PubMed · 11971249
An overview of the factors affecting the declining severity of asthma.
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A Ross. Declining asthma severity.. https://doi.org/10.7748/ns.15.10.33.s58
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Rats were nose-only exposed for 6 h to polymeric methylenediphenyl-diisocyanate (pMDI). Concentrations varied from 0.12 to 12.7 mg/m(3) using a highly respirable aerosol. In regard to the concentration of the monomeric fraction of MDI contained in pMDI, the lowest concentration was in the range of the current workplace limit of MDI which is 0.05 mg/m(3). Biomarkers of exposure were determined in hydrolyzed urine (collection started after cessation of exposure for approximately 18 h; acid hydrolysis) and hydrolyzed hemoglobin (collection of blood approximately 20 h after cessation of exposure; alkaline hydrolysis). The determination revealed two-order of magnitudes higher yields of the biomarkers in urine when compared to hemoglobin. The concentration of analytes from the respective biological matrix was highly correlated with the airborne concentration of pMDI whilst their yields exhibited a reciprocal relationship to the airborne concentration of pMDI. A linear relationship could only be demonstrated by using a logarithmic transformation of data. With respect to the amount of 4,4'-methylenediphenyldianiline creatinine (MDA/g creatinine) in hydrolyzed urine of rats at an exposure level similar to the current workplace concentration of MDI, this marker of exposure was approximately 10-times lower in rats than predicted for humans. This suggests that the extrapolation of animal data to man as well as from one exposure regimen to another, without taking into consideration the different deposition/retention patterns of vapors (<or=0.05 mg/m(3)) or aerosols of MDI, might be error prone. In summary, taking into account previous and current experimental evidence, these data substantiate further that the formation of MDI-related biomarkers appear to be governed by spontaneously occurring, scavenging reactions at the portal-of-entry. Comparison of MDI with its corresponding amine support that the analytes determined stem from conjugated MDI rather than in vivo hydrolyzed MDI.
Anthropogenically induced exposures may, due to their adjuvant effect, promote development of sensitisation to commonly occurring aeroallergens. No generally accepted model exists for determination of adjuvant effect of airborne substances. Therefore, BALB/cJ mice were exposed for 10 consecutive days with ovalbumin (OVA) solution, 25 mg/l-10 g/l (0.0025-1%) for 20 min/day, with and without the Al(OH)(3) adjuvant (0.5%). Four days after the last aerosol exposure, no OVA specific IgE and only low IgG1 were produced. Subsequent parenteral OVA administration showed that the 10 g/l solution induced full tolerance of the IgE response, whereas only partial tolerance was apparent with 25 mg/l OVA. The Al(OH)(3) adjuvant counteracted development of tolerance that was fully prevented at the 25 mg/l OVA concentration. Development of IgG1 was increased in a concentration-dependent manner with 500 mg/l-10 g/l OVA. No increase occurred at the 25 mg/l level, but addition of Al(OH)(3) increased IgG1 production to the same level as the higher OVA concentrations. Concentrations from 1.25 mg/l to 10 g/l OVA were studied with ten exposures followed by once-weekly aerosol exposure for uptil 6 weeks. In the range from 1.25 mg/l to 10 g/l, IgE production was time- and concentration-dependent. Both the IgE and IgG1 production were markedly promoted by Al(OH)(3). However, with aerosol exposures, the IgE antibody productions were not sufficient to increase the level of inflammatory cells in broncho-alveolar lavage fluid. Overall, this study showed that airborne Al(OH)(3) was able to counteract tolerance and increase specific IgE and IgG1 production.
Allergic asthma is characterized by airway hyperreactivity, inflammation, and a Th2-type cytokine profile favoring IgE production. Beneficial effects of TGF-beta and conflicting results regarding the role of Th1 cytokines have been reported from murine asthma models. In this study, we examined the T cell as a target cell of TGF-beta-mediated immune regulation in a mouse model of asthma. We demonstrate that impairment of TGF-beta signaling in T cells of transgenic mice expressing a dominant-negative TGF-beta type II receptor leads to a decrease in airway reactivity in a non-Ag-dependent model. Increased serum levels of IFN-gamma can be detected in these animals. In contrast, after injection of OVA adsorbed to alum and challenge with OVA aerosol, transgenic animals show an increased airway reactivity and inflammation compared with those of wild-type animals. IL-13 levels in bronchoalveolar lavage fluid and serum as well as the number of inducible NO synthase-expressing cells in lung infiltrates were increased in transgenic animals. These results demonstrate an important role for TGF-beta signaling in T cells in the regulation of airway responses and suggest that the beneficial effects observed for TGF-beta in airway hyperreactivity and inflammation may be due to its regulatory effects on T cells.