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

Abstract

BackgroundCarbonaceous 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.Methods5 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.Results1 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.ConclusionConsidering 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.

Pulmonary DWCNT exposure causes sustained local and low-level systemic inflammatory changes in mice

“…2), which indicate a failure of particle clearance. In contrast, we have shown in previous instillation studies, with similar dosing but spherical carbon nanoparticles, that the respective acute pulmonary inflammatory response is completely resolved within 7 days at the cellular and molecular level [10]. Notwithstanding that even in the latter case, considerable amounts of the carbon nanoparticle agglomerates remain in the lungs as well but do not induce giant cell formation.…”

“…In this context, 'frustrated phagocytosis' has been considered as the underlying mechanism of chronic toxicity of fibre-shaped materials, (e.g. asbestos or particular samples of multi-walled carbon nanotubes), which follow the classical fibre pathogenicity paradigm [10,38]. For less rigid tubes like single-and double-walled carbon nanotubes, as investigated in this study, a rather curled but not needle-shaped agglomerate structure was observed (Fig.…”

“…Independent of particle shape, pulmonary exposure to sufficient doses of carbonaceous nanoparticles has been shown to trigger acute inflammatory effects on the lungs dependent on the total particle surface area, which might resolve after a few days [10][11][12]. Once aerosolized and airborne, one of the most hazardous exposure routes is the respiratory tract, where inhaled sub-100 nm particles may deposit in the periphery of the lungs and biopersist by insufficient clearance [13].…”

Exposure to Air Pollutants and Disease Activity in Juvenile‐Onset Systemic Lupus Erythematosus Patients

“…Most studies have evaluated short-term (up to 7 days) or long-term (more than 14 weeks) effects on systemic outcomes, but there are very few studies evaluating medium-term effects. In an experimental study, Ganguly et al, evaluating a mouse strain (C3H/HeJ-C3) exposed to a moderately toxic carbon nanoparticle, observed elevated levels of several inflammatory chemokines in lung and/or bronchoalveolar lavage fluid at day 7 after exposure, even after complete resolution of polymorphonuclear cell influx (20). These findings suggest the possibility that such proinflammatory markers can cause systemic effects in the weeks following exposure.…”

Maternal exposure to carbon black nanoparticle increases collagen type VIII expression in the kidney of offspring

“…It was suspended at 1 mg/ml in saline (Otsuka Pharmaceutical Factory Inc., Tokushima, Japan) with 0.05 % (v/v) Tween 80 and sonicated for more than 30 min just before administration. The carbon black can be used to examine the exclusive surface reactivity of carbon because it consists of 98% of pure carbon (Ganguly et al, 2009). The size distribution of carbon black nanoparticle in the suspension was analyzed by dynamic lightscattering using an FPAR-1000 particle analyser and the CONTIN program algorithm (Otsuka Electronics Co., Ltd., Osaka, Japan).…”