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E C LeRoy

Publications and source records attributed to E C LeRoy.

At least 73 records · Page 4Linked to original sources
PubMed1989

Adoptive transfer of tsk skin fibrosis to +/+ recipients by tsk bone marrow and spleen cells.

The tight skin mouse (Tsk/+) is an autosomal dominant example of inherited fibrosis whose pathogenesis is unclear. Autoimmune phenomena have been described previously. This study demonstrates the adoptive transfer of skin fibrosis to lethally irradiated syngeneic +/+ recipients by the transplantation of both bone marrow and spleen cells. The recipient skin fibrosis was not associated with mast cell proliferation or degranulation as it is in the tsk/+ mouse, representing for the first time a dissociation between mast cells and fibrosis and introducing the potential for direct T cell-fibroblast interactions.

Animals↗
PubMed1988

Familial clustering of scleroderma spectrum disease.

This is the second case report of familial scleroderma (systemic sclerosis) in South Carolina. The family includes two cases of scleroderma meeting American Rheumatism Association criteria, one of systemic sclerosis sine scleroderma, and two other cases of undifferentiated connective tissue disease with features of scleroderma spectrum disorders; there are also two cases of Raynaud's phenomenon (one associated with rheumatoid arthritis), for a total of seven affected relatives. Evidence of scleroderma spectrum disorders was sought in six siblings of the two co-index cases and in 23 of the 35 offspring. Laboratory studies included antinuclear antibody determinations and typing for the following genetic markers: HLA (A, B, C, DR), complotypes, Gm and Km allotypes, and alpha-1 antitrypsin phenotypes. No common genetic markers restricted to affected members of this family were found, and no environmental exposures were detected that could explain this familial clustering of cases. This report should, however, add to the slowly accumulating information on the genetic characteristics of families at unusually high risk for scleroderma spectrum disorders. Positive antinuclear antibody tests at a titer of 1/40 or higher were present in 57 percent of the first-degree relatives of the affected cases.

Adult↗
PubMed1988

Effect of lymphotoxin and tumor necrosis factor on endothelial and connective tissue cell growth and function.

In an approach to understand the immune basis of human vascular and fibrotic disorders, the effects of recombinant human tumor necrosis factor alpha (rTNF) and lymphotoxin (rLT) on the in vitro growth and function of vascular and connective tissue cells were studied. Both rTNF and rLT stimulated fibroblast growth and protein, fibronectin, and collagen synthesis in dose-dependent fashion. In contrast, endothelial cell (EC) growth was inhibited by both cytokines; true EC cytotoxicity was seen at high concentrations (greater than or equal to 500 mu/ml). Addition of recombinant interferon-gamma markedly enhanced EC cytotoxicity while the growth factor beta-transforming growth factor reversed EC growth inhibition. Both rTNF and rLT stimulated factor VIII-Ag synthesis by EC. These contrasting effects of rTNF and rLT on fibroblast and endothelial cell growth and function in vitro are intriguing because they are the same contrasting effects observed in vivo in connective tissue and vascular disorders, raising the possibility of a role for these cytokines in these disorders. Study of the in vitro and in vivo mechanisms of these diverse effects may contribute to the understanding of certain human disorders characterized by endothelial injury and fibroblast activation leading to fibrosis.

Animals↗
PubMed1988

Elevated expression of c-myc proto-oncogene in scleroderma fibroblasts.

Scleroderma is a connective tissue disease characterized by the overproduction of extracellular matrix components. The mechanisms of fibrosis may involve increased fibroblast proliferation in the scleroderma lesion due to the presence of cells with abnormal growth properties, in addition to the well-known over-production of several matrix components. The c-myc proto-oncogene has been implicated in dysregulation of cell growth in neoplastic cells and as an essential element of the response to growth factors in normal cells. Therefore, to investigate the molecular basis of growth in scleroderma, we compared expression of c-myc gene in scleroderma and control cells. In this report, we show that under low serum conditions (1% serum), scleroderma fibroblasts express 2.5-3 higher level of c-myc message. Moreover, stimulation of c-myc after addition of fresh 10% serum is blunted in scleroderma compared to control cells. Observed c-myc expression in scleroderma is similar to c-myc expression in transformed cells. In addition, there is also increased proliferation of scleroderma cells in 1% serum as measured directly by a nuclear label assay. These data suggest the presence of fibroblasts with abnormal growth properties in the scleroderma lesion.

Blotting, Southern↗
PubMed1987

TGF-beta inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression.

Transforming growth factor-beta (TGF-beta) inhibits the growth of endothelial cells derived from various sources, including human umbilical vein, bovine aorta, and rat heart. Long-term exposure of rat heart endothelial cells to TGF-beta also induces dramatic changes in morphology that are characteristic of senescent cells. These changes are accompanied by a decrease in the number of high-affinity receptors for epidermal growth factor (EGF), with almost no change in total receptor number. Additionally, the EGF-induced expression of specific competence genes (c-myc, JE, KC) is decreased, whereas the induction of c-fos gene expression by EGF is unaltered by TGF-beta treatment. These data suggest that growth inhibitors such as TGF-beta may act by altering the cell's response to growth-stimulatory factors.

Animals↗
PubMed1987

Inhibition of fibrosis in TSK mice by blocking mast cell degranulation.

The Tsk mouse has a genetically transmitted connective tissue disease whose skin lesions resemble those of scleroderma. After treatment with disodium cromoglycate, a marked decrease in skin fibrosis was observed, raising the possibility that disodium cromoglycate may be a potential treatment for human scleroderma.

Animals↗
PubMed1987

Fibroblast heterogeneity in scleroderma: Clq studies.

Fibroblast heterogeneity has been the basis of a pathogenetic theory of scleroderma in which one subpopulation of high collagen producing cells is expanded by selective growth. In studies by others using gingival cells, fibroblast membrane Clq receptor affinity correlates positively with collagen production. We have demonstrated distinctly higher amounts of Clq binding of fibroblasts from 2 patients with early scleroderma compared to late scleroderma and controls. These observations are consistent with the overgrowth of a normally occurring subpopulation of cells and provide support for clonal selection in the pathogenesis of scleroderma.

Adult↗
PubMed1986

Interstitial lung disease in scleroderma. Immune complexes in sera and bronchoalveolar lavage fluid.

Interstitial lung disease is a common feature of scleroderma (systemic sclerosis), and it may be a major determinant of morbidity and mortality. Analysis of bronchoalveolar lavage fluid from patients with scleroderma has shown evidence of inflammation in the lower respiratory tract of many patients. We have analyzed sera and bronchoalveolar lavage fluid from scleroderma patients for the presence of immune complexes, which may play a role in the inflammatory process. Using a solid-phase C1q enzyme-linked immunosorbent assay, we detected immune complexes in the sera of 6 of 23 patients (26%) and in none of 32 controls (P less than 0.01). All 6 patients with serum immune complexes had inflammatory cells in bronchoalveolar lavage fluid, and the presence of serum immune complexes correlated with the percentage of neutrophils in lavage fluid (P less than 0.02). Immune complexes were detected in lavage fluid of 11 of 21 patients (52%) compared with 1 of 7 normal controls (14%). Subjects having immune complexes in lavage fluid had a lower forced vital capacity than did those without lavage fluid immune complexes (P less than 0.05). The levels of immune complexes in bronchoalveolar lavage fluid exceeded those in serum by a mean of 45-fold, suggesting either local formation or selective deposition of immune complexes in the lower respiratory tract of some scleroderma patients.

Adult↗
PubMed1986

Prevalence of Raynaud phenomenon in the general population. A preliminary study by questionnaire.

A short questionnaire inquiring about cold sensitivity of the fingers was administered to 1752 randomly selected subjects in a probability sample drawn from the adult population of the state of South Carolina. The overall prevalence of reported cold sensitivity was approximately 10% and showed no sex or race difference. A female preponderance was revealed only after subjects exposed to vibrating tools were excluded, and then only in the white group. Estimates of the prevalence of Raynaud phenomenon were obtained using the following criteria: cold sensitive subjects reporting white and/or blue color changes: 4.6%; cold sensitivity leading to medical consultation: 3.0%; combination of the two criteria above: 1.9%.

Adolescent↗
PubMed1986

Raynaud phenomenon.

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Arterial Occlusive Diseases↗
PubMed1986

Human monocyte modulation of endothelial cells and fibroblast growth: possible mechanism for fibrosis.

Several human diseases are characterized by vascular pathology, fibroblast activation, and excessive fibrosis (e.g., scleroderma, chronic graft versus host disease, pulmonary fibrosis). An intense inflammatory exudate of mononuclear cells which are derived from the peripheral blood precedes the vascular and fibrotic changes. We examined, in vitro, the effects of human peripheral blood mononuclear cell culture supernatants (PBM-SN) on the growth and survival of human endothelial cells (EC) and of human dermal fibroblasts (FB). The same PBM-SN consistently induced inhibition of EC and stimulation of FB proliferation. PBM-SN derived from 42 patients with scleroderma induced 32 +/- 5% (mean +/- SE) more inhibition of EC and 42 +/- 18% more stimulation of FB compared with PBM-SN derived from 30 healthy subjects. Depletion of phagocytic cells or adherent cells from PBM resulted in SN with no demonstrable activity on either EC or FB. Partial purification of PBM-SN on ion exchange and gel filtration chromatography revealed the presence of two fractions that stimulated and one fraction that inhibited FB proliferation, and two fractions that inhibited and one that stimulated EC proliferation. These data suggest that monocytes are capable of releasing mediators that stimulate or suppress EC or FB. However, when activated by surface adherence, resulting SN inhibit EC and stimulate FB proliferation. Serum is required for the expression of FB proliferation.

Cell Adhesion↗
PubMed1986

Effect of scleroderma serum on human fibroblast collagen production: possible selection through proliferation.

The effects on cell proliferation and on collagen and protein synthesis of prolonged exposure of control and scleroderma skin fibroblasts to control and scleroderma serum were studied. The previously described mitogenic effect originally noted at 3 days was observed to a lesser degree at 21 days, at which time a doubling of protein synthesis and a 3-fold increase in collagen synthesis were noted. Since earlier studies of shorter exposure times did not show effects on protein or collagen synthesis, the prolonged exposure of heterogeneous mass cultures of dermal fibroblasts to the mitogenic effects of scleroderma serum may result in the emergence of high collagen producing cells.

Cell Count↗
PubMed1985

Collagen deposition in autoimmune diseases: the expanding role of the fibroblast in human fibrotic disease.

Fibrosis, usually considered an extension of the normal process of wound healing, follows to a variable degree host responses of an inflammatory nature, both immune and non-immune. The immediate mesenchymal effector cell of fibrosis, the fibroblast, has more or less been taken for granted in this process, due largely to its monotonous morphological uniformity. An emerging realization that the fibroblast can react in a variety of ways, both as an amplifying population of cells and in selective ways as the final arbiter of the extracellular matrix, is the subject of this report. This heterogeneity of fibroblast behaviour is characterized and, since many types of cells (endothelial, smooth muscle, epithelial) have now been shown to respond to matrix-derived signals, the potential for mesenchymal cell selection as a mechanism for understanding human fibrotic disease is probed. Signals which selectively alter fibroblast proliferation and fibroblast phenotypic expression are emphasized.

Aging↗
PubMed1985

Cellular immunity to collagen and laminin in scleroderma.

Peripheral blood mononuclear cells (PBMC) obtained from scleroderma patients and normal controls were cultured in the presence of types I and IV collagen, intima collagen, laminin, and phytohemagglutinin. PBMC from 9 of 19 patients (47%) demonstrated lymphocyte transformation in response to laminin, and those from 2 of 17 patients (12%) demonstrated reactivity to type IV collagen. None of the patient PBMC were responsive to type I collagen or to intima collagen. Healthy controls failed to demonstrate lymphocyte transformation in response to laminin or collagens. Analysis of clinical data, including age, disease duration, and degree of skin thickening and internal organ involvement, failed to predict the response to laminin or type IV collagen. The significance and disease specificity of this cellular immunity to laminin and, with lower frequency, to type IV collagen, that occurs in some scleroderma patients are unknown.

Adult↗
PubMed1985

Mast cells and their degranulation in the Tsk mouse model of scleroderma.

The Tsk mouse is a genetically transmitted example of cutaneous fibrosis which has been compared with human scleroderma. During a systematic histopathological study of the Tsk mouse, both an increased number and an increased proportion of degranulated mast cells were observed. The consistent association of mast cells and fibrosis in scleroderma, graft-vs-host reactions (GVHR), and now the Tsk mouse raises the question of a pathogenetic role for mast cells in fibrotic disorders in general.

Age Factors↗