ABSTRACT
The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO3)2 NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO3)2 NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO3)2 NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFß1), interleukin 6(IL-6), IL-1α and IL-1ß , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO3)2 NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period.
Subject(s)
Air Pollutants/pharmacokinetics , Lead/pharmacokinetics , Lung/drug effects , Macrophages, Alveolar/drug effects , Metal Nanoparticles/toxicity , Nitrates/pharmacokinetics , Actins/agonists , Actins/genetics , Actins/immunology , Administration, Inhalation , Air Pollutants/toxicity , Animals , Biological Availability , Female , Gene Expression , Half-Life , Inhalation Exposure/analysis , Interleukin-1alpha/agonists , Interleukin-1alpha/genetics , Interleukin-1alpha/immunology , Interleukin-1beta/agonists , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-6/agonists , Interleukin-6/genetics , Interleukin-6/immunology , Lead/toxicity , Liver/drug effects , Liver/immunology , Liver/pathology , Lung/immunology , Lung/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , Metal Nanoparticles/administration & dosage , Mice , Mice, Inbred ICR , NF-kappa B/agonists , NF-kappa B/genetics , NF-kappa B/immunology , Nitrates/toxicity , Spectrophotometry, Atomic , Tissue Distribution , Transforming Growth Factor beta1/agonists , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/immunology , Tumor Necrosis Factor-alpha/agonists , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
In a previous study, we showed that barrier recovery was delayed after acute barrier disruption in the skin treated with topical calcineurin inhibitors. Tacrolimus decreases lipid synthesis and the expressions of antimicrobial peptide (AMP) and IL-1α in the epidermis. IL-1α is an important cytokine for improving barrier function, lamellar body (LB) production, and lipid synthesis in keratinocytes (KCs). We aimed to evaluate whether IL-1α stimulation could restore the barrier dysfunction observed in tacrolimus-treated skin. Topical imiquimod, an IL-1α inducer, restored the epidermal permeability barrier recovery that had been inhibited by tacrolimus treatment in human (n=15) and murine (n=10) skins, and improved stratum corneum integrity by restoring corneodosmosomes in murine skin (n=6). Imiquimod co-applied on the epidermis resulted in an increase in the production of LB and three major lipid synthesis-related enzymes, and in the expressions of mBD3, CRAMP, and IL-1α (n=5). Furthermore, intracutaneous injection of IL-1α restored permeability barrier recovery (n=6). In IL-1 type 1 receptor knockout mice, topical imiquimod was unable to restore permeability barrier recovery after tacrolimus treatment (n=21). In conclusion, IL-1α stimulation induced positive effects on epidermal permeability and antimicrobial barrier functions in tacrolimus-treated skin. These positive effects were mediated by an increase in epidermal lipid synthesis, LB production, and AMP expression.
