Health effects of diesel exhaust emissions.

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, both in vivo and in 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.

Histamine secretion induced by neuromedin-N.

Neuromedin-N dose-dependently stimulated the release of histamine from rat serosal mast cells and was 10 to 100 times less potent than neurotensin. The threshold concentration was 10(-6) M, and 10(-3) M neuromedin-N released 31% of the total cell histamine content. The histamine release induced by neuromedin-N was temperature-dependent with an optimum around 30-37 degrees C. Skin vascular permeability increased dose-dependently in response to intradermal injections of neuromedin-N and this peptide was 10 to 100 times less potent than neurotensin. Mepyramine inhibited the effect on vascular permeability suggesting that the effect of neuromedin-N was mediated via the release of histamine.

Prostaglandin E2 prevents diclofenac-induced enhancement of histamine release and inflammation evoked by in vivo challenge with compound 48/80 in the hamster cheek pouch.

Based on observations obtained by the use of intravital microscopy, we report that prostaglandins (PGs) can exert inhibitory effects on mast cell-dependent inflammation. Thus, the PG-synthesis inhibitors diclofenac and indomethacin potentiated extravasation of plasma evoked by challenge with the mast cell secretagogue compound 48/80. Although the plasma leakage induced by compound 48/80 was in large mediated by histamine, neither diclofenac nor indomethacin potentiated the plasma leakage caused by exogenous histamine. These findings indicated that endogenous PGs inhibited the mast cell-dependent reaction at the level of mediator release. This mode of action was confirmed, as diclofenac was found to enhance the in vivo release of histamine that ensued challenge with compound 48/80. Moreover, the enhancement of the response to compound 48/80 observed after diclofenac treatment was prevented by local administration of PGE2 (30 nM). This inhibition included both the histamine release and the plasma leakage. In addition, diclofenac enhanced the leukocyte emigration after compound 48/80 challenge, and PGE2 reversed also this effect, suggesting that endogenous PGs (e.g. PGE2) also inhibited the release of chemotactic mediators.

Stimulation of histamine release by the peptide kinetensin.

The peptide kinetensin isolated from pepsin-treated human plasma induced a dose-dependent release of histamine when exposed to rat peritoneal mast cells. The threshold concentration was around 10(-6) M, the ED50 was 10(-5) M, and the optimal concentration of between 10(-4) to 10(-3) M released 80% of the total histamine. Kinetensin was 10 to 100 times less potent than neurotensin and equipotent with the opioid peptide dynorphin. The histamine release was clearly temperature-dependent, with no release occurring at 0 degrees or 45 degrees C and with an optimum around 37 degrees C. The histamine release was significantly reduced in the absence of extracellular calcium. Kinetensin also induced a dose-dependent increase in vascular permeability when injected intradermally into rats. The findings indicate that kinetensin is a potent histamine releaser in the rat and may serve as an inflammatory mediator.

Dual inhibitory action of nedocromil sodium on antigen-induced inflammation.

In human lung tissue in vitro, nedocromil sodium inhibited the release of histamine and leukotrienes induced by anti-IgE, as well as the contraction of isolated bronchi which followed this challenge. In the hamster cheek pouch in vivo, nedocromil sodium inhibited the inflammatory response induced by challenge with either antigen or the individual inflammatory mediators, histamine and leukotriene B4. The findings thus indicate that nedocromil sodium has a dual anti-inflammatory action: inhibition of mediator secretion and antagonism of mediator action.

Characteristics of beta-endorphin-induced histamine release from rat serosal mast cells. Comparison with neurotensin, dynorphin and compound 48/80.

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.

Enhancement of acute allergic inflammation by indomethacin is reversed by prostaglandin E2: apparent correlation with in vivo modulation of mediator release.

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 anti-inflammatory.

Effects of beta-endorphin on rat mast cells.

The endogenous opioid peptide beta-endorphin induced a dose-dependent release of histamine from rat peritoneal mast cells. The threshold concentration was around 10(-6) M and the optimal concentration of 2 X 10(-5) M released 35% of the total histamine. The release of histamine was very rapid, complete within 10 s, and very similar to that induced by neurotensin or compound 40/80. The histamine release was temperature dependent and inhibited at increased extracellular calcium concentrations. Taken together, the findings indicate that the release of histamine induced by beta-endorphin is a specific, energy-dependent process. The pattern of release has much in common with that induced by other basic peptides, such as neurotensin, dynorphin and substance P.

Exposure to carbachol induces several changes in muscarinic cholinergic parameters in N1E-115 mouse neuroblastoma cells.

Mouse N1E-115 neuroblastoma cells were used to study carbachol induced changes in muscarinic cholinergic parameters. Cells were treated with carbachol (1 mM) for up to 96 hours. The number of muscarinic receptors, measured in 3H-3-quinuclidinyl benzilate binding experiments, decreased approximately 50% after 4 hours exposure to carbachol. This was followed by an increase in binding sites, and after 24 hours the number of binding sites was the same as in control cells. The changes observed in the choline esterase activity followed the same pattern. The increase in number of binding sites was not dependent on protein synthesis, while the increase in choline esterase activity was. The muscarinic receptor-stimulated uptake of 45Ca2+ showed an initial decrease, which was followed by a significantly increased basal uptake of 45Ca2+. It is suggested that all these changes are adaptations of long time exposure to carbachol.

Stimulus-dependence and time-course of histamine and leukotriene release from chopped and dispersed human lung tissue.

The calcium ionophore A23187 and anti-human IgE provoked a dose-dependent release of histamine and cysteinyl-leukotrienes (LTC4, LTD4 and LTE4) from dispersed human lung cells. Optimal release of histamine peaked at 3 min after challenge whereas the release of cysteinyl-leukotrienes peaked at 30 min. The molar ratio between released histamine and cysteinyl-leukotrienes was approximately 100:1. The ionophore, but not anti-IgE caused additional formation of LTB4 in the dispersed cells or the chopped lung, indicating that this chemoattractant is formed from cells not primarily activated by IgE-dependent mechanisms. Indomethacin failed to alter release of histamine or leukotrienes from dispersed cells, whereas further inhibition of lipoxygenases by NDGA abolished leukotriene formation and reduced the release of histamine.

Non-muscarinic effects of scopolamine on N1E-115 neuroblastoma cells.

Membrane effects of scopolamine on N1E-115 neuroblastoma cells were studied using intracellular recording techniques. Scopolamine in concentrations of 50 nM-1 microM induced a depolarization together with a decreased cell input resistance. This response had a reversal potential at +10 to +20 mV in a medium with normal sodium concentration (146.5 mM), and a reversal potential around -10 mV when the sodium concentration in the medium was lowered to 80 mM. The scopolamine-induced depolarization could not be blocked by carbachol (100 microM), and had a reversal potential at +10 to +20 mV. The simplest explanation of the results obtained is that scopolamine increases the membrane permeability for sodium and potassium, in a manner which is not related to muscarinic cholinergic receptors.

The histamine-releasing effect of dynorphin and other peptides possessing Arg-Pro sequences.

The basic opioid peptide dynorphin was tested for histamine-releasing activity on peritoneal rat mast cells. Dynorphin was found to induce a dose-dependent histamine release from the mast cells. The threshold concentration was 2 X 10(-7) M and release was maximal (40% of total) at 2 X 10(-6) M of the peptide. The dynorphin-induced histamine release was a very rapid process completed within 10 seconds at 37 degrees C. The release was independent of extracellular calcium. Experiments with naloxone and a specific kappa-agonist (U-50,488H) gave results indicating that the dynorphin induced histamine release was probably not mediated through opioid kappa-receptors. A couple of other Arg-Pro containing peptides of different origin were also screened for histamine-releasing activity. Most of these peptides elicited a more or less pronounced histamine release, provided the peptide contained more than 5 amino acids, suggesting that the Arg-Pro sequence is of importance for the histamine-releasing effect of peptides such as dynorphin.

On the mechanism by which theophylline inhibits histamine release from rat mast cells.

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.

Evidence against a role of cyclic nucleotides in the regulation of anaphylactic histamine release in isolated rat mast cells.

The effect of different phosphodiesterase (PDE) inhibitors on the antigen or 48/80 induced histamine release from isolated Hooded Lister rat mast cells was tested. The unselective PDE inhibitors theophylline (2.5 mM) and IBMX (0.2 mM) and the selective cyclic GMP PDE inhibitor M & B 22948 (0.1 mM) inhibited the antigen induced histamine release by 50% while 48/80 induced release was inhibited by about 25%. The cyclic AMP selective PDE inhibitors ICI 63197 (0.5 mM) or Ro 20-1724 (0.2 mM) had no effect on 48/80 induced histamine release but tended to enhance antigen induced release. There was no correlation between the measured levels of cyclic AMP and the effect on histamine release by the investigated PDE inhibitors. Cyclic AMP or cyclic GMP up to 10(-3) M did not affect the anaphylactic histamine release. Dibutyryl-cAMP and dibutyryl-cGMP (10(-4) M) both inhibited the release about 20% but this effect could be explained by the effect of butyric acid as sodium butyrate (2 X 10(-4) M) also inhibited the release by 20%. The presence results suggest that cyclic nucleotides are not important regulators of histamine release from isolated mast cells.

Effect of sensitization and non-antibody IgE on 48/80 induced histamine release from isolated rat mast cells.

Histamine release from isolated rat mast cells from non-immunized and immunized Hooded Lister rats was induced by compound 48/80. The histamine release was decreased with a lower maximum at the optimal concentration of 48/80 when using cells from immunized rats compared to non-immunized control rats. The stimulation of IgE antibody production, after immunization using B. pertussis as an adjuvant was also accompanied by an elevation of total serum IgW. The 48/80 induced histamine release from Sprague Dawley mast cells was not inhibited by immunization. Non-antibody IgE showed a non-competitive inhibition of 48/80 induced histamine release when myeloma IgE was incubated with mast cells from both Hooded Lister and Sprague Dawley rats. The results indicate the existence of different receptors for IgE and 48/80.

Total serum IgE influence on the anaphylactic and 48/80 induced histamine release from isolated rat mast cells.

We have investigated the influence of non-specific IgE on histamine release induced by antigen or compound 48/80. Our results indicate that increased amounts of IgE influence antigen mediated histamine release as well as release induced by a non-immunological stimulus like compound 48/80.