Levels of 5-hydroxyindoleacetic acid, indoleacetic acid and total indoles were determined in the urine of 23 patients with systemic scleroderma and 7 patients with cutaneous scleroderma, before and after peroral loading with L-tryptophan (0-1 g/kg body weight). Before loading, 5-hydroxyindoleacetic acid levels were normal in nearly all cases of systemic scleroderma as well as of cutaneous scleroderma; however after loading, in nearly one half of cases there was no normal increase of this metabolite. These results suggest impaired transformation of serotonin into 5-hydroxyindoleacetic acid. A disproportionately high ratio of total indoles to indoleacetic acid suggests the presence of excess of tryptamine. The results of the study may indicate that in scleroderma metabolism of biogenic amines derived from tryptophan is abnormal, probably as a result of impaired activity of monoamine oxidase.

Objective. Perivascular infiltrates in skin, subcutaneous tissue, and internal organs are a characteristic feature of early systemic sclerosis (SSc). We studied the first step of migration of peripheral blood mononuclear cells (PBMC) through the vessel wall to the extravascular space, i.e., adhesion of PBMC to endothelial cells (EC), in patients with various forms of SSc (limited scleroderma, diffuse scleroderma, and the transitional form).Methods. Radioisotope-labeled patient PBMC were coincubated with umbilical cord EC in vitro, and the percentage adhesion was measured.Results. Adhesion of PBMC to EC was markedly decreased, while adhesion of isolated active rosetteforming cells (ARFC) was significantly increased, in SSc patients compared with healthy controls. Decreased adhesion of PBMC to EC was found to correlate with a diminished percentage of ARFC in the peripheral blood. Preincubation of PBMC from healthy donors with interleukin-2 (IL-2) enhanced their adhesion to EC, while preincubation of PBMC from SSc patients with this cytokine resulted in a decrease in adhesion in 10 of 14 individuals. IL-1, interferon-y, and transforming growth factor p had no significant effect on adhesion of of PBMC to EC among the SSc subgroups were not significant . Conclusion.Our findings suggest that in SSc, activation of subpopulations of PBMC leads to their enhanced adhesion to vascular endothelium in vivo and to migration of these cells to the extravascular space, resulting in the elimination from the peripheral blood of those PBMC with high ability to adhere to EC.

The effects of acitretin and etretinate on angiogenesis induced in Balb/c mice by intradermal injection of keratinocyte tumor cell lines were evaluated. It was shown that both retinoids are capable of inhibiting angiogenesis evoked by a human epidermoid carcinoma cell line (A431). Acitretin, but not etretinate, inhibited also angiogenesis induced by the spontaneously transformed murine keratinocyte cell line Pam 212 and by the established tumorigenic SKv cell line harboring the HPV16 genome. We suggest that inhibition of blood vessel formation may be one of the mechanisms responsible for the anticancerogenic effect of retinoids.

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Sera from 93 patients with systemic scleroderma including incipient or prodromal acroscleroderma and from 43 healthy individuals were studied for cytotoxic effects on endothelial cells by means of three different in vitro methods. Inhibition of 3H-thymidine incorporation by endothelium was caused by about 33% of sera, almost exclusively from patients with diffuse scleroderma and the transitional form: acroscleroderma--diffuse scleroderma. An antibody-dependent cellular cytotoxicity assay revealed cytotoxicity of about 37% of sera from patients with diffuse scleroderma and the transitional form but also of a proportion of sera from patients with CREST syndrome with pronounced vascular changes. Serum cytotoxic activity, revealed by both methods, was related with more frequent involvement of muscle and kidney in the patients. A direct 51Cr release assay showed the cytotoxicity only in 4 of 68 cases in diffuse scleroderma with pronounced internal organ involvement. Thus, depending on the method used, various types of cytotoxicity could be detected in sera from patients with systemic scleroderma.