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Rapid Response of Endoneurial Macrophages to Nerve Injury
Macrophages play an important role in peripheral nerve injury. It is generally assumed that macrophages found in areas of nerve degeneration are infiltrating cells from the peripheral blood. However, little is known about resident endoneurial macrophages, mostly because there are no markers to distinguish between peripheral blood and resident endoneurial macrophages. Mueller et al (Am J Pathol 2001, 159:2187–2197) produced chimeric rats by transplanting wild-type Lewis bone marrow cells into irradiated TK-tsa transgenic Lewis rats. In these animals only the resident cells express the transgene. Two days after sciatic nerve crush injury and before the influx of hematogenous macrophage, resident, transgene-positive, endoneurial macrophages became activated, proliferated, and phagocytized myelin. In subsequent days, resident macrophages expressed ED1 antigen and became morphologically indistinguishable from peripheral blood macrophages. The results indicate that resident endoneurial macrophages are critically involved in nerve injury and may act in a similar way as microglial cells in the central nervous system.
Neutralization of CXC Chemokines Inhibits Renal Ischemia/Reperfusion Injury
CXC chemokines direct neutrophils to sites of inflammation and
play a role in reperfusion injury of ischemic tissues. Miura et al
(Am J Pathol 2001, 159:2137–2145) tested the effect of
antibodies against two CXC chemokines, GRO
(KC) and macrophage
inflammatory protein-2 (MIP-2), in mouse kidneys reperfused after 1
hour of ischemia. Treatment with neutralizing antibodies against MIP-2
and KC inhibited neutrophil infiltration during reperfusion, restored
renal function, and reduced tissue damage. While approximately 40% of
untreated mice died during the first 3 days after ischemia/reperfusion,
antibody injection resulted in complete survival. This work
demonstrates that neutralization of CXC chemokines prevents injury in
the ischemic kidney.
Cathepsin B Deficiency Protects Against Hepatocyte Apoptosis Mediated by Tumor Necrosis Factor
Tumor necrosis factor (TNF) participates in many types of liver
injury. While TNF by itself does not cause apoptosis in mouse liver,
TNF injection coupled with inhibition of transcription/translation or
blockage of NF
B activation causes massive liver apoptosis.
Guicciardi et al (Am J Pathol 2001, 159:2045–2054)
show that knockout mice lacking cathepsin B (Cath B-/-) are resistant
to TNF-mediated liver apoptosis. They injected Cath B-/- and
wild-type littermates (WT) with an adenovirus vector that expresses a
super-repressor of NFB activation, followed 24 hours after by TNF
administration. WT mice showed massive liver apoptosis which developed
very rapidly and included caspase 3 and 9 activation and cytochrome
c release. In contrast, livers of Cath B-/- mice
showed much less apoptosis, had no caspase activation, and had only
15% mortality (compared to 80% in WT mice). Injection of the
cathepsin B inhibitor CA-074Me in WT mice reduced TNF liver damage in
these animals. This work demonstrates that cathepsin B plays an
important role in TNF-mediated liver injury and suggests that
cathepsin B may serve as a potential therapeutic target to prevent
liver injury.
Determination of B- and T-Cell Clonality and Detection of Chromosomal Translocations in a Single Reaction
Determination of B- and T-cell clonality and the chromosomal
translocations t(14;18) and t(11;14) require costly and time-consuming
separate polymerase chain reaction (PCR) assays for each test. Meier et
al (Am J Pathol 2001, 159:2031–2043) developed a
multiplex PCR assay for the simultaneous detection of these markers
using a four-color fluorescence and high resolution fragment analysis
in a single reaction. The 26 primers used in the multiplex PCR assay
recognize more than 90% of the 69 variable and 6 join IgH genes and
100% of the TCR
variable and join genes that can participate in
rearrangements. The primers also detect the major breakpoint regions of
the two chromosomal translocations, the minor breakpoint regions of
t(14;18), and include a ß globin gene as internal control. The
multiplex PCR assay is highly specific as indicated from analyses of T-
and B-cell lymphomas including mantle cell and follicular lymphomas.
Large Cell Minimally Differentiated Carcinoma of the Colon: A New Entity with Distinct Molecular Pathogenesis
Hinoi et al (Am J Pathol 2001, 159:2239–2248) identified a subset of poorly differentiated colon carcinomas that they named large cell minimally differentiated carcinoma of the colon (LCMDC), which includes a group of carcinomas that have been described as medullary adenocarcinomas. In contrast to differentiated carcinomas of the colon, 87% of LCMDC showed reduced expression of CDX2, a homeobox protein normally expressed in intestinal and colonic epithelium. Sixty percent of LCMDCs had microsatellite instability with DNA mismatch repair defects (MSI-H phenotype) while this phenotype was uncommon in differentiated adenocarcinomas. The findings indicate that the molecular pathogenesis of LCMDC differs for that of differentiated adenocarcinomas of the bowel, and that it constitutes a distinct, newly recognized entity.
Interleukin-6 Acts as an Autocrine Growth Factor for Primary Prostate Cancer
Prostate cancer is the second leading cause of cancer deaths in men. In the last few years several important markers for the disease have been identified but the major steps in the pathogenesis of prostate cancer have not been elucidated. Interleukin-6 (IL-6) is produced by many different cells. Its role in multiple myeloma is well established and there is evidence that IL-6 may serve as an autocrine growth factor in epithelial malignancies in the kidney, lung, and prostate. Cell lines derived from metatastic prostate cancer may secrete IL-6 and express high-affinity IL-6 receptors, and expression of the receptors has been reported to increase in localized prostate carcinoma. Giri et al (Am J Pathol 2001, 159:2159–2165) analyzed 40 primary prostate cancers and 10 non-cancerous samples from radical prostatectomy specimens and report that IL-6 protein concentration as well as that of the receptor are greatly increased in the cancers and correlates with cell proliferation. Normal and neoplastic epithelial cells in culture secreted IL-6 while non-secreting cell lines were stimulated to grow by addition of exogenous IL-6. The findings suggest that IL-6 plays an important role as an autocrine growth factor for primary prostate cancers.
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