Endothelial cell apoptosis in chronically obstructed and reperfused pulmonary artery.
BACKGROUND
Endothelial dysfunction is a major complication of pulmonary endarterectomy (PTE) that can lead to pulmonary edema and persistent pulmonary hypertension. We hypothesized that endothelial dysfunction is related to increased endothelial-cell (EC) death.


METHODS
In piglets, the left pulmonary artery (PA) was ligated to induce lung ischemia then reimplanted into the main PA to reperfuse the lung. Animals sacrificed 5 weeks after ligation (n = 5), 2 days after reperfusion (n = 5), or 5 weeks after reperfusion (n = 5) were compared to a sham-operated group (n = 5). PA vasoreactivity was studied and eNOS assayed. EC apoptosis was assessed by TUNEL in the proximal and distal PA and by caspase-3 activity assay in the proximal PA. Gene expression of pro-apoptotic factors (thrombospondin-1 (Thsp-1) and plasminogen activator inhibitor 1 (PAI-1)) and anti-apoptotic factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was investigated by QRT-PCR.


RESULTS
Endothelium-dependent relaxation was altered 5 weeks after ligation (p = 0.04). The alterations were exacerbated 2 days after reperfusion (p = 0.002) but recovered within 5 weeks after reperfusion. EC apoptosis was increased 5 weeks after PA ligation (p = 0.02), increased further within 2 days after reperfusion (p < 0.0001), and returned to normal within 5 weeks after reperfusion. Whereas VEGF and bFGF expressions remained unchanged, TSP and PAI-1 expressions peaked 5 weeks after ligation (p = 0.001) and returned to normal within 2 days after reperfusion.


CONCLUSIONS
Chronic lung ischemia induces over-expression of pro-apoptotic factors. Lung reperfusion is followed by a dramatic transient increase in EC death that may explain the development of endothelial dysfunction after PE. Anti-apoptotic agents may hold considerable potential for preventing postoperative complications.
Sage
Edouard
E
UPRES EA2705, Laboratoire de Chirurgie Expérimentale, Hôpital Marie Lannelongue, Le Plessis Robinson, France. edouardsage@yahoo.fr
Mercier
Olaf
O
Van den Eyden
Frederic
F
de Perrot
Marc
M
Barlier-Mur
Anne Marie
AM
Dartevelle
Philippe
P
Eddahibi
Saadia
S
Herve
Philippe
P
Fadel
Elie
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D004691:Endarterectomy / Q000009:adverse effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology* / Q000601:surgery; D011897:Random Allocation; D012016:Reference Values; D015427:Reperfusion Injury / Q000209:etiology / Q000473:pathology*; D013552:Swine
D016166:Free Radical Scavengers; D010431:Pentoxifylline