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PubMed2004

Effects of an inducible nitric oxide synthase inhibitor on experimentally induced rat pulpitis.

Nitric oxide (NO) is a biological effector molecule involved in a large variety of reactions and, as synthesized by inducible nitric oxide synthase (iNOS), has many important roles in inflammatory conditions. This study aimed to evaluate the anti-inflammatory effects of an iNOS-specific inhibitor, N-(3-(aminomethyl)benzyl)acetamidine (1400W), on experimentally induced rat pulpitis in the upper incisors of 6-wk-old male Wistar rats. 1400W (1 mg kg(-1)), the non-specific NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg kg(-1)), or sterile saline (control) were administered before the application of lipopolysaccharide (LPS). Rats were killed 3, 6, 9, 12, 24, 48, and 72 h after LPS application, and immunocompetent cells were detected immunohistochemically. The numbers of granulocytes infiltrating into the pulp were significantly depressed in the 1400W group compared with the saline and L-NAME groups. The kinetics of the macrophages and Ia(+) cells in the 1400W group were similar to those in the L-NAME group, while the maximum numbers in both groups were significantly reduced compared with those in the saline group. These results suggest that NO may be responsible for the infiltration of immunocompetent cells in the progress of pulpitis, and that 1400W is a promising candidate for controlling pulpal inflammatory reactions.

Amidines↗
PubMed2005

Do glucose transporters have other roles in addition to placental glucose transport during early pregnancy?

Human placenta regulates the transport of maternal molecules to the fetus. It is known that glucose transport occurs via glucose transporters (GLUTs) in the feto-placental unit. Data on the expression of GLUTs during implantation are very scarce. Moreover, the question of how the decidual leukocytes obtain the energy for their activation during implantation mechanism is still under investigation. We studied the distributions of GLUT1, GLUT3, and GLUT4 in tissue sections of first trimester pregnancies the human maternal-fetal interface. GLUT1 was present in apical microvilli of the syncytiotrophoblast, in cytotrophoblast, and in vascular patterns of the villous core, whereas GLUT3 was localized in cytotrophoblasts of placental villi and in some fetal endothelial cells. Moreover, the proliferating cells of the proximal cell columns were also immunopositive for GLUT1 and GLUT3. We did not observe any positive immunoreactivity for GLUT4 in placental and decidual tissues. Essentially, GLUT3 and also to some extent GLUT1 was present in maternal leukocytes and platelets. In conclusion, our results suggest that the glucose taken up via GLUT1 and GLUT3 from the maternal circulation might not only be needed for placental functions but also for successful implantation by trophoblast invasion, proliferation and also by having a role to support energy for maternal leukocytes.

Antigens, CD↗
PubMed1992

Distinctive distribution of HLA class II presenting and bone marrow derived cells in the anterior segment of human eyes.

Cells of bone marrow origin that normally occupy the stroma of the murine iris and ciliary body have been implicated in the immune phenomenon, anterior chamber associated immune deviation (ACAID). Following injection of antigen into the anterior chamber, cells of this type deliver an ACAID inducing signal into the systemic circulation, presumably through the outflow tract. In an effort to identify such cells in man, anterior chambers of 34 human donor eyes of different age groups were stained immunocytochemically with monoclonal antibodies directed at HLA class II molecules, CD 45 (a molecular marker of bone marrow-derived cells) and macrophage-associated membrane molecules (CD 68, CD 14). Within the outflow tissue, the cells of the filtering trabecular meshwork stained with none of those reagents. However, infrequent single, dispersed, dendritic cells were positively stained in the intertrabecular spaces. More numerous labelled cells were found in the anterior- and posterior-most portions of the non-filtering part of the trabecular meshwork. These cells were continuous with stained cells adjacent to the outer wall of Schlemm's canal and to the collector channels. Numerous labelled cells were seen in the vicinity of the intra- and episcleral vessels, the ciliary meshwork, the stroma of the ciliary muscle and epithelial processes, and the iris stroma. With advancing age, increasing numbers of CD 45+, HLA class II expressing cells appeared to accumulate in the so-called uveoscleral pathway. These results indicate that bone marrow-derived cells with the potential to function of ACAID induction reside within human eyes, and that cells of this type are located not only in the stroma of iris and ciliary body, but within the non-filtering portions of the trabecular meshwork and the uveoscleral pathway. The appearance of rare CD 45+ cells "in transit" in the filtering trabecular meshwork is compatible with the view that cells carrying ACAID-inducing signals to the systemic immune apparatus escape from the eye by this route.

Adult↗
PubMed1999

Abundant expression of chemokines in malignant and infective human lymphadenopathies.

Lymph nodes can be the primary target of infection or malignant transformation and may exhibit characteristic patterns of leukocyte infiltration analogous to those seen in inflammation of other tissues. Leukocyte migration to lymph nodes in vivo is a highly regulated, multi-step process that depends upon adhesion molecules and as yet, uncharacterized chemotactic signals. Chemokines are a key part of the orchestrated code of signals that directs leukocyte subsets to sites of inflammation or immune response. The potential role of these chemoattractants in selective trafficking of leukocyte subsets into lymph nodes was assessed by determining the expression of chemokines on a range of pathological and normal human lymph nodes and by evaluating the cellular composition of each lymph node. In situ hybridization using chemokine riboprobes and immunohistochemistry using specific antibodies were performed in order to correlate the mRNA and protein expression of the chemokines. The cellular source(s) of each chemokine was assessed by immunohistochemical staining of adjacent sections using antibodies directed against distinctive cellular markers. Substantial, but varied, expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, macrophage chemotactic protein (MCP)-1, eotaxin, and interleukin 8 (IL-8) were detected in the pathological lymph nodes by diverse cell types. Control lymph nodes showed expression only of RANTES, mainly by high endothelial venules. In all lymph nodes, except the nodes infiltrated with breast cancer, chemokine mRNA expression was highly concordant with the corresponding protein. In contrast with in vitro studies that have suggested discrete target cell specificity of chemokines, this study showed that with the possible exception of the neutrophil chemoattractant, IL-8, no chemokine appeared to be uniquely associated with the accumulation of a specific leukocyte subset. These data implicate chemokines in the recruitment of leukocytes to lymph nodes affected by diverse disease states.

Antigens, CD↗
PubMed2004

Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root.

Fractalkine (CX3CL1) is of particular interest in atherogenesis because it can serve as an adhesion molecule and a chemokine. Fractalkine and its receptor CX3CR1 are expressed in atherosclerotic lesions of humans and mice. However, the effect of fractalkine deficiency on atherosclerosis susceptibility is unknown. Fractalkine-deficient mice on the C57BL/6 (B6) background were bred to the atherosclerosis-sensitizing B6.ApoE(-/-) and B6.LDLR(-/-) backgrounds. Compared with controls, aortic-root lesion area was unchanged in fractalkine-deficient male and female B6.ApoE(-/-) mice at 16 weeks of age and males at 12 weeks of age, but it was mildly reduced (30%, P = 0.005) in females at 12 weeks of age. In contrast, lesion area at the brachiocephalic artery (BCA) was reduced dramatically by approximately 85% in fractalkine-deficient females [42,251 +/- 26,136 microm(2) (n = 15) vs. 6,538 +/- 11,320 microm(2);(n = 24), P < 0.0001] and males [36,911 +/- 32,504 microm(2) (n = 24) vs. 6,768 +/- 8,595 microm(2) (n = 14); P = 0.001] at 16 weeks of age. Fractalkine-deficient B6.ApoE(-/-) mice were comparable with controls in body weight, plasma cholesterol, plasma high-density lipoprotein cholesterol and white blood cell counts. On the B6.LDLR(-/-) background, lesion areas were reduced by 35% at the aortic root (P < 0.01) and by 50% at the BCA (P < 0.05) in fractalkine-deficient females at 16 weeks of age. Lesions in fractalkine-deficient mice on the B6.ApoE(-/-) and B6.LDLR(-/-) backgrounds were less complex and contained significantly fewer macrophages than controls. In conclusion, the major reduction of atherosclerosis in fractalkine-deficient mice appears to be at the BCA rather than the aortic root.

Animals↗
PubMed1999

Progression of clinical deterioration and pathological changes in patients with Alzheimer disease evaluated at biopsy and autopsy.

OBJECTIVES: To quantify the progression of senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, and microglial activation in the cortex and white matter of patients with Alzheimer disease evaluated at both biopsy and subsequent autopsy and correlate these changes with the progression of neurologic impairment. SETTING: Academic referral center for patient with Alzheimer disease. PATIENTS: Four patients meeting the clinical criteria for Alzheimer disease, enrolled in a pilot study for the evaluation of response to intracerebroventricular administration of bethanechol chloride. The patients were followed up until death occurred and autopsy was performed. RESULTS: All 4 patients had progressive deterioration from the time of biopsy to autopsy (9-11 years). Pathological investigations showed a striking increase in the density of senile plaques and neurofibrillary tangles in 2 of 4 patients from biopsy to autopsy, and a significant increase in microglial activation in 1 of 4 cases. Severity of cerebral amyloid angiopathy varied significantly among patients, 1 of whom displayed striking amyloid deposition with associated subcortical white matter atrophy. CONCLUSIONS: These unique data demonstrate that the progressive neurologic impairment in Alzheimer disease is accompanied by a significant increase in senile plaque and neurofibrillary tangle counts in the frontal cortex and, possibly in some patients, by increased microglial cell activation. Cerebral amyloid angiopathy was associated with significant white matter disease.

Aged↗
PubMed1999

Malignant fibrous histiocytoma of the conjunctiva.

We report the clinical and pathological findings in a case of malignant fibrous histiocytoma in the conjunctiva of a 60-year-old man. The patient initially had an atypical limbal lesion, resembling a pterygium, which was excised. Two local recurrences, noted during the following year, were treated by surgical excision followed by cryotherapy. Histopathologic examination of the conjunctival lesions showed a stromal neoplastic infiltrate composed of atypical spindle cells and histiocytelike cells. The immunohistochemical and ultrastructural studies suggested that the tumor was composed of various cellular elements: fibroblasts, myofibroblasts, and histiocytes.

Actins↗
PubMed2001

Gelatinase B in vernal keratoconjunctivitis.

OBJECTIVES: To investigate the expression of gelatinase B in the conjunctiva of patients with vernal keratoconjunctivitis (VKC) and the cellular source of this enzyme. METHODS: Conjunctival biopsy specimens from 12 patients with active VKC and 12 control subjects were studied using immunohistochemical techniques and a monoclonal antibody against gelatinase B. The phenotype of gelatinase B(+) inflammatory cells was examined using double immunohistochemical analysis and monoclonal antibodies against eosinophil peroxidase or macrophage CD68. Quantitative zymography was used to compare the activity of gelatinase B in conjunctival biopsy specimens from 10 patients with active VKC and 7 control subjects. RESULTS: Gelatinase B was detected in a few polymorphonuclear cells in 8 control specimens. All VKC specimens showed gelatinase B immunoreactivity in the epithelial and stromal inflammatory infiltrate. Compared with control specimens, VKC specimens showed significantly more gelatinase B-positive cells (mean +/- SD, 40.8 +/- 29.9 vs 10.3 +/- 2.4; P<.02). Most gelatinase B-positive cells were eosinophils (90.2% +/- 3.6%). Zymography revealed that gelatinase B levels in VKC specimens were significantly higher than the levels found in normal conjunctiva (3780.3 +/- 3541.0 vs 610.1 +/- 397.1 scanning units; P<.03). CONCLUSIONS: These findings suggest overexpression of gelatinase B by eosinophils in VKC specimens and participation of gelatinase B in the pathologic changes in VKC. CLINICAL RELEVANCE: Control of the release and/or activation of gelatinase B in eosinophils may provide a new therapeutic strategy for treating VKC.

Adolescent↗
PubMed2001

Overexpression of epidermal growth factor receptor restricted to macrophages in uveal melanoma.

OBJECTIVE: To determine whether expression of the epidermal growth factor receptor (EGFR) is of prognostic value in uveal melanoma. METHODS: Thirty consecutive patients treated for primary posterior uveal melanoma by enucleation or local resection were studied. Tumors were examined for EGFR and CD68 expression by immunohistochemistry on formalin-fixed, paraffin-embedded sections. Extracted DNA from paired frozen tumor and blood samples was examined for loss of heterozygosity on chromosome 3 using polymerase chain reaction-based microsatellite analysis. Immunoreactivity for EGFR was correlated with clinicopathological, chromosome 3, and follow-up data. RESULTS: Immunoreactivity for EGFR was observed in 7 (23%) of 30 uveal melanomas, but was restricted to solitary or small groups of cells with macrophage-like morphology. Immunoreactive cells were confirmed as macrophages using an antibody to the macrophage marker CD68. Chromosome 3 loss, epithelioid cells, and microvascular loops were detected in 17 (57%), 22 (73%) and 19 (63%) of the 30 tumors, respectively. Metastatic disease was detected in 5 patients (17%). No correlation was found between any of these variables and EGFR positivity. CONCLUSIONS: The absence of EGFR immunoreactivity in tumor cells does not support the use of EGFR expression as a prognostic indicator in patients with uveal melanoma. Future EGFR studies in uveal melanoma should be interpreted with caution in view of our findings that tumor-associated macrophages can express this receptor.

Antigens, CD↗
PubMed2001

Combined effect of cyclosporine and sirolimus on improving the longevity of recombinant adenovirus-mediated transgene expression in the retina.

OBJECTIVES: To reevaluate the longevity and intraocular safety of recombinant adenovirus (rAd)-mediated gene delivery after subretinal injection, and to prolong transgene expression through the combination of 2 synergistic immunosuppressants. METHODS: An rAd vector carrying green fluorescent protein (GFP) gene was delivered subretinally in the rat eye. The GFP expression was monitored in real time by fundus fluorescent photography. Intraocular safety was examined by observation of changes of retinal pigmentation, cell infiltration in virus-contacted area, immunophenotyping for CD4(+) and CD8(+) cytotoxic T lymphocytes, and CD68(+) macrophages, histologic findings, and dark-adapted electroretinography. Two synergistic immunosuppressants, cyclosporine and sirolimus, were used alone or in combination to prolong transgene expression by temporary immunosuppression. RESULTS: The GFP expression peaked on day 4, dramatically decreased on day 10, and was not detectable on day 14. The decreased GFP expression was coincident with cell infiltration in virus-contacted area. Immunostaining showed that the infiltrating cells were CD4(+) and CD8(+) cytotoxic T lymphocytes and CD68(+) macrophages. Clumped retinal pigmentation and decreased b wave of dark-adapted electroretinogram were observed at 3 to 4 weeks after injection. Histologic examination confirmed rAd-induced retinal degeneration. Transient immunosuppression by cyclosporine and sirolimus, either alone or in combination, improved transgene expression, with the combination being the most efficient. The combined immunosuppression attenuated but did not retard the rAd-induced retinal damage. CONCLUSIONS: Transgene expression mediated by rAd after subretinal delivery is short-term and toxic to the retina. Combination of cyclosporine and sirolimus may act as an immunosuppressive adjunct to prolong rAd-mediated gene transfer. CLINICAL RELEVANCE: The intraocular safety of rAd should be carefully considered before clinical trials are performed.

Adenoviridae↗
PubMed1998

Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and periampullary region.

BACKGROUND: Undifferentiated carcinomas with osteoclast-like giant cells are rare pancreatic and periampulary neoplasms that morphologically mimic giant cell tumor of bone. Despite numerous publications based primarily on single case reports, the terminology, histogenesis, and biologic behavior of these tumors remain controversial. METHODS: The authors studied one periampullary and nine pancreatic neoplasms of this type. Immunohistochemistry was performed on nine of the cases and clinical follow-up data was obtained in eight. RESULTS: The neoplasms were large (average 9 cm), partially or completely multicystic, and hemorrhagic. Histologically, they were composed predominantly of ovoid or spindle-shaped bland mononuclear cells and evenly spaced osteoclast-like giant cells. However, three neoplasms had foci in which the nuclear pleomorphism of the mononuclear cells approached that observed in anaplastic spindle and giant cell carcinomas. Other histologic features included phagocytosis of the mononuclear cells by the osteoclast-like giant cells (in 7 of 10 cases), osteoid or bone formation (in 3 of 10 cases), and chondroid differentiation (in 1 of 10 cases). Four neoplasms had foci of conventional adenocarcinoma and two arose in preexisting mucinous cystic neoplasms of the pancreas. The mononuclear cells were positive for epithelial markers in six of nine tumors tested (cytokeratins AE-1, AE-3, Cam 5.2, and/or epithelial membrane antigen). They were negative for the histiocytic markers (CD-68, lysozyme) in all nine cases tested. In contrast, the osteoclast-like giant cells were positive for CD-68 in all nine cases, positive for lysozyme in four cases, and negative for cytokeratins (AE-1, AE-3, and Cam 5.2) in all nine cases. p53 stained the mononuclear tumor cells in three cases and MIB-1 stained the mononuclear tumor cells in four cases, but the osteoclast-like giant cells did not stain with either antibody in all nine cases tested. Most of the patients died of disease within 1 year of diagnosis; only 1 patient was alive and disease free 14 years after surgical excision. CONCLUSIONS: The association of these tumors with conventional adenocarcinoma or mucinous cystic neoplasms, the histologic features, and the immunohistochemical profile supports an epithelial phenotype for the mononuclear cells and a reactive histiocytic lineage for the nonneoplastic osteoclast-like giant cells. These neoplasms, which are better classified as undifferentiated carcinomas, follow an aggressive clinical course; most patients die of disease within 1 year.

Adenocarcinoma↗
PubMed1999

Emperipolesis of erythroblasts within Kupffer cells during hepatic hemopoiesis in human fetus.

The state in which cells can inhabit other cells without damage is known as emperipolesis. Emperipolesis has been found in various physiological and pathological conditions. We performed a study of emperipolesis of erythroblasts within Kupffer cells in the human fetal liver. We found that Kupffer cells, identified by CD68 immunolabeling, contained 4-8 erythroblasts in a hypertrophic cytoplasm on light microscopy. Emperipoletic erythroblasts were present in various maturation stages from proerythroblast to reticulocyte. By electron microscopy, we found that erythroblasts occupied membrane-bound vacuoles that were separated from each other by thin partitions of Kupffer cell cytoplasm. Neither emperipoletic erythroblasts nor their Kupffer cell hosts showed evidence of damage. Emperipoletic cells in mitosis were found, which suggests the capacity for the proliferation of erythroblasts within Kupffer cells. Some Kupffer cells were seen to contain both emperipoletic cells and phagosomes, without evidence of interaction. Erythroblasts and other hemopoietic cells were also found to be closely associated with the sinusoidal surface of Kupffer cells. However, intercellular junctions, if present, were inconspicuous. On occasion, Kupffer cells engorged with erythroblasts nearly occluded the sinusoidal lumen. Our results demonstrate that emperipolesis of erythroblasts within Kupffer cells occurs in human fetal hepatic hemopoiesis. We suggest that emperipolesis may be one of the mechanisms that support the maturation of erythroblasts in the fetal liver.

Antigens, CD↗
PubMed1997

The anti-tumor effect of Ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes.

The present study was to ascertain the immunomodulating and anti-tumor effects of Ganoderma (G.) lucidum. Polysaccharides (PS) from fresh fruiting bodies of G. lucidum (PS-G) were isolated and used to potentiate cytokine production by human monocytes-macrophages and T lymphocytes. Our results had shown that the levels of interleukin (IL)-1 beta, tumor necrosis factor (TNF)- alpha, and IL-6 in macrophage cultures treated with PS-G (100 micrograms/ml) were 5.1-, 9.8- and 29-fold higher, respectively, than those of untreated controls. In addition, the release of interferon (IFN)- gamma from T lymphocytes was also greatly promoted in the presence of PS-G (25-100 micrograms/ml). Furthermore, these cytokine-containing mononuclear cell-conditioned media (PSG-MNC-CM) were found to suppress the proliferation and clonogenicity of both the HL-60 and the U937 leukemic cell lines. DNA labeling and gel electrophoresis showed that treatment with PSG-MNC-CM markedly induced leukemic-cell apoptosis. Flow-cytometric analysis revealed that few (2.3 +/- 0.8%) apoptotic cells were seen in the control cultures, while PSG-MNC-CM treatment resulted in a significant increase in the apoptotic population both in the HL-60 (38.3 +/- 4.5%) and in the U937 (44.5 +/- 3.8%) cells. In addition, 40 to 45% of the treated leukemic cells were triggered to differentiate into mature monocytic cells expressing CD14 and CD68 surface antigens. However, PS-G alone had no such effects even at a higher dose of 400 micrograms/ml. Since untreated macrophages and T lymphocytes produced little or no cytokine, and normal MNC-CM did not suppress leukemic cell growth, it was suggestive that the anti-tumor activity of PSG-MNC-CM was derived from the elevated levels of cytokines. Antibody-neutralization studies further revealed that the anti-tumor cytokines in the PSG-MNC-CM were mainly of TNF- alpha and IFN- gamma, and these 2 cytokines acted synergistically on the inhibition of leukemic-cell growth.

Adjuvants, Immunologic↗
PubMed1999

Differing expression of MMPs-1 and -9 and urokinase receptor between diffuse- and intestinal-type gastric carcinoma.

Gastric cancer is classified into intestinal and diffuse types, which exhibit different biological behavior. Urokinase-type plasminogen activator (uPA), its receptor (uPAR) and matrix metalloproteinases (MMPs)-1 and -9 are considered to play important roles in cancer invasion and metastasis. We have already suggested a functional duality of these matrix-degrading enzymes/factors; they may also be involved in the matrix turnover (remodeling) or host immune/inflammatory reactions as far as they are expressed by host cells. We performed a retrospective study on the immuno-histochemical expression of these enzymes/factors in surgical specimens from patients with gastric cancer, including 26 with the diffuse and 78 with the intestinal type. We also evaluated macrophages since they are major sources of uPAR. The positivity rate for uPA in cancer cells was significantly lower in diffuse-type than in intestinal-type. Stromal expression was seen mainly along the invasive margin (tumor-host interface). The degree of stromal expression of uPAR and MMP-9 and the macrophage number were markedly decreased in diffuse-type compared with intestinal-type. Stromal expression of uPAR and macrophage number in intestinal-type were higher in patients without liver metastasis than in patients with liver metastasis, while uPA expression in cancer cells was more pronounced in patients with liver metastasis. Studies using frozen sections revealed that the expression of MMP-1, restricted to the stromal area, was more decreased in diffuse-type (18 patients) than in intestinal-type (21 patients). Our results show that the in situ expression of matrix-degrading enzymes/factors in gastric cancer is significantly more diminished in diffuse-type than in intestinal-type, suggesting a multifunctional aspect of the matrix-degradation process in cancer tissue.

Antigens, CD↗
PubMed1999

Microglial/macrophage expression of interleukin 10 in human glioblastomas.

Interleukin 10 (IL-10) expression has been found to be correlated with the extent of malignancy in gliomas. In vitro, IL-10 increases proliferation and migratory capacity in human glioma cell lines. In this study, we localized the site of IL-10 synthesis in gliomas to cells of microglial origin. Biopsy specimens from 11 patients with malignant glioma were processed on native tissues and at early cell culture passages (0-4). IL-10 mRNA was analyzed by RT-PCR and in situ hybridization. Protein was quantitatively assessed by ELISA in cell culture supernatants, and cells expressing IL-10 were determined by a combination of immunohistochemistry for CD68 (specific for microglia/macrophage lineage) and IL-10 in situ hybridization. IL-10 mRNA decreased from passage 0 to 4 in all samples and was undetectable beyond passage 5. Such downregulation of mRNA leads to a steep decrease of IL-10 protein in culture supernatants (below detection level, 0.05 ng/ml, beyond passage 1). The combination of in situ hybridization for IL-10 and CD68 immunostaining revealed that only cells of the microglia/macrophage lineage produced IL-10 mRNA. Our results identify microglia/macrophage cells as the major source of IL-10 expression in gliomas which decreases markedly during early passages of primary cultures of human gliomas due to a progressive reduction of microglia/macrophages present.

Adult↗
PubMed1999

Monocyte-chemo-attractant-protein-1 (MCP-1)-gene expression in cervical intra-epithelial neoplasias and cervical carcinomas.

Chemokines play a central role in the chemotactic activation of immunological effector cells. One of the currently best characterized chemokines is the monocyte-chemo-attractant protein-1 (MCP-1), which is involved in the cross-talk with cells of the monocyte-macrophage lineage. Since macrophages and macrophage-derived cytokines appear to be important in the transcriptional regulation of "high-risk" types of human papillomaviruses (HPV), we monitored MCP-1 expression by in situ hybridization (ISH) in histologically distinct stages of cervical intra-epithelial neoplasms (CIN), cervical cancer and non-HPV-associated cases of erosive endocervicitis. Here, we demonstrate that high-grade dysplasia (CIN III, n = 9) completely lacks both MCP-1 expression and CD68+-macrophage infiltration, while MCP-1-specific signals were occasionally detectable in one out of 5 CIN-II and in one out of 3 CIN-I lesions. Inspection of hyperplastic squamous epithelium adjacent to cervical carcinomas reveals high MCP-1 expression and accumulation of infiltrating macrophages. In contrast, no macrophages could be detected in corresponding hyperplastic tissue areas surrounding CIN-II and CIN-III lesions, although MCP-1 was found to be highly expressed. Finally, in agreement with our earlier in vitro data, invasive carcinomas of the cervix uteri showed MCP-1-specific hybridization signals and macrophage infiltration only in the stroma surrounding the carcinoma cells and in endothelial cells of capillaries, especially at the invasion front of the tumor, while the inner mass of the carcinomas was completely negative. On the other hand, ISH and histochemical evaluation of inflammatory, non-HPV-associated cases of erosive endocervicitis indicate strong MCP-1 expression, which is regularly accompanied by chemotactic appearance of macrophages. These observations indicate that dysregulation of MCP-1-gene expression may represent an important step during HPV-linked carcinogenesis, allowing the escape of virus-positive cells from local immune response.

Adult↗
PubMed1999

High expression of cyclooxygenase-2 in macrophages of human colonic adenoma.

Cyclooxygenase (COX)-2 is a possible molecular target for suppression of colon carcinogenesis by non-steroidal anti-inflammatory drugs (NSAIDs). However, the expression of COX-2 in human colonic tumors during the adenoma-carcinoma sequence has not been elucidated. In the present study, we examined immuno-histochemically the expression and localization of the COX-2 protein in human colonic adenomas and cancers. Twelve human colonic adenomas and 9 advanced cancers were studied. Immunoreactive COX-2 was predominantly and strongly expressed in sub-epithelial interstitial cells broadly present in the surface area of adenomas. The staining pattern of macrophages was similar to that observed for COX-2 in adenomas. Adjacent normal colonic mucosa was negative for COX-2 expression. In contrast, COX-2 was relatively weakly expressed in both tumor cells and interstitial cells in advanced colon cancers. In conclusion, the target of NSAIDs in preventing colon carcinogenesis may be the COX-2 expressed in interstitial cells, possibly macrophages, of colonic adenomas.

Adenoma↗
PubMed1996

Fine-needle aspirates of granular cell lesions of the breast: report of three cases, with emphasis on differential diagnosis and utility of immunostaining for CD68 (KP1).

Fine-needle aspiration biopsy (FNA) has been recognized as a safe and reliable procedure for evaluating breast lesions. We herein report cytologic findings for needle aspirates from three granular cell nodules of the breast. The nodules were detected by diagnostic imaging and ranged from 0.6 to 1 cm in diameter. Ultrasound-guided FNA was used in all cases and revealed cellular aspirates with similar cytomorphologic features consisting of sheets of large granular cells intersected by arborizing thin-walled blood vessels. The cells had round to oval nuclei, inconspicuous nucleoli, and abundant, often ill-defined granular cytoplasm. Tissue sections of resected specimens yielded final diagnoses of granular cell metaplasia of histiocytes and stromal cells in one case and granular cell tumor (GCT) in the other two cases. FNA smears in all three cases were strongly positive for the lysosomal marker CD68 (KP1) and S-100 protein; therefore, it was not possible to distinguish true GCT from granular cell metaplasia/granular histiocytes. When breast aspirates reveal granular cell changes, excisional biopsy should be done for a definitive diagnosis.

Adult↗