Role of endogenous endothelin-1 in transplant obliterative airway disease in the rat.
Endothelin-1 (ET-1) expression is increased after lung transplantation in association with ischemia reperfusion injury and acute rejection. However, little is known of the role of ET-1 during the development of obliterative bronchiolitis. In this study, we investigated the biological significance of ET-1 in obliterative airway disease development using a rat tracheal allograft model. Immunoreactivity of ET-1 and its receptors ET-RA and ET-RB was increased four-fold in allografts compared with syngrafts and localized to mononuclear cells and smooth muscle cells of the myofibroproliferative lesion and airway wall, indicating that ET-1 may mediate its effects in both a paracrine and autocrine manner in smooth muscle cells. Inhibition of ET-1 action by a nonselective ET-1 receptor antagonist, bosentan, significantly decreased tracheal occlusion, which was linked to delayed epithelial necrosis, suppressed smooth muscle cell proliferation, and a marked reduction in the number of interleukin-1beta and interleukin-2 immunoreactive cells. Our findings show that endogenous ET-1 activation is associated with obliteration of the airway wall, and blocking signaling downstream of ET-1 receptors leads to attenuation of obliterative airway disease. The results suggest that ET-1 has a proproliferative and proinflammatory role in the development of obliterative bronchiolitis.
Tikkanen
Jussi M
JM
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. jussi.tikkanen@helsinki.fi
Koskinen
Petri K
PK
Lemström
Karl B
KB
D000402:Airway Obstruction / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D001989:Bronchiolitis Obliterans / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016040:Lung Transplantation; D008297:Male; D051381:Rats; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000637:transplantation
D000959:Antihypertensive Agents; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan