endothelin-1 and Sarcoidosis

Sarcoidosis is a chronic inflammatory disease, characterized by granulomatous inflammation, prominently involving the respiratory system. The etiology of this disease has not yet been elucidated and the contribution of genetic is not yet completely understood. We searched for novel candidate genes, utilizing a system biology approach, based on data from published transcriptional, proteomic and linkage studies of sarcoidosis. The search revealed several new potential candidate genes involved in the pathogenesis of inflammatory lung diseases: 25-(OH)-vitamin D(3)-1alpha-hydroxylase (CYP27B1), endothelin-1 (EDN1) and glutathione S-transferase Pi (GSTP1). Variants of selected polymorphisms: -1260/ C>A in CYP27B1, Lys198Asn in EDN1, and Ile105Val in GSTP1, were examined to determine if they confer susceptibility to sarcoidosis, based on an analysis of 180 Slovenian patients in comparison with 283 healthy controls. Polymerase chain reactions using allele-specific oligonucleotides were performed. This disease was not significantly associated with genotypes CC at -1260/ C>A polymorphism in CYP27B1 (P = 0.68, odds ratio (OR) = 1.10, 95% confidence interval (CI) = 0.75-1.61), GG genotype at Lys198Asn polymorphism in EDN1 (P = 1.00, OR = 0.97, 95%CI = 0.65-1.44) and AA genotypes at Ile105Val polymorphism in GSTP1 (P = 0.53, OR = 0.87, 95%CI = 0.60-1.27). There was no association of polymorphisms in any of the genes with sarcoidosis.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Adult; Endothelin-1; Female; Genetic Predisposition to Disease; Glutathione S-Transferase pi; Humans; Immunity; Male; Middle Aged; Polymorphism, Genetic; Sarcoidosis; Slovenia

Sarcoidosis is a chronic systemic disease, characterized by an imbalance of immunity processes and the presence of granuloma. Endothelin-1, a new vasoactive and bronchoconstrictive peptide, is a powerful mitogen for smooth muscle cells and fibroblasts and plays a role in the inflammation state. We postulate that endothelin-1 has a role in sarcoidosis.. We studied the behaviour of circulating levels of endothelin-1 in 20 patients with sarcoidosis and its correlation with some biochemical parameters of activity disease, such as erythrocyte sedimentation rate (ESR) and serum angiotensin-converting enzyme (SACE). We measured serum levels of ESR, SACE, calcium and plasma endothelin-1 levels in all patients at the beginning of the study and one again in 9 patients with clinical-biochemical remission of disease after steroid treatment.. In patients with sarcoidosis, circulating levels of endothelin-1, SACE and ESR were significantly higher (p<0.001) than those of healthy subjects. Moreover, in patients with pulmonary involvement, there was a significant statistical difference (p<0.001) between endothelin-1 levels and radiological stage compared to normal subjects. In the 9 patients with remission of disease, both endothelin-1 levels and parameters of activity disease normalized.. Our results seem to suggest that the increase of plasma endothelin-1 levels in active sarcoidosis can represent an expression of the endothelial dysfunction and reflect the picture of cellular activation.

Topics: Adrenal Cortex Hormones; Adult; Blood Sedimentation; Calcium; Endothelin-1; Endothelium, Vascular; Female; Humans; Lung Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Sarcoidosis

Endothelin-1 (ET-1) is a potent constrictor and mitogen peptide which is expressed in several pulmonary diseases. To elucidate the involvement of ET-1 in lung interstitial pathologic events, we assessed ET-1 secretion by alveolar macrophages (AM) and fibroblasts recovered from the bronchoalveolar lavage (BAL) of patients with idiopathic pulmonary fibrosis (IPF), sarcoidosis (SA) and from control subjects. We characterized in vitro alveolar fibroblasts of all subjects using monoclonal antibody specific to alpha-smooth muscle actin (alpha-SM actin) and human fibroblast marker. We also examined the effect of ET-1 on the fibroblasts' mitogenesis and on their cytoskeletal phenotype. The AM recovered from IPF patients showed increased spontaneous secretion of ET-1 compared with cells from SA and control subjects. The expression of alpha-SM actin in the fibroblasts from IPF patients was significantly higher than in SA fibroblasts and normal lung fibroblasts. Assessing alveolar fibroblasts purity revealed a negative staining for alpha-SM actin in all SA and control fibroblasts, while alveolar fibroblasts recovered from IPF were 100% positive for alpha-SM actin, a reliable differentiation marker of myofibroblastic cells. Exposure of SA alveolar fibroblasts to ET-1 resulted in an increased expression of alpha-SM actin. Addition of exogenous ET-1 to alveolar fibroblasts culture stimulated DNA synthesis and proliferation in all groups. Moreover, neutralization of ET-1 by monoclonal antibody was shown to decrease 3H-thymidine incorporation in fibroblasts cultured with AM supernatants. These results suggest possible interactions between AM, myofibroblasts and fibroblasts in interstitial lung diseases (ILD). By modulating alpha-SM actin expression and exertion of the mitogenic effect on alveolar fibroblasts, ET-1 might play an important role in the fibrogenesis of ILD.

Topics: Actins; Adult; Aged; Bronchoalveolar Lavage Fluid; Cell Division; Cells, Cultured; Endothelin-1; Female; Fibroblasts; Humans; Male; Middle Aged; Mitogens; Muscle, Smooth; Pulmonary Fibrosis; Sarcoidosis