TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury

Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-α, we hypothesized that this cell type has developed specific defense mechanisms against TNF-α-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-α and/or iron and were then challenged with H₂O₂. Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-α stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H₂O₂ under oxidative stress was kept unchanged by TNF-α and/or iron. However, TNF-α increased basal levels of glutathione by up-regulating the synthesis of γ-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-α inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.     

MRI diagnosis of brown tumor based on magnetic susceptibility

A 56-year-old male with chronic renal failure was incidentally found to have lytic bone lesions in the pubic symphysis, left femoral head, left acetabulum, left iliac bone, and L1 vertebra on computed tomography (CT). Subsequent magnetic resonance imaging (MRI) of the abdomen was performed (for evaluation of a renal lesion) which demonstrated marked loss of signal intensity in the L1 bone lesion on increasing TE gradient echo images, consistent with magnetic susceptibility effect due to hemosiderin. Brown tumor was confirmed at biopsy. The susceptibility imaging probes one particular histological characteristic of tissues and allows a restricted differential of lytic tumors that contain significant hemosiderin, including brown tumor.     

Copper- and iron-rich matrices in hepatocellular lipofuscin particles of a young male patient: diagnostic ultrastructures for Wilson disease

A 17-year-old male patient appeared with the biochemical liver damage associated with hypoceruloplasminemia and mild iron overload. Genetic analysis identified a compound heterozygosity of ATP7B responsible for the primary copper toxicosis of Wilson disease without mutations in HFE. A liver specimen consisted of cirrhotic nodules of large-sized hepatocytes with fatty change and those of fat-free small-sized hepatocytes. Histochemically, iron was distributed diffusely in the small-sized hepatocytes, while copper grains appeared in a few of the hepatocytes near the fibrous bands. X-ray microanalysis on the liver tissue fixed with a 0.1% osmium tetroxide solution and embedded in epoxy resin disclosed (1) complex formation of copper with sulfur, and iron with phosphorus in the hepatocyte lipofuscin particles, (2) intraparticle localization of the cuprothionein in the less dense matrix and ferric proteins in the dense matrix, and (3) high affinity of the cuprothionein to lead staining. Considering the fact that ceruloplasmin is the major ferroxidase essential for iron efflux, iron deposits in the hypoceruloplasminemic patients with Wilson disease are not a complication, but a natural event. This study disclosed for the first time the diagnostic ultrastructures of Wilson disease, which might represent different detoxification processes to the reactive metals of copper and iron.     

Separate MRI quantification of dispersed (ferritin‐like) and aggregated (hemosiderin‐like) storage iron

A new MRI method is proposed for separately quantifying the two principal forms of tissue storage (nonheme) iron: ferritin iron, a dispersed, soluble fraction that can be rapidly mobilized, and hemosiderin iron, an aggregated, insoluble fraction that serves as a long‐term reserve. The method utilizes multiple spin echo sequences, exploiting the fact that aggregated iron can induce nonmonoexponential signal decay for multiple spin echo sequences. The method is validated in vitro for agarose phantoms, simulating dispersed iron with manganese chloride, and aggregated iron with iron oxide microspheres. To demonstrate feasibility for human studies, preliminary in vivo data from two healthy controls and six patients with transfusional iron overload are presented. For both phantoms and human subjects, conventional R₂ and R₂* relaxation rates are also measured in order to contrast the proposed method with established MRI iron quantification techniques. Quantification of dispersed (ferritin‐like) iron may provide a new means of monitoring the risk of iron‐induced toxicity in patients with iron overload and, together with quantification of aggregated (hemosiderin‐like) iron, improve the accuracy of estimates for total storage iron. Magn Reson Med 63:1201–1209, 2010. © 2010 Wiley‐Liss, Inc.     

Visualization of cerebral microbleeds with dual‐echo T2*‐weighted magnetic resonance imaging at 7.0 T

Purpose:

To assess the visualization of cerebral microbleeds with dual echo T2*‐weighted imaging at 7.0 T magnetic resonance imaging (MRI).

Materials and Methods:

Ten consecutive participants (eight men, two women, mean age 54 ± 12 years) with vascular disease or risk factors from the second manifestations of arterial disease (SMART) study were included. Dual‐echo T2*‐weighted scans (echo time: 2.5/15.0 msec) were made for all participants at 7.0 T MRI. The number of visible microbleeds and the diameter of the microbleeds were recorded on minimal intensity projection images of both echoes.

Results:

The first echo image shows dark microbleeds against a homogeneous, more hyperintense signal of the brain tissue without contrast for veins and basal ganglia. In eight patients microbleeds were observed, with a total of 104 microbleeds. Of these, 88 (84.6%) were visible on the first and 102 (98.0%) on the second echo. The mean diameter of the microbleeds was 1.24 mm for the first echo and 2.34 mm for the second echo.

Conclusion:

T2*‐weighted imaging at two echo times at 7.0 T combines the advantages of the first and second echo. Microbleeds visible on the first echo show large contrast with the surrounding tissue, even in the presence of paramagnetic ferritin. The second echo enables visualization of smaller microbleeds than the first echo. J. Magn. Reson. Imaging 2010;32:52–59. © 2010 Wiley‐Liss, Inc.     

THE CYTOLOGY OF CEREBROSPINAL FLUID ASSOCIATED WITH NEONATAL INTRAVENTRICULAR HEMORRHAGE

We describe the morphologic features seen in cytocentrifuge preparations of cerebrospinal fluid (CSF) from neonates with intraventricular hemorrhage (IVH). These CSF specimens from lumbar punctures or ventricular taps often contain degenerated red blood cells with blebs and buds, forming microspherocytes resembling budding yeast or cocci. Hemosiderin-laden macrophages and foamy histiocytes occur in early specimens and persist through multiple specimens. Hematoidin, foreign body giant cells, and CSF eosinophilia are later findings. Brain tissue fragments are frequently seen at the time of ventricular shunt placement. These cytocentrifuge specimens are essentially cytology specimens and in children should be reviewed by a qualified pathologist to interpret the findings in a clinically relevant manner.     

靶样含铁血黄素沉积性血管瘤一例并文献复习

报道1例靶样含铁血黄素沉积性血管瘤并对相关文献进行复习。患者,女,61岁，左上臂皮疹半年。皮疹表现为单发境界清楚的蚕豆大紫红色斑块。组织病理示：表皮萎缩，真皮血管不规则增生扩张，内皮细胞似鞋钉样突向管腔。外科手术切除。     

Improvement of serum bilirubin levels after venesection in a patient with Dubin-Johnson syndrome and HCV-positive chronic liver disease

Direct-type hyperbilirubinemia in Dubin-Johnson syndrome is due to the genetic dysfunction of multidrug resistance protein 2. However, serum bilirubin levels may fluctuate as a result of acquired conditions. Iron-reduction therapy by venesection, an alternative to interferon, was performed in a 55-year-old male patient with Dubin-Johnson syndrome complicated by hepatitis C virus-positive chronic liver disease and hepatic iron overload. His pretreatment serum total bilirubin was 10.2mg/dl, with a dominant direct fraction. The treatment induced a significant reduction in serum total bilirubin, although it remained as high as 7.9mg/dl. A negative correlation between serum total bilirubin and cumulative bled volume suggested that venesection could suppress bilirubin production from aged erythrocytes. The hepatic iron overload was distributed in hepatocyte lysosomes with Dubin-Johnson granules; thus, it seems that iron removal from the lysosomal granules may also help to reduce serum bilirubin. In conclusion, deep jaundice in a patient with Dubin-Johnson syndrome complicated by hepatitis C virus-positive chronic liver disease and iron overload was partially improved by iron-reduction therapy.     

Hemosiderin deposits in chronic graft-vs.-host disease related myopathy

Chronic graft-vs.-host disease (cGVHD) occurs in 20-50% of patients who survive for at least 100 d after allogeneic stem cell transplantation (SCT). cGVHD includes scleroderma-like skin changes, chronic cholangitis, obstructive lung disease and general wasting syndrome. Polymyositis or myopathy are rare manifestations of cGVHD with approximately 40 reported cases. Polymyositis accompanied by hemosiderin deposits in cGVHD has been reported only once, and there are no reports on lipofuscin deposits in skeletal muscle cells in cGVHD. We report here on a 56-yr-old male who underwent allogeneic SCT in 1999 for osteomyelofibrosis and progressive hematopoietic insufficiency. In February 2004, the patient was hospitalized for progressive muscular weakness with loss of the ability to walk. Laboratory tests demonstrated normal values for serum creatine kinase, aldolase and lactic dehydrogenase; the ferritin level was highly elevated. The femoral muscle biopsy showed mostly perifascicular atrophy as well as numerous subsarcolemmal hemosiderin and lipofuscin deposits. Intravenous administration of the chelating agent deferoxamine was ineffective. Three weeks later the patient died of aspiration pneumonia. Interestingly, autopsy disclosed moderate hemosiderin deposits in the liver, the organ usually involved in hemosiderosis.     

Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis.

AIM: Although hepatic iron deposition unrelated to hereditary hemochromatosis is commonly observed in cirrhosis, its clinical significance is unclear. The aim of this study was to examine the outcomes of cirrhotic patients with and without hemosiderosis. METHODS: Patients with an initial liver biopsy demonstrating cirrhosis between January 1993 and December 1997 were identified using the Department of Pathology database. Based on iron staining, patients were characterized as siderotic or nonsiderotic. Charts were reviewed to determine outcomes. RESULTS: Siderotic patients had significantly higher Child-Pugh (CP) and model for end-stage liver disease (MELD) scores. Their median survival without transplant was 23 months vs. 85 months in the nonsiderotics (P<0.0001, confidence interval: 95%). On univariate analysis, siderosis was associated with a hazard ratio of 2.74 (P<0.0001). On multivariate analysis, the effect of siderosis was reduced but remained significant after correction for the CP or MELD score (hazard ratios 1.82 and 2.06, P=0.05 and 0.02, respectively). Child's A cirrhotics with hemosiderosis decompensated more rapidly and had shorter median survival than those without siderosis (P=0.007 and P=0.01, respectively). CONCLUSIONS: The presence of siderosis is associated with more advanced liver dysfunction. Even when the effects of baseline liver function are taken into account, siderosis is associated with decreased survival and more rapid decompensation in cirrhosis.