Pathway focused protein profiling indicates differential function for IL-1B, -18 and VEGF during initiation and resolution of lung inflammation evoked by carbon nanoparticle exposure in mice

<p>Abstract</p> <p>Background</p> <p>Carbonaceous nanoparticles possess an emerging source of human exposure due to the massive release of combustion products and the ongoing revolution in nanotechnology. Pulmonary inflammation caused by deposited nanoparticles is central for their adverse health effects. Epidemiological studies suggest that individuals with favourable lung physiology are at lower risk for particulate matter associated respiratory diseases probably due to efficient control of inflammation and repair process. Therefore we selected a mouse strain C3H/HeJ (C3) with robust lung physiology and exposed it to moderately toxic carbon nanoparticles (CNP) to study the elicited pulmonary inflammation and its resolution.</p> <p>Methods</p> <p>5 μg, 20 μg and 50 μg CNP were intratracheally (i.t.) instilled in C3 mice to identify the optimal dose for subsequent time course studies. Pulmonary inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers.</p> <p>Results</p> <p>1 day after instillation of CNP, C3 mice exhibited a typical dose response, with the lowest dose (5 μg) representing the 'no effect level' as reflected by polymorphonuclear leucocyte (PMN), and BAL/lung concentrations of pro-inflammatory proteins. Histological analysis and BAL-protein concentration did not reveal any evidence of tissue injury in 20 μg CNP instilled animals. Accordingly time course assessment of the inflammatory response was performed after 3 and 7 days with this dose (20 μg). Compared to day 1, BAL PMN counts were significantly decreased at day 3 and completely returned to normal by day 7. We have identified protein markers related to the acute response and also to the time dependent response in lung and BAL. After complete resolution of PMN influx on day 7, we detected elevated concentrations of 20 markers that included IL1B, IL18, FGF2, EDN1, and VEGF in lung and/or BAL. Biological pathway analysis revealed these factors to be involved in a closely regulated molecular cascade with IL1B/IL18 as upstream and FGF2/EDN1/VEGF as downstream molecules.</p> <p>Conclusion</p> <p>Considering the role of VEGF, FGF2 and EDN1 in lung development and morphogenesis together with the lack of any evident tissue damage we suggest a protective/homeostatic machinery to be associated in lungs of stable organisms to counter the CNP challenge as a precautionary measure.</p

Impaired resolution of inflammatory response in the lungs of JF1/Msf mice following carbon nanoparticle instillation

<p>Abstract</p> <p>Background</p> <p>Declined lung function is a risk factor for particulate matter associated respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). Carbon nanoparticles (CNP) are a prominent component of outdoor air pollution that causes pulmonary toxicity mainly through inflammation. Recently we demonstrated that mice (C3H/HeJ) with higher than normal pulmonary function resolved the elicited pulmonary inflammation following CNP exposure through activation of defense and homeostasis maintenance pathways. To test whether CNP-induced inflammation is affected by declined lung function, we exposed JF1/Msf (JF1) mice with lower than normal pulmonary function to CNP and studied the pulmonary inflammation and its resolution.</p> <p>Methods</p> <p>5 μg, 20 μg and 50 μg CNP (Printex 90) were intratracheally instilled in JF1 mice to determine the dose response and the time course of inflammation over 7 days (20 μg dosage). Inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers.</p> <p>Results</p> <p>24 h after instillation, 20 μg and 50 μg CNP caused a 25 fold and 19 fold increased polymorphonuclear leucocytes (PMN) respectively while the 5 μg represented the 'no observable adverse effect level' as reflected by PMN influx (9.7 × 10E3 vs 8.9 × 10E3), and BAL/lung concentrations of pro-inflammatory cytokines. Time course assessment of the inflammatory response revealed that compared to day1 the elevated BAL PMN counts (246.4 × 10E3) were significantly decreased at day 3 (72.9 × 10E3) and day 7 (48.5 × 10E3) but did not reach baseline levels indicating slow PMN resolution kinetics. Strikingly on day 7 the number of macrophages doubled (455.0 × 10E3 vs 204.7 × 10E3) and lymphocytes were 7-fold induced (80.6 × 10E3 vs 11.2 × 10E3) compared to day1. At day 7 elevated levels of IL1B, TNF, IL4, MDC/CCL22, FVII, and vWF were detected in JF1 lungs which can be associated to macrophage and lymphocyte activation.</p> <p>Conclusion</p> <p>This explorative study indicates that JF1 mice with impaired pulmonary function also exhibits delayed resolution of particle mediated lung inflammation as evident from elevated PMN and accumulation of macrophages and lymphocytes on day7. It is plausible that elevated levels of IL1B, IL4, TNF, CCL22/MDC, FVII and vWF counteract defense and homeostatic pathways thereby driving this phenomenon.</p

Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed

Deoxynivalenol (DON) is a mycotoxin primarily produced by Fusarium fungi, occurring predominantly in cereal grains. Following the request of the European Commission, the CONTAM Panel assessed the risk to animal and human health related to DON, 3-acetyl-DON (3-Ac-DON), 15-acetyl-DON (15-Ac-DON) and DON-3-glucoside in food and feed. A total of 27,537, 13,892, 7,270 and 2,266 analytical data for DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside, respectively, in food, feed and unprocessed grains collected from 2007 to 2014 were used. For human exposure, grains and grain-based products were main sources, whereas in farm and companion animals, cereal grains, cereal by-products and forage maize contributed most. DON is rapidly absorbed, distributed, and excreted. Since 3-Ac-DON and 15-Ac-DON are largely deacetylated and DON-3-glucoside cleaved in the intestines the same toxic effects as DON can be expected. The TDI of 1 μg/kg bw per day, that was established for DON based on reduced body weight gain in mice, was therefore used as a group-TDI for the sum of DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside. In order to assess acute human health risk, epidemiological data from mycotoxicoses were assessed and a group-ARfD of 8 μg/kg bw per eating occasion was calculated. Estimates of acute dietary exposures were below this dose and did not raise a health concern in humans. The estimated mean chronic dietary exposure was above the group-TDI in infants, toddlers and other children, and at high exposure also in adolescents and adults, indicating a potential health concern. Based on estimated mean dietary concentrations in ruminants, poultry, rabbits, dogs and cats, most farmed fish species and horses, adverse effects are not expected. At the high dietary concentrations, there is a potential risk for chronic adverse effects in pigs and fish and for acute adverse effects in cats and farmed mink

Discharges of dust from NORM facilities: Key parameters to assess effective doses for public exposure

In transposing Directive 2013/59/Euratom (European Basic Safety Standards or EU BSS) into national law, it was necessary to identify industrial sectors which involve naturally occurring radioactive materials (NORM) which may lead to public exposure that cannot be disregarded from a radiation protection point of view. A research project was implemented that resulted in a comprehensive survey of all potentially relevant industrial sectors operating in Germany. Major efforts were made to determine source terms of airborne discharges, atmospheric dispersion models, and dose calculations.The study arrived at the conclusion that the discharge and the settlement of dust in agricultural and horticultural areas is the most relevant dispersion and exposure pathway, while discharges of radon are of minor importance.The original study used a number of rather complex models that may distract from the fact that very few key parameters and assumptions determine the effective dose of members of the public. This paper revisits the study and identifies those parameters and assumptions and provides a simplified, generic, yet sufficiently reliable and robust assessment methodology to determine the radiological relevance of dust discharges from NORM industries under the typical geographical and meteorological conditions of Germany.This paper provides examples of dose estimates for members of the public for selected industries operating in Germany. Due to its simplicity and robustness, the methodology can also be used to assess effective doses resulting from discharges in other industries in Germany, and it can be adapted to conditions in other countries in a straightforward way. Keywords: NORM, Dust discharge, Public exposure, High temperature processes, Atmospheric dispersion mode

Fraction of exhaled nitric oxide is associated with disease burden in the German Asthma Net severe asthma cohort

In a severe asthma cohort of 1007 patients, high FENO was associated with chronic rhinosinusitis/ polyps, later asthma onset, poor lung function and asthma control, low quality of life, frequent exacerbations and the need for maintenance OCS. #GANregistry https://bit.ly/3sNrtI

The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort

Bal C, Idzko M, Milger K, et al. The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort. Wiener Klinische Wochenschrift . 2022;134(19-20):739-740

The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort in comparison to patients on maintenance OCS therapy

Bal C, Korn S, Milger-Kneidinger K, et al. The German Asthma Net: Anti-IL5(R) therapy reduces disease burden in a real-life severe asthma cohort in comparison to patients on maintenance OCS therapy. Pneumologie. 2023;77(S 01):S45