Endothelin-1 receptor antagonists prevent the development of pulmonary emphysema in rats.
We hypothesised that endothelin (ET)-1 plays an important role in the pathogenesis of emphysema. We attempted to apply ET-1 receptor antagonists to demonstrate and further elucidate the molecular pathogenesis pathways through which ET-1 may cause emphysematous changes. Sprague-Dawley rats were divided into four groups: control, cigarette smoke extract (CSE), CSE+BQ-123 (a selective endothelin receptor type A (ET(A)) antagonist) and CSE+bosentan (a mixed ET(A)/ET(B) receptor antagonist). The CSE was injected intraperitoneally once a week for 3 weeks, and BQ-123 or bosentan was administered daily for the same duration. The expression of ET(A) receptor, apoptosis index, caspase-3 activity, matrix metalloproteinase (MMP)-2 and MMP-9 activity, and tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations were measured in the lung tissue. The ET-1 levels and antioxidant activity were measured in the serum. Both BQ-123 and bosentan prevented the development of CSE-induced emphysema, blocked the expression of ET(A) receptor, inhibited pulmonary apoptosis, inactivated MMP-2 and MMP-9 activities in the lung tissues, reduced the concentrations of inflammatory cytokines TNF-alpha and IL-1beta, and improved the biological antioxidant activity in the serum. Emphysema development is suppressed by ET-1 receptor antagonists. ET-1 may cause emphysematous changes through molecular pathogenesis pathways involving apoptosis, proteinase and antiproteinase imbalance, inflammation and oxidative stress.
Chen
Y
Y
First Dept of Medicine, Shinshu University School of Medicine, Asahi, Matsumoto, Japan.
Hanaoka
M
M
Droma
Y
Y
Chen
P
P
Voelkel
N F
NF
Kubo
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D015153:Blotting, Western; D000077300:Bosentan; D053148:Caspase 3 / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D013449:Sulfonamides / Q000494:pharmacology*
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C505410:Casp3 protein, rat; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)