- 作者：Michel White ; Bernard Cantin ; Haissam Haddad ; Jon A. Kobashigawa ; Heather Ross ; Michel Carrier ; Peter W. Pflugfelder ; Debra Isaac ; Renzo Cecere ; Lucette Whittom ; Imtiaz S. Ali ; Shao-Hua Wang ; Ying He ; Adrienne Groulx ; Rhian M. Touyz
- 关键词：biomarkers ; immunosuppression ; transplantation ; inflammation ; signal transduction
- 刊名：The Journal of Heart and Lung Transplantation
- 出版年：December, 2013
- 年：2013
- 卷：32
- 期：12
- 页码：1222-1232
- 全文大小：575 K
Background
We investigated cardiac proinflammatory, mitogenic, and apoptotic signaling events, and plasma biomarkers of inflammation and oxidative stress in de novo adult cardiac transplant (CTX) patients receiving tacrolimus (TAC) or cyclosporine A (CsA).Methods
One hundred CTX recipients were randomized 1:1 to TAC/CsA in a prospective, randomized open-label multicenter study. Biomarkers of inflammation, immunity, oxidative stress, and cardiac signaling underlying growth and inflammation (extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase, mitogen-activated protein kinase kinases [MEK] 1/2 and 3/6, c-Src), and apoptosis and survival (c-Jun NH2-terminal kinases [JNK], Bax/Bcl2, Akt) were assessed at 2, 4, 12, 26, and 52 weeks post-CTX. Plasma from healthy controls (n聽=聽30) and tissue from explanted non-failing hearts (n = 6) were used as controls.
Results
Biomarkers of inflammation/immunity (interleukin -6 and -18, soluble intercellular adhesion molecule, E-selectin, monocyte chemoattractant protein-1, osteopontin, fibrinogen, N-terminal prohormone brain natriuretic peptide, high-sensitive C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances, nitrotyrosine) were increased, and antioxidant capacity was (glutathione/glutathione disulfide) decreased in patients vs healthy controls (p < 0.05). Phosphorylation of mitogen-activated protein kinases and Akt was increased, and Bax/Bcl was decreased in transplanted vs non-transplanted hearts. Except for plasma fibrinogen, which was lower in TAC vs CsA, (p = 0.01), there were no significant differences in parameters studied between TAC vs CsA immunoprophylaxis.
Conclusions
De novo CTX recipients exhibit significant sub-clinical inflammation and oxidative stress that persists 12 months after transplantation. Associated with this is activation of myocardial growth and inflammatory signaling and decreased apoptosis. Our findings suggest that CTX is an inflammatory condition associated with oxidative stress and myocardial growth regardless of CsA or TAC immunoprophylaxis and independently of rejection status.