histamine release from such isolated cells is potentiated by the addition of 2% boiled rat serum. This potentiation is dose-dependent and has a temperature optimum of about 25 degrees C. The potentiating activity was localized to the serum phospholipid fraction. Of the pure phospholipids studies (LPC, PC, PE, PI, PS and SM) only phosphatidylserine and lysophosphatidylcholine were found to potentiate the histamine release. The mechanism behind this potentiation is discussed and it is suggested that the potentiation by phosphatidylserine and lysophosphatidylcholine is due to a requirement of these phospholipids for the ion exchange (Na+, K+ and Ca++) or the adenylcyclase activity essential for the histamine release process.

The histamine-releasing activity of some basic peptides was tested on mast cells from Sprague-Dawley or Brown % 70. Norway rats. Somatostatin, bombesin, vasoaetive intestinal H~ peptide (VIP) or substance P did not give any histamine release release in concentrations up to 10 -6 M. Somatostatin in 10 -2 M concentration released 25% of total histamine. However, 50. neurotensin induced a significant histamine release from Brown Norway mast ceils at 10 -8 M. The neurotensininduced histamine release was found to be selective and in some aspects similar to that induced by compound 48/80.

Inbred Hooded Lister rats were immunized with egg albumin with B. pertussis vaccine used as an adjuvant. The serum levels of total IgE and IgE antibody (egg albumin specific) were determined by radioimmunoassay techniques before and after immunization. The basic level of total IgE in serum was 560 +/- 110 ng/ml. After immunization a maximal peak at day 11 of 1940 +/- 160 ng/ml was registered. Anti-egg albumin IgE antibody showed a maximum around day 13 of 75 +/- 11 units/ml. Pleural mast cells were isolated on Ficoll between day 14 and 20 after immunization. A significant negative correlation between the basic total IgE level and histamine release by antigen (egg albumin) was found and also a significant positive correlation of specific IgE antibody (determined at day 11) and histamine release. The correlation between IgE level and histamine release was slightly improved if instead the ratio of specific IgE antibody over total IgE was used.

Theophylline (2.5 mM) did not influence the spontaneous release of histamine but inhibited histamine release induced by antigen, compound 48/80 or phosphatidylserine. The effect on 48/80-induced histamine release could not be reversed by increasing extracellular Ca2+. Exogenous adenosine (10(-8) to 10(-4) M) did not influence spontaneous histamine release or 48/80-induced release but potentiated antigen-induced release. The adenosine potentiation was competitively inhibited by theophylline in concentrations (10(-5) to 10(-4) M) lower than those required to inhibit antigen-induced histamine release in the absence of adenosine. In order to see if endogenous adenosine levels are high enough to potentiate an anaphylactic histamine release in vivo, adenosine was determined in mast cell incubates and in plasma from 4 different strains of rat. The levels were 0.18 to 0.99 microM in plasma, which is sufficient to cause significant potentiation of histamine release, but only 3 x 10(-8) M in mast cell incubates. Theophylline (2.5 mM) increased cAMP levels about 100%, whereas adenosine (10(-5) M) had little effect on cAMP and cGMP levels. However, when incubated together, adenosine could inhibit the theophylline-induced increase in cAMP levels but not the inhibition of histamine release. It is concluded that the effect of low concentrations of theophylline could be due partly to antagonism of adenosine effects. In addition, in higher doses, theophylline appears to exert an inhibitory action that is unrelated to cyclic nucleotides, extracellular calcium and adenosine.