Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4-or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2 ؎ 0.5 versus 0.8 ؎ 0.1 mg/dl; P ؍ 0.007), kidney tubular injury (scores 1.44 ؎ 0.15 versus 0.22 ؎ 0.08; P < 0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-␣, IL-1, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4-and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.
Rat fetal kidney mRNA was analyzed by RT-PCR to identify protein kinases. This screening demonstrated expression of a protein kinase consistent with SK2, a group II germinal center kinase and homolog of human Ste20-like kinase (SLK). SK2 mRNA, protein expression, and kinase activity were increased in rat fetal kidney homogenates ( embryonic days 17–21) compared with adult controls. In adult kidneys subjected to cross-clamping of the renal artery, followed by reperfusion, SK2 mRNA, protein expression, and kinase activity were increased compared with untreated contralateral controls. By immunohistochemistry, SK2 expression was evident mainly in the cytoplasm of tubular epithelial cells in fetal and adult kidneys. There was also some expression in developing and mature podocytes, but staining of the interstitium was negative. In cultured renal tubular epithelial cells, SK2 kinase activity was increased after incubation with serum, or after exposure to chemical anoxia plus reexposure to glucose. Stable overexpression of SLK reduced cell proliferation and increased apoptosis and exacerbated apoptosis and necrosis after chemical anoxia plus reexposure to glucose. Thus SK2 is a renal epithelial protein kinase whose expression and activity are increased during development and recovery from acute renal failure, where tubular epithelial regeneration may recapitulate developmental processes. The actions of SK2 appear to be antiproliferative and may facilitate cell injury.
T cells have been demonstrated to modulate ischemia-reperfusion injury (IRI) in kidney, lung, liver and intestine. The underlying mechanisms for T-cell engagement in IRI are unknown. We hypothesized that the T-cell receptor (TCR) plays a role in renal IRI, and examined the effects of TCR alpha/beta (alphabeta) and gamma/delta (gammadelta) deficiency on ischemic acute renal failure (ARF). TCR-specific deficiency in specific mice was confirmed by fluorescence-activated cell sorting analysis using monoclonal antibodies (Abs). IRI was induced by bilateral clamping of kidney pedicles for 30 min, followed by reperfusion. Serum creatinine and kidney histopathology were used to assess the severity of experimental ARF. TCR alphabeta-deficient mice were significantly protected from kidney dysfunction compared to wild-type (WT) littermates after IRI (P<0.05). Histologic analysis demonstrated a significant reduction in renal tubular injury in both TCR alphabeta- and gammadelta-deficient mice compared to WT mice postischemia. TCR alphabeta-deficient mice had reduced tumor necrosis factor-alpha and interleukin-6 protein expression in kidney tissue compared to WT mice at 24 h postischemia using a microbead-based protein detection platform. Relative protection from kidney IRI did not correlate with neutrophil and macrophage infiltration of kidney tissue. Thus, the TCR plays a direct but modest pathophysiological role in kidney IRI. These data suggest that alloantigen-independent activation in IRI can lead to engagement of antigen-specific molecules on T cells. Furthermore, given that the TCR is already a target for diagnostics and therapeutic strategies in immune diseases, these approaches can now be harnessed for IRI.
We aimed to analyze CT features of persistent subsolid nodules (SSN) ≦3 cm diagnosed pathologically as adenocarcinoma spectrum to investigate whether parameters enable distinction between invasive pulmonary adenocarcinomas (IPAs) and pre-invasive lesions. A total of 129 patients with 141 SSNs confirmed with surgically pathologic proof were retrospectively reviewed. Of 141 SSNs, there were 57 pure ground-glass nodules (GGNs), 22 heterogeneous GGNs, and 62 part-solid nodules. SSN subclassification showed a significant linear trend with invasive degree of the adenocarcinoma spectrum (pure GGNs 7%; heterogeneous GGNs 36.4%; part-solid nodules 85.5%, P for trend <0.0001). For IPA detection in 141 SSNs, a solid part of ≧3 mm was the most specificity (sensitivity, 76.9%; specificity, 94.7%), followed by air-bronchogram sign (sensitivity, 53.8%; specificity, 89.5%), SSN subclassification (sensitivity, 81.5%; specificity, 88.2%), and a lesion size ≧12 mm (sensitivity, 84.6%; specificity, 76.3%). For IPA detection in 79 pure or heterogeneous GGNs, the heterogeneous GGN sign was the most useful finding, with most specificity (sensitivity, 66.7%; specificity, 79.1%), followed by CT attenuation (HU) of ≧−493 (sensitivity, 75%; specificity, 74.6%) and a lesion size ≧10 mm (sensitivity, 83.3%; specificity, 70.1%). In conclusion, this simple combined visual and semiquantitative analysis of CT features helps distinguish IPAs from pre-invasive lesions.
Although numerous epidemiological studies revealed an association between ambient fine particulate matter (PM2.5) exposure and Alzheimer’s disease (AD), the PM2.5-induced neuron toxicity and associated mechanisms were not fully elucidated. The present study assessed brain toxicity in 6-month-old female triple-transgenic AD (3xTg-AD) mice following subchronic exposure to PM2.5 via an inhalation system. The treated mice were whole-bodily and continuously exposed to real-world PM2.5 for 3 months, while the control mice inhaled filtered air. Changes in cognitive and motor functions were evaluated using the Morris Water Maze and rotarod tests. Magnetic resonance imaging analysis was used to record gross brain volume alterations, and tissue staining with hematoxylin and eosin, Nissl, and immunohistochemistry methods were used to monitor pathological changes in microstructures after PM2.5 exposure. The levels of AD-related hallmarks and the oxidative stress biomarker malondialdehyde (MDA) were assessed using Western blot analysis and liquid chromatography-mass spectrometry, respectively. Our results showed that subchronic exposure to environmental levels of PM2.5 induced obvious neuronal loss in the cortex of exposed mice, but without significant impairment of cognitive and motor function. Increased levels of phosphorylated-tau and MDA were also observed in olfactory bulb or hippocampus after PM2.5 exposure, but no amyloid pathology was detected, as reported in previous studies. These results revealed that a relatively lower level of PM2.5 subchronic exposure from the environmental atmosphere still induced certain neurodegenerative changes in the brains of AD mice, especially in the olfactory bulb, entorhinal cortex and hippocampus, which is consistent with the nasal entry and spreading route for PM exposure. Systemic factors may also contribute to the neuronal toxicity. The effects of PM2.5 after a more prolonged exposure period are needed to establish a more comprehensive picture of the PM2.5-mediated development of AD.
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