110 research outputs found
The underlying roles of macrophage populations in myocardial fibrosis
Myocardial fibrosis is one of the main structural changes following cardiomyocyte injury such as infarction. Macrophages play a central role in the development of fibrotic lesions. In myocardial fibrosis, three different populations of macrophages are recognized: exudate macrophages, resident macrophages, and interstitial dendritic cells. Exudate macrophages, which are derived from blood monocytes and recruited into injured areas through chemoattractants and cell adhesion molecules, release various fibrogenic growth factors in early stages of the fibrosis. Transforming growth factor-beta and platelet-derived growth factors are proposed as the most probable growth factors produced by exudate macrophages to induce the modulation of fibroblasts towards myofibroblasts. Emerging evidence shows that macrophage-secreted nerve growth factor may also be involved in that process. The myofibroblasts are capable of producing extracellular matrix proteins which contribute to myocardial fibrosis. The exudate macrophages also participate in the induction ofapoptosis in injured myocytes and myofibroblasts in the fibrotic lesions. These apoptotic cells are phagocytized by exudate macrophages, and the macrophages themselves also disappear by apoptosis. The decrease in cellularity by apoptosis leads to the evolution of fibrous granulation tissues into scar tissues (reparative fibrosis). The resident macrophages particiapte exclusively in the late stages of the myocardial fibrosis, when their mitotic activity increases in the lesions; they are presumed to have the same roles as the exudate macrophages. In addition, the resident macrophages and interstitial dendritic cells both act as immune mediators to recruit T-lymphocytes into the lesions. In contrast to hepatic, pulmonary, and renal fibrosis, the roles of macrophage populations in myocardial fibrosis has not yet been extensively investigated.Biomedical Reviews 1999; 10: 89-105
Immunohistochemical Expressions of Main PGE2 Biosynthesis-related Enzymes and PGE2 Receptor in Rat Nephrogenesis
Endogenous prostaglandin (PG) E2 plays important roles in renal homeostasis.
Immunoexpressions of PGE2 biosynthesis-related enzymes, cyclooxygenase (COX)-2
and microsomal PGE2 synthetase (mPGES)-1 and EP4 (a PGE2 receptor),
were investigated in renal development. Kidney tissues were obtained from fetuses on
gestation days 18 and 21 and neonates on days 1 to 18. In fetuses and early neonates, the
expressions of COX-2, mPGES-1 and EP4 were observed in developing renal tubules,
indicating that COX-2 and its product, PGE2, play important roles in blastemal
cell-derived renal tubular development via EP4. Cyclin D1 expression was seen in both the
nucleus and cytoplasm of the developing tubules. These findings differed from the
decreased COX-2 expression and exclusive nuclear expression of cyclin D1 seen in abnormal
epithelial regeneration of injured renal tubules in cisplatin-treated rats in our previous
articles. Collectively, PGE2, induced by COX-2, regulates renal tubular
epithelial formation via EP4
Metabolic Fingerprinting in Toxicological Assessment Using FT-ICR MS
Detection of the toxicity of a candidate compound at an early stage of drug
development is an emerging area of interest. It is difficult to determine all of
the effects of metabolism of a compound using traditional approaches such as
histopathology and serum biochemistry. The goal of a metabolomics approach is to
determine all metabolites in a living system, with the potential to detect and
identify biomarkers involved in toxicity onset. Here, we summarize the metabolic
fingerprints for detection and identification of metabolic changes and
biomarkers related to drug-induced toxicity using Fourier transform ion
cyclotron resonance mass spectrometry (FT-ICR MS)
Comparative Gene Expression Analysis in the Skeletal Muscles of Dysferlin-deficient SJL/J and A/J Mice
Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted to
determine whether or not there are interstrain or site-dependent differences in the gene
expression profiles of skeletal muscles in SJL/J and A/J mice as dysferlinopathy models.
Upon analysis by qRT-PCR, SJL/J mice showed a trend of increased gene expression level of
uncoupling protein 2 in the rectus femoris and longissimus lumborum at 30 weeks of age
when dystrophic lesions became histopathologically pronounced. Heme oxygenase 1 and S100
calcium binding protein A4 were upregulated in the rectus femoris, longissimus lumborum
and abdominal muscles, in which dystrophic lesions occur more commonly in SJL mice. The
gene expression levels of heat shock protein 70 in most muscles of A/J mice were lower
than those of BALB/c mice as control. SJL/J mice exhibited a marked lowering of
decay-accelerating factor 1/CD55 gene expression level in all studied muscles except for
the heart at all ages compared with that of BALB/c mice. This study showed that there were
some interstrain differences in the gene expres sion profiles of skeletal muscles between
SJL/J and A/J mice. Further investigation is required to reveal whether these alterations
of the expression levels are the cause of dystrophic changes or occur subsequent to muscle
damage
Thy-1 Expressing Mesenchymal Cells in Rat Nephrogenesis in Correlation with Cells Immunoreactive for α-Smooth Muscle Actin and Vimentin
Thy-1 expression may influence myofibroblast development. Through the
epithelial-mesenchymal transition (EMT), injured renal epithelial cells undergo
regression to the metanephric mesenchymal phenotype and then acquire a
myofibroblastic nature (expressing α-smooth muscle actin; α-SMA). Because the
metanephric blastema differentiates into mesenchymal and renal epithelial cells,
we investigated Thy-1 immunoexpression during nephrogenesis in F344 rats in
correlation with vimentin and α-SMA expressions. Kidney samples were obtained
from fetuses on gestation days 18 and 21, neonates on days 1-18 and adults at 6
weeks of age. Mesangial cells in S-shaped bodies and immature and mature
glomeruli continuously expressed both Thy-1 and α-SMA during early nephrogenesis
(fetuses and neonates on days 1-9). During early nephrogenesis, loosely-arranged
blastemal cell-derived mesenchymal cells in the cortex and medulla also
exhibited Thy-1 and α-SMA, although the α-SMA expression was weaker than that of
Thy-1. Vimentin expression coincided with that of Thy-1. These findings indicate
that the derivation of α-SMA-expressing myofibroblastic cells may be related to
mesangial or blastemal cells expressing both Thy-1 and α-SMA. Interestingly,
there was a difference in Thy-1 expression between cortical and medullary
tubulointerstitial cells from late nephrogenesis (neonates on days 12-18) and
those from adults in that the cortical cells reacted faintly or negatively to
Thy-1, whereas the medullary cells reacted strongly to Thy-1; additionally,
bundle-arranged mesenchymal cells that were only observed in the neonates on
days 1-12 reacted strongly to α-SMA, but faintly to Thy-1. Blastemal
cell-derived mesenchymal cells seem to alter the immunoexpressions of Thy-1 and
α-SMA, depending on the conditions which they develop. Thy-1 immunoexpression
would be useful for investigation of reverse embryogenesis, which might occur in
fibrotic kidneys
A Rhabdomyosarcoma Arising in the Larynx of a Dog
A neoplastic nodular lesion, 2 × 3 cm in diameter, was found in the larynx of a
6-year-old spayed female dog. The tumor was ill-circumscribed, consisting histologically
of large round cells with abundant cytoplasm interspersed with small round cells with less
cytoplasm and occasional multinucleated cells (myotubes). Immunohistochemically, tumor
cells were positive for myoglobin, desmin and vimentin in varying degrees, but negative
for S-100 protein, GFAP or cytokeratin. Cytoplasmic myofilaments/myofibrils with a dense
Z-line-like structure were seen, the fine structures of which were complemented by PTAH
stain. Based on these findings, the tumor was diagnosed as a rhabdomyosarcoma, a very rare
tumor in the larynx of dogs
Relationship of Cell Proliferating Marker Expressions with PGE2 Receptors in Regenerating Rat Renal Tubules after Cisplatin Injection
Cisplatin, an anticancer drug, is well known to have nephrotoxicity as an adverse
effect. We investigated the expressions of cell cycle markers and prostaglandin
E2 (PGE2) receptors (EP) in the affected renal tubules
in rats injected with a single dose (6 mg/kg body weight) of cisplatin. On days
1–3 after dosing, the affected renal epithelial cells were almost desquamated,
showing necrosis. On day 5 onwards, the renal tubules were rimmed by flattened
or cuboidal epithelial cells with basophilic cytoplasm; BrdU-immunopositive
cells began to significantly increase, indicating regeneration. Simultaneously,
TUNEL-positive apoptotic cells were also seen. On days 1–5, cyclin
D1-immunopositive cells were decreased with an increased expression in p21 mRNA,
indicating G1 arrest in the cell cycle. The affected renal epithelial
cells began to react to EP4 receptor, but not to EP2 receptor. Some EP4
receptor-reacting epithelial cells gave a positive reaction to BrdU or cyclin
D1. Collectively, the affected renal tubules underwent various alterations such
as necrosis, apoptosis, regeneration and G1 arrest; the aspects might
be influenced by endogenous PGE2 through EP4 receptor
Comparative Nephrotoxicity of Cisplatin and Nedaplatin: Mechanisms and Histopathological Characteristics
The antineoplastic platinum complexes cisplatin and its analogues are widely used in the
chemotherapy of a variety of human malignancies, and are especially active against several
types of cancers. Nedaplatin is a second-generation platinum complex with reduced
nephrotoxicity. However, their use commonly causes nephrotoxicity due to a lack of tumor
tissue selectivity. Several recent studies have provided significant insights into the
molecular and histopathological events associated with nedaplatin nephrotoxicity. In this
review, we summarize findings concerning the renal histopathology and molecular
pathogenesis induced by antineoplastic platinum complexes, with a particular focus on the
comparative nephrotoxicity of cisplatin and nedaplatin in rats
Observational Study Design in Veterinary Pathology, Part 1: Study Design
Observational studies are the basis for much of our knowledge of veterinary pathology and are highly relevant to the daily practice of pathology. However, recommendations for conducting pathology-based observational studies are not readily available. In part 1 of this series, we offer advice on planning and conducting an observational study with examples from the veterinary pathology literature. Investigators should recognize the importance of creativity, insight, and innovation in devising studies that solve problems and fill important gaps in knowledge. Studies should focus on specific and testable hypotheses, questions, or objectives. The methodology is developed to support these goals. We consider the merits and limitations of different types of analytic and descriptive studies, as well as of prospective vs retrospective enrollment. Investigators should define clear inclusion and exclusion criteria and select adequate numbers of study subjects, including careful selection of the most appropriate controls. Studies of causality must consider the temporal relationships between variables and the advantages of measuring incident cases rather than prevalent cases. Investigators must consider unique aspects of studies based on archived laboratory case material and take particular care to consider and mitigate the potential for selection bias and information bias. We close by discussing approaches to adding value and impact to observational studies. Part 2 of the series focuses on methodology and validation of methods
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