Endothelin and endothelin‐converting‐enzyme‐1 in inflammatory neuropathies: an immunohistological study

Endothelin (ET), a vasoconstrictive peptide, has a role in different biological processes. The isoform ET1, the most active in inflammation, is expressed by endothelial and glial cells, macrophages, leukocytes, fibroblasts and myocardiocytes. ET1 works as pro-inflammatory cytokine in infectious vasculitis and myocarditis, and experimental myocardial infarction where antagonists of ET-receptors are effective. Endothelin-Converting-Enzyme-1 (ECE1), a zinc-dependent metalloprotease, cleaves inactive precursors into mature ETs. ECE1 up-regulation has been shown in experimental hypoglossal nerve axotomy and diabetic neuropathy. Interactions among cytokines, active mediators and matrix metalloproteases are currently being investigated in inflammatory neuropathies. We carried out immunohistochemical analysis of ET1 and ECE1 on sural nerves from nine patients with peripheral nerve vasculitis (NV), CIDP and CIDP-diabetic neuropathy. NVs showed a clear ET1 up-regulation on vessel walls of endoneurium and epineurium, notably in smooth muscle cells, and in inflammatory cells. ECE1 was expressed by endoneurial macrophages and Schwann cells. Both immunolocalizations were weaker in CIDP specimens, whereas CIDP-diabetic neuropathy showed an intermediate pattern. Endothelin system may have a dual role in NV, as a vasoconstrictive agent contributing to fascicle ischaemia and as a pro-inflammatory cytokine. Highest ECE1 expression in fascicles with severe axonal loss is possibly also due to its wider peptidase activity. In CIDP-diabetic neuropathy, up-regulation of ET1 and ECE1 is likely to depend on increase of ET-receptors induced by hyperglycaemia.