ELEVATED EXPRESSION OF ENDOTHELIN-1 AND ENDOTHELIN-CONVERTING ENZYME-1 IN IDIOPATHIC PULMONARY FIBROSIS - POSSIBLE INVOLVEMENT OF PROINFLAMMATORY CYTOKINES
D. Saleh et al., ELEVATED EXPRESSION OF ENDOTHELIN-1 AND ENDOTHELIN-CONVERTING ENZYME-1 IN IDIOPATHIC PULMONARY FIBROSIS - POSSIBLE INVOLVEMENT OF PROINFLAMMATORY CYTOKINES, American journal of respiratory cell and molecular biology, 16(2), 1997, pp. 187-193
Endothelin-1 (ET-1) is a vasoconstrictor, bronchoconstrictor, and mito
genic peptide which is enzymatically converted from a biologically ina
ctive big ET to mature ET (21 amino acid) by the ET-converting enzyme
(ECE). Here, we investigate the expression of ECE-1, big ET-1, and ET-
1 in the lungs of patients with idiopathic pulmonary fibrosis (IPF) an
d compare it to those of normal subjects using immunohistochemistry an
d in situ hybridization. In normal lungs, focal moderate expression of
all three molecules is localized to airway epithelium, pulmonary endo
thelium, and airway and vascular smooth muscle cells. Serous bronchial
glands also expressed ET-1 and ECE-1. In IPF, strong diffuse expressi
on of ECE-I was seen in airway epithelium, proliferating type II pneum
ocytes, and in endothelial and inflammatory cells. ECE-1 immunostainin
g was colocalized to big ET-1 and ET-1 immunostaining, and correlated
with disease activity (P < 0.05). To study regulatory mechanisms of ET
-1 and ECE-1 expression, human normal bronchial epithelial (NBE) cells
were treated with cytokines and analyzed by radioimmunoassay and Nort
hern blot. Incubation of human NBE cells with IL-1 alpha and -beta or
tumor necrosis factor alpha (TNF alpha) resulted in a significant incr
ease in ET-1 release and mRNA expression. TNF alpha resulted in a sign
ificant increase in ECE-1 mRNA expression. These findings demonstrated
the colocalization of the precursor and active ET-1, and ECE-1 in the
same cell, and that ECE-1 expression is elevated in IPF In addition,
increased expression of ET-1 and ECE-1 in IPF may be mediated by proin
flammatory cytokines.