Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-kappaB and endothelin-1.
Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kappaB vasoconstrictive pathways in pulmonary hypertension. The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n = 23). NF-kappaB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA. In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p<0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kappaB pathways. Genistein restored vasodilation in subjects with an abnormal response. Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kappaB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.
Henno
P
P
UFR Biomédicale des Saints Pères, UPRES EA 4068, Paris, France.
Maurey
C
C
Danel
C
C
Bonnette
P
P
Souilamas
R
R
Stern
M
M
Delclaux
C
C
Lévy
M
M
Israël-Biet
D
D
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D014652:Vascular Diseases / Q000175:diagnosis* / Q000503:physiopathology
D019332:Endothelin-1; D016328:NF-kappa B; D019833:Genistein; D000109:Acetylcholine