Biomedical subjects

K Matossian

Publications and source records attributed to K Matossian.

12 recordsLinked to original sources

PubMed1999

Eosinophil-derived transforming growth factors (TGF-alpha and TGF-beta 1) in human periradicular lesions.

Inflammatory mediators of periradicular lesions are poorly understood. Transforming growth factors-alpha and -beta 1 (TGF-alpha and TGF-beta 1) have been linked with the cellular processes for both soft and hard tissue wound healing. The purpose of this study is to demonstrate the cellular sources of TGF-alpha and TGF-beta 1 mRNA and protein in periapical lesions by in situ hybridization and immunohistochemistry. Nine periapical granulomas and nine periapical cysts were examined. TGF-alpha mRNA and protein were not detectable in the granulomas examined. However, eosinophils surrounding the periapical cysts demonstrated both TGF-alpha mRNA and protein. The vast majority of eosinophils present in the periapical granulomas and cysts also demonstrated TGF-beta 1 mRNA and protein. Other cells producing TGF-beta 1 were lymphocytes, fibroblasts, and monocytes. The presence of wound repair cytokines, such as TGF-alpha and TGF-beta 1, suggests a mechanism by which the host inflammatory response may participate in the repair and remodeling of periapical tissues.

Adult↗

PubMed1994

Expression of transforming growth factors-alpha and beta 1 messenger RNA and product by eosinophils in nasal polyps.

Nasal polyps are thought to develop as a manifestation of a chronic inflammatory process involving the upper airways. The eosinophil characteristically represents a prominent component of the inflammatory cell infiltrate of these lesions. However, the major clinical problem associated with nasal polyps, nasal obstruction, reflects the proliferation of the stromal and epithelial elements, which constitute the bulk of these lesions. We recently reported that blood eosinophils of patients with hypereosinophilia can produce the cytokines transforming growth factors-alpha (TGF-alpha) and beta 1 (TGF-beta 1). These cytokines have many biologic activities, which include the regulation of epithelial proliferation, the promotion of extracellular matrix formation, and the induction of angiogenesis. We therefore used in situ hybridization to determine whether the eosinophils that infiltrate nasal polyps express TGF-alpha and/or TGF-beta 1 messenger RNA and used immunohistochemistry to determine whether these eosinophils also express TGF-alpha and TGF-beta 1 proteins. We found that eosinophils represented a major source of both transforming growth factors in each case of nasal polyposis examined and that in most cases the majority of all eosinophils expressed both TGF-alpha and TGF-beta 1. These results suggest that production of TGF-alpha and TGF-beta 1 by the infiltrating eosinophils may contribute to some of the pathologic changes observed in nasal polyposis, such as thickening of the epithelial basement membrane, stromal fibrosis, angiogenesis, and epithelial and glandular hyperplasia.

Aniline Compounds↗

PubMed1993

Human eosinophils can express the cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-1 alpha.

By in situ hybridization, 44-100% of the blood eosinophils from five patients with hypereosinophilia and four normal subjects exhibited intense hybridization signals for TNF-alpha mRNA. TNF-alpha protein was detectable by immunohistochemistry in blood eosinophils of hypereosinophilic subjects, and purified blood eosinophils from three atopic donors exhibited cycloheximide-inhibitable spontaneous release of TNF-alpha in vitro. Many blood eosinophils (39-91%) from hypereosinophilic donors exhibited intense labeling for macrophage inflammatory protein-1 alpha (MIP-1 alpha) mRNA, whereas eosinophils of normal donors demonstrated only weak or undetectable hybridization signals for MIP-1 alpha mRNA. Most tissue eosinophils infiltrating nasal polyps were strongly positive for both TNF-alpha and MIP-1 alpha mRNA. By Northern blot analysis, highly enriched blood eosinophils from a patient with the idiopathic hypereosinophilic syndrome exhibited differential expression of TNF-alpha and MIP-1 alpha mRNA. These findings indicate that human eosinophils represent a potential source of TNF-alpha and MIP-1 alpha, that levels of expression of mRNA for both cytokines are high in the blood eosinophils of hypereosinophilic donors and in eosinophils infiltrating nasal polyps, that the eosinophils of normal subjects express higher levels of TNF-alpha than MIP-1 alpha mRNA, and that eosinophils purified from the blood of atopic donors can release TNF-alpha in vitro.

Cells, Cultured↗

PubMed1993

Sequential expression of transforming growth factors alpha and beta 1 by eosinophils during cutaneous wound healing in the hamster.

Transforming growth factor-alpha (TGF-alpha) and TGF-beta 1 have been proposed as important regulators of processes critical to successful wound healing. Although various cells present in wounds represent potential sources of either TGF-alpha and/or TGF-beta, including macrophages, neutrophils, keratinocytes, fibroblasts, and endothelial cells, we recently identified eosinophils as an additional potential source of these cytokines. We therefore used in situ hybridization and immunohistochemistry to determine whether eosinophils represent significant sources of TGF-alpha and/or TGF-beta 1 in skin wounds in the hamster. We found that these wounds developed a prominent infiltration of eosinophils, and that eosinophils were a cellular source of both TGF-alpha and TGF-beta 1 mRNAs. TGF-alpha and TGF-beta 1 proteins were detectable both within eosinophils and extracellularly. Moreover, there was a sequential pattern of TGF-alpha and TGF-beta 1 expression by infiltrating eosinophils, with the onset of eosinophil-associated TGF-alpha expression preceding that of TGF-beta 1. This sequential pattern of TGF expression suggests that eosinophils may help to regulate critical biological processes during wound healing.

Amino Acid Sequence↗

PubMed1991

Eosinophils from patients with blood eosinophilia express transforming growth factor beta 1.

The infiltration of eosinophils into tissues during pathologic responses is often associated with extracellular matrix alterations such as fibrosis. Transforming growth factor-beta 1 (TGF-beta 1) is a well-characterized multifunctional cytokine known to exert potent effects on the extracellular matrix. In this report, we showed the production of TGF-beta 1 by human eosinophils from patients with blood eosinophilia. Northern blot analysis using RNA isolated from eosinophils purified from a patient with the idiopathic hypereosinophilic syndrome (HES) detected the 2.5-kb TGF-beta 1 transcript. In situ hybridization and immunohistochemistry of leukocytes from two patients with HES and two patients with blood eosinophilia localized TGF-beta 1 messenger RNA (mRNA) and protein to eosinophils. No other cell type contained TGF-beta 1 mRNA by in situ hybridization, whereas other leukocytes contained detectable TGF-beta 1 protein by immunohistochemistry. Eosinophils from four normal donors contained little or no detectable TGF-beta 1 protein by immunohistochemistry, whereas eosinophils from two of these four normal donors labeled weakly for TGF-beta 1 mRNA by in situ hybridization. These results show that eosinophils in the peripheral blood of patients with blood eosinophilia can express TGF-beta 1, but that eosinophils in the blood of normal donors contained little or no TGF-beta 1.

Adult↗

PubMed1991

Cellular sources of transforming growth factor-alpha in human oral cancer.

Aberrant expression of TGF-alpha is associated with human malignant oral epithelium. Experiments were initiated to determine the cellular sources of transforming growth factor-alpha (TGF-alpha) in human oral cancer. Ten freshly resected human oral cancers and four specimens of normal human oral epithelium were studied by in situ hybridization and immunohistochemistry. Tissues were probed with 35S-labeled sense and antisense riboprobes to (i) human TGF-alpha (hTGF-alpha), (ii) human epidermal growth factor receptor (EGFR) to determine the distribution of TGF-alpha responsive cells, and (iii) histone H3 to examine TGF-alpha and/or EGFR's possible contribution to altered proliferation in transformed epithelium. Results of our experiments showed that TGF-alpha mRNA could be detected in normal and transformed human oral epithelium. More surprising, we have identified the major source of TGF-alpha mRNA to be the infiltrating eosinophils. A monoclonal antibody to the mature human TGF-alpha peptide stained similar areas in normal and malignant specimens. Eosinophils associated with tumors exhibited positive cytoplasmic immunostaining for TGF-alpha protein. Labeling of EGFR mRNA in human oral epithelium demonstrated uniform labeling of basal layers in normal, hyperplastic, and mildly dysplastic epithelium. In severely dysplastic epithelium and carcinomas (particularly moderate to poorly differentiated types), cellular levels of EGFR mRNA were significantly higher. The profile of altered cellular levels of EGFR mRNA correlated well with the profile of altered proliferation as indicated by H3 mRNA labeling. We hypothesize that the overproduction of EGFR mRNA in tumor epithelium--together with the localized delivery of high amounts of TGF-alpha by eosinophils at tumor-developing sites--is responsible for the increased proliferation of the tumor epithelium.

Antibodies, Monoclonal↗

PubMed1991

Localization of transforming growth factor-alpha in adult Syrian hamster tissues.

Using the cheek pouch of the Syrian hamster as an experimental model for oral carcinogenesis, it has been shown that the expression of transforming growth factor-alpha (TGF-alpha) is consistently associated with the malignant transformation process. We have recently shown that production of TGF-alpha has been localized to normal hamster oral epithelium and bone marrow eosinophils. In this study we investigated the production of this cytokine in other normal hamster adult tissues. By using an EGF-radioreceptor assay, immunohistochemistry, Northern blot analysis, and in situ hybridization we have now further detected the presence of TGF-alpha mRNA and/or protein in the kidney, stomach, and pancreas of normal adult hamster. Together with the previously reported detection of TGF-alpha in oral mucosa and bone marrow eosinophils, these adult normal tissue/cellular sources can serve as sites of TGF-alpha production. The availability of hamster specific reagents (cDNA and monoclonal antibodies) and the delineation of the various adult tissues that could produce TGF-alpha make the Syrian hamster a suitable model for the study of how this multifunctional cytokine can influence normal and pathological processes.

Animals↗

PubMed1990

Human eosinophils express transforming growth factor alpha.

Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.

Adenocarcinoma↗

PubMed1990

Production of transforming growth factor alpha by hamster eosinophils.

Previously it was demonstrated that malignant transformation of the Syrian hamster cheek pouch mucosa is associated with the expression of TGF-alpha. Therefore in situ hybridization and immunohistochemistry was used to investigate the cellular sources of TGF-alpha production in this model system. Surprisingly one cell type in the inflammatory infiltrate present in the connective tissue adjacent to the transformed epithelium represented a major source of TGF-alpha mRNA. Detailed analysis of these cells revealed that they were eosinophils. In addition to TGF-alpha mRNA, about 40% of the eosinophils associated with the oral tumors exhibited TGF-alpha product reactive with a monoclonal antibody against the C terminus of the mature TGF-alpha peptide. Normal hamster bone marrow eosinophils also exhibited TGF-alpha mRNA and product by in situ hybridization and immunohistochemistry. These results suggest that the eosinophil represents a biologically significant source of TGF-alpha.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Detection of transforming growth factor-alpha messenger RNA in normal and chemically transformed hamster oral epithelium by in situ hybridization.

We have recently demonstrated the consistent detection of transforming growth factor alpha (TGF-alpha) in chemically transformed hamster oral tumors. By Northern blot analysis, no TGF-alpha mRNA can be detected in normal cheek pouch mucosa. The consistent expression of TGF-alpha associated with the malignant transformation in the well-defined hamster oral cancer model prompted us to hypothesize that the aberrant expression of this important cellular gene could be related to a specific stage of epithelial alteration. In situ hybridization was used to test this hypothesis. We now report that by in situ hybridization we can detect TGF-alpha mRNA in normal hamster oral epithelium and also at all stages of transformation. In all epithelium, labeling of TGF-alpha mRNA in the basal layer is more pronounced than that observed in the spinous and squamous layers. There is a significant increase of TGF-alpha mRNA labeling early in 7,12-dimethylbenz(a)anathracene-induced oral carcinogenesis. This increase is associated with morphological changes of epithelial hyperplasia or dysplasia. Although lesions exhibiting full-thickness epithelial dysplasia (carcinoma in situ) showed more labeling of TGF-alpha mRNA than do areas of lesser dysplasia, the transition to full-fledged papillary or invasive squamous cell carcinoma is not associated with further elevations of TGF-alpha expression.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

Detection of Ki-ras messenger RNA in normal and chemically transformed hamster oral keratinocytes.

The cheek pouch of the Syrian hamster is an excellent model for the experimental study of oral carcinogenesis. The carcinogenic chemical 7,12-dimethylbenz[a]anthracene consistently produces epidermoid carcinomas in the cheek pouch of the Syrian hamster, giving rise to characteristic histopathological lesions in a time-dependent manner. We now present experimental evidence that c-Ki-ras mRNA can be detected in all 7,12-dimethylbenz[a]anthracene-induced tumors examined (in vivo and in vitro) in this experimental oral cancer model while no detectable c-Ki-ras mRNA can be found in the normal hamster cheek pouch epithelium. Cellular synchronization experiments using a cell line (hamster cheek pouch carcinoma cell line 1) derived from one of these 7,12-dimethylbenz[a]anthracene-induced hamster oral tumors revealed that the c-Ki-ras protooncogene is expressed during the G1 phase of the cell cycle (proliferation dependent). Serum starvation and RNA synthesis inhibition experiments using hamster cheek pouch carcinoma cell line 1 cells suggest that the c-Ki-ras protooncogene is indeed quiescent in the normal hamster cheek pouch epithelium and that failure to detect its mRNA is not related to the slower proliferation of the normal epithelial cells. These results suggest that the transcription of the c-Ki-ras protooncogene is associated with malignant transformation in the cheek pouch of the Syrian hamster.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1989

TGF-alpha and EGF-receptor mRNAs in human oral cancers.

Transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) have been shown to be present in most squamous cell carcinomas. Using the Syrian hamster oral cancer model, we have recently demonstrated the consistent presence of TGF-alpha and EGFR mRNAs in chemically transformed hamster oral keratinocytes. We now present evidence that in human oral cancer (in vivo and in vitro), TGF-alpha and EGFR mRNAs can also be consistently detected. No TGF-alpha mRNA can be detected in normal human oral epithelium by Northern blot analysis. These findings reinforce the use of the hamster cheek pouch as an experimental model for the study of oral cancer development, at least in reference to the possible participation of TGF-alpha in the malignant transformation process.

Animals↗