BACKGROUND: Glucocorticoids (GCs) are generally envisioned as immunosuppressive, but in conditions such as rosacea and perioral dermatitis they can lead to increased skin inflammation. In lung epithelia, GCs promote expression of the proinflammatory cytokine CCL20, which contributes to steroid-resistant asthma. In the skin, CCL20 stimulates inflammation by recruiting T helper 17 T lymphocytes and dendritic cells, and is elevated in papulopustular rosacea. OBJECTIVES: To understand if, and how, GCs affect CCL20 expression in human keratinocytes. CCL20 expression was assessed by quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. METHODS: Selective inhibition of candidate genes and signalling pathways was performed using RNA interference and chemical inhibitors. The binding of activated GC receptor to genomic DNA was determined by chromatin immunoprecipitation, and enhancer activity of genomic sequences was measured with a reporter assay. RESULTS: We found that GC treatment increased CCL20 expression in human keratinocytes and murine skin, both in the undisturbed state and with tumour necrosis factor-α stimulation. GC repressed proinflammatory signalling pathways, including nuclear factor kappa B and p38/mitogen-activated protein kinase, but these inhibitory effects were opposed by the direct binding of activated GC receptor to the CCL20 enhancer, promoting CCL20 expression. CONCLUSIONS: Viewed together, these findings demonstrate a mechanism by which GCs induce expression of CCL20 in keratinocytes, which may contribute to the inflammation seen in steroid-exacerbated skin conditions.

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disea

Background and purpose

Fractional flow measured on 3D-TOF-MRA was proposed to quantify cerebral hemodynamic changes in patients with artery stenosis. We investigated the association between fractional flow and cerebral perfusion changes in patients with symptomatic MCA stenosis.

Materials and methods

This prospective study was approved by the institutional review board, and all participants provided written informed consent. From June 2015 to May 2018, four hundred twenty-nine patients with symptomatic intracranial arterial stenosis were consecutively recruited and underwent conventional brain MR imaging, 3D-TOF-MRA, and brain CTP. A total of 91 patients with unilateral M1 segment stenosis of the MCA and a stenosis degree of 50%∼99% were included in the analysis. Fractional flow was measured by comparing distal and proximal signal intensity changes across the stenosis on 3D-TOF-MRA. The cutoff value for fractional flow for discriminating between normal perfusion and hypoperfusion was obtained from the receiver operating characteristic curve. Associations between fractional flow and hypoperfusion were assessed using univariate and multivariate analyses.

Results

The receiver operating characteristic curve showed a significant fractional flow threshold value at 0.90 (sensitivity, 70.1%; 95% CI, 55.9%-81.2%; specificity, 69.6%; 95% CI, 47.6%-84.1%). Participants with a fractional flow of ≤0.90 were independently associated with cerebral hypoperfusion downstream from the stenosis site (adjusted OR, 3.68; 95% CI, 1.63-11.62; P = .027).

Conclusions

Fractional flow measured on 3D-TOF-MRA may serve as a noninvasive and practical tool for determining the cerebral hypoperfusion in patents with symptomatic MCA stenosis.

The purpose of this paper is to elucidate the key role of NADPH oxidase in NLRP3 inflammasome activation and generation of pulmonary fibrosis by multi-walled carbon nanotubes (MWCNTs). Although it is known that oxidative stress plays a role in pulmonary fibrosis by single-walled CNTs, the role of specific sources of reactive oxygen species, including NADPH oxidase, in inflammasome activation remains to be clarified. In this study, three long aspect ratio (LAR) materials (MWCNTs, single-walled carbon nanotubes, and silver nanowires) are used to compare with spherical carbon black and silver nanoparticles for their ability to trigger oxygen burst activity and NLRP3 assembly. All LAR materials but not spherical nanoparticles induce robust NADPH oxidase activation and respiratory burst activity in THP-1 cells, which are blunted in p22phox-deficient cells. The NADPH oxidase is directly involved in lysosomal damage by LAR materials, as demonstrated by decreased cathepsin B release and IL-1β production in p22phox-deficient cells. Reduced respiratory burst activity and inflammasome activation are also observed in bone marrow-derived macrophages from p47phox-deficient mice. Moreover, p47phox-deficient mice have reduced IL-1β production and lung collagen deposition in response to MWCNTs. Lung fibrosis is also suppressed by N-acetyl-cysteine in wild-type animals exposed to MWCNTs. NADPH oxidase-induced oxidative stress is directly involved in NLRP3 inflammasome activation and generation of lung fibrosis by multi-walled carbon nanotubes. Long aspect ratio engineered nanomaterials exert their effects through NADPH oxidase activation and oxidative burst, which lead to lysosomal damage, mitochondrial reactive oxygen species generation, oxidative stress, and subsequent NLRP3 inflammasome activation.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. 2D molybdenum disulfide (MoS2) has distinct optical and electronic properties compared to aggregated MoS2, enabling wide use of these materials for electronic and biomedical applications. However, the hazard potential of MoS2 has not been studied extensively. Here, a comprehensive analysis of the pulmonary hazard potential of three aqueous suspended forms of MoS2 - aggregated MoS2 (Agg-MoS2), MoS2 exfoliated by lithiation (Lit-MoS2), and MoS2 dispersed by Pluronic F87 (PF87-MoS2) - is presented. No cytotoxicity is detected in THP-1 and BEAS-2B cell lines. However, Agg-MoS2 induces strong proinflammatory and profibrogenic responses in vitro. In contrast, Lit- and PF87-MoS2 have little or no effect. In an acute toxicity study in mice, Agg-MoS2 induces acute lung inflammation, while Lit-MoS2 and PF87-MoS2 have little or no effect. In a subchronic study, there is no evidence of pulmonary fibrosis in response to all forms of MoS2. These data suggest that exfoliation attenuates the toxicity of Agg-MoS2, which is an important consideration toward the safety evaluation and use of nanoscale MoS2 materials for industrial and biological applications. The pulmonary hazard potential of three forms of MoS2 - aggregated (Agg-MoS2), lithiation-exfoliated (Lit-MoS2), and Pluronic F87 dispersed MoS2 (PF87-MoS2) - is studied. Although Agg-MoS2 induces profibrogenic responses in vitro and acute lung inflammation in vivo, Lit- and PF87-MoS2 have no such effect. These data suggest that exfoliation attenuates Agg-MoS2's toxicity, which is important toward its industrial and biological applications.