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Role of Endogenous Endothelin‐1 in Transplant Obliterative Airway Disease in the Rat
Author(s) -
Tikkanen Jussi M.,
Koskinen Petri K.,
Lemström Karl B.
Publication year - 2004
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2004.00414.x
Subject(s) - medicine , proinflammatory cytokine , endothelin receptor , transplantation , autocrine signalling , paracrine signalling , receptor , bosentan , bronchiolitis obliterans , endothelin 1 , lung transplantation , receptor antagonist , immunology , pathology , inflammation , antagonist
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‐1β 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.