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Navarrette C.R.,Pulmonary | Sisson J.H.,Pulmonary | Nance E.,Johns Hopkins University | Allen-Gipson D.,Pulmonary | And 4 more authors.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2012

Background: The lung's ability to trap and clear foreign particles via the mucociliary elevator is an important mechanism for protecting the lung against respirable irritants and microorganisms. Although cigarette smoke (CS) exposure and particulate inhalation are known to alter mucociliary clearance, little is known about how CS and nanoparticles (NPs) modify cilia beating at the cytoskeletal infrastructure, or axonemal, level. Methods: We used a cell-free model to introduce cigarette smoke extract (CSE) and NPs with variant size and surface chemistry to isolated axonemes and measured changes in ciliary motility. We hypothesized that CSE would alter cilia beating and that alterations in ciliary beat frequency (CBF) due to particulate matter would be size- and surface chemistry-dependent. Demembranated axonemes were isolated from ciliated bovine tracheas and exposed to adenosine triphosphate (ATP) to initiate motility. CBF was measured in response to 5% CSE, CSE filtrate, and carboxyl-modified (COOH), sulphate (SO 4)-modified (sulfonated), or PEG-coated polystyrene (PS) latex NPs ranging in size from 40nm to 500 nm. Results: CSE concentrations as low as 5% resulted in rapid, significant stimulation of CBF ( p < 0.05 vs. baseline control). Filtering CSE through a 0.2-μm filter attenuated this effect. Introduction of sulphate-modified PS beads ∼300 nm in diameter resulted in a similar increase in CBF above baseline ATP levels. Uncharged, PEG-coated beads had no effect on CBF regardless of size. Similarly, COOH-coated particles less than 200nm in diameter did not alter ciliary motility. However, COOH-coated PS particles larger than 300nm increased CBF significantly and increased the number of motile points. Conclusions: These data show that NPs, including those found in CSE, mechanically stimulate axonemes in a size- and surface chemistry-dependent manner. Alterations in ciliary motility due to physicochemical properties of NPs may be important for inhalational lung injury and efficient drug delivery of respirable particles. © 2012 Mary Ann Liebert, Inc. Source

Mikhaylova O.,University of Cincinnati | Stratton Y.,University of Cincinnati | Hall D.,University of Cincinnati | Kellner E.,University of Cincinnati | And 9 more authors.
Cancer Cell | Year: 2012

The von Hippel-Lindau tumor-suppressor gene (VHL) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Of note, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF-regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor-suppressing regulator of autophagic programs. © 2012 Elsevier Inc. Source

Fang Y.,University of Missouri | Chen K.,University of Missouri | Jackson D.A.,University of Missouri | Sharp G.C.,University of Missouri | And 2 more authors.
Immunology | Year: 2010

Summary Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTg)-sensitized splenocytes activated with MTg and interleukin (IL)-12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)-γ-/- and wild-type (WT) DBA/1 mice both develop severe G-EAT. Thyroid lesions in IFN-γ-/- mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils. Thyroid lesions in IFN-γ-/- mice consistently resolve by day 40-50, whereas those in WT mice have ongoing inflammation and fibrosis persisting for more than 60 days. To determine if the extensive infiltration of eosinophils in thyroids of IFN-γ-/- mice contributes to thyroid damage and/or early resolution of G-EAT, anti-IL-5 was used to inhibit migration of eosinophils to thyroids. G-EAT severity was compared at day 20 and day 40-50 in IFN-γ-/- recipients given anti-IL-5 or control immunoglobulin G (IgG). Thyroids of anti-IL-5-treated IFN-γ-/- mice had few eosinophils and more neutrophils at day 20, but G-EAT severity scores were comparable to those of control IgG-treated mice at both day 20 and day 40-50. Expression of chemokine (C-X-C motif) ligand 1 (CXCL1) mRNA was higher and that of chemokine (C-C motif) ligand 11 (CCL11) mRNA was lower in thyroids of anti-IL-5-treated IFN-γ-/- mice. IL-5 neutralization did not influence mRNA expression of most cytokines in IFN-γ-/- mice. Thus, inhibiting eosinophil migration to thyroids did not affect G-EAT severity or resolution in IFN-γ-/- mice, suggesting that eosinophil infiltration of thyroids occurs as a consequence of IFN-γ deficiency, but these cells have no apparent pathogenic role in G-EAT. © 2009 Blackwell Publishing Ltd. Source

Kawedia J.D.,University of Cincinnati | Kawedia J.D.,University of Houston | Yang F.,University of Cincinnati | Yang F.,City of Hope Comprehensive Cancer Center | And 5 more authors.
PLoS ONE | Year: 2013

The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5), we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70%) decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQP5 mRNA and protein expression in the mouse lung epithelial cell line MLE-12. The action of hypoxia and cobalt on AQP5 transcription was demonstrated by directly quantifying heternonuclear RNA by real-time PCR. Dominant negative mutants of Hypoxia Inducible Factor (HIF-1α) and HIF-1α siRNA blocked the action of cobalt, showing that HIF-1α is a key component in this mechanism. The proteasome inhibitors, lactacystin or proteasome inhibitor-III completely abolished the effect of hypoxia and cobalt both at the protein and mRNA level indicating that the proteasome pathway is probably involved not only for the stability of HIF-1α protein, but for the stability of unidentified transcription factors that regulate AQP5 transcription. These studies reveal a potentially important physiological mechanism linking hypoxic stress and membrane water channels. © 2013 Kawedia et al. Source

Czyzyk-Krzeska M.F.,University of Cincinnati | Czyzyk-Krzeska M.F.,VA Research Service | Zhang X.,University of Cincinnati
Oncogene | Year: 2014

MicroRNAs are increasingly being recognized as oncogenes and tumor suppressors in cancer. MicroRNA-155 (miR-155) is an established oncomiR in breast cancer and regulates several pro-oncogenic pathways. In light of this, Chiang's group has discovered a novel pathway regulated by miR-155. MiR-155 directly targets the VHL tumor suppressor and, by doing so, promotes the activity of HIF transcription factors and angiogenesis. This pathway appears to be particularly relevant in triple-negative breast cancer. © 2014 Macmillan Publishers Limited. Source

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