Abstract
BackgroundEndothelial 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.MethodsIn 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.ResultsEndothelium-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.ConclusionChronic 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.
Highlights
Endothelial dysfunction is a major complication of pulmonary endarterectomy (PTE) that can lead to pulmonary edema and persistent pulmonary hypertension
PTE is associated with two major complications, persistent pulmonary hypertension and acute pulmonary edema, both of which can be related to endothelial cell (EC) dysfunction [4,5,6]
We investigated whether chronic pulmonary artery (PA) obstruction followed by reperfusion in piglets altered EC function and pulmonary vascular reactivity and/or EC apoptosis
Summary
Endothelial dysfunction is a major complication of pulmonary endarterectomy (PTE) that can lead to pulmonary edema and persistent pulmonary hypertension. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for patients with CTEPH, as it restores perfusion to previously occluded zones and normalizes pulmonary vascular resistance [2]. PTE is associated with two major complications, persistent pulmonary hypertension and acute pulmonary edema, both of which can be related to endothelial cell (EC) dysfunction [4,5,6]. Acute lung ischemia and reperfusion induced apoptosis in over 30% of parenchymal lung cells in humans and animal models after lung transplantation [9,10]. Increased apoptosis may contribute substantially to the development of many of the adverse events seen after PTE, most notably pulmonary edema and persistent pulmonary hypertension
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