Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis
Interleukin 10 gene transfection of donor lungs ameliorates posttransplant cell death by a switch from cellular necrosis to apoptosis
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DOI：
10.1016/s0022-5223(03)00114-4
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发表时间：
2003-10-01
影响因子：
6
通讯作者：
Keshavjee, S
中科院分区：
文献类型：
--
作者：
Fischer, S;de Perrot, M;Keshavjee, S
背景资料：我们以前已经表明，细胞死亡是缺血再灌注的病理生理后果，白细胞介素-10基因治疗可改善移植肺的功能。白细胞介素-10下调炎症反应并可抑制细胞凋亡。目的是确定供体肺转染白细胞介素-10基因是否通过减少移植后细胞死亡而改善肺功能障碍。方法：在3组大鼠中进行单肺移植（每组n = 5）：AdhIL-10，经气管给予Ad 5E 1 RSVhIL-10（5 × 10（9）pfu）; EV，空载体;和VD，载体稀释液（3%蔗糖）。体内转染后，切除供体肺，在4 ℃下保存24小时，然后移植。再灌注2小时后，用台盼蓝冲洗肺并固定。TUNEL法检测细胞凋亡。结果：白细胞介素-10组（P = 0.0001）的肺功能上级EV和VD组（Pao（2）：分别为240 +/- 31 mm Hg vs 98 +/- 17 mm Hg vs 129 +/- 11 mm Hg）。虽然死亡细胞的总数（以总细胞的百分比计）在所有组中相似（32.7% +/-3.2%，30.2% +/-2.5%和30.3% +/- 3.8%），有趣的是，细胞凋亡在白细胞介素-10肺中最高（9.7 ± 1.9 vs 2 ± 1.9和1.8 ± 2，P = .0001），白细胞介素-10组坏死最少（20.6 ± 5.7 vs 28.3 ± 3.1和30.3 ± 4.2，P = .01）。结论：AdhIL-10基因转染可改善移植肺功能。虽然移植过程中死亡的细胞总数没有改变，但细胞死亡的方式似乎已经改变。AdhIL-10可能通过减少促炎性细胞因子的产生，改善整体损伤，并保持受损细胞的能力，使其经历更静止和更少的组织损伤模式的细胞死亡-凋亡，而不是坏死。
Background: We have previously shown that cell death is a pathophysiologic consequence of ischemia-reperfusion and that interleukin-10 gene therapy improves the function of transplanted lungs. Interleukin-10 downregulates the inflammatory response and can inhibit apoptosis. The objective was to determine whether donor lung transfection with the interleukin-10 gene ameliorates lung dysfunction by decreasing cell death after transplantation.Methods: Single lung transplants were performed in 3 groups of rats (n = 5 each): AdhIL-10, transtracheal administration of Ad5E1RSVhIL-10 (5 X 10(9) pfu); EV, empty vector; and VD, vector diluent (3% sucrose). After in vivo transfection, donor lungs were excised, stored at 4degreesC for 24 hours, and then transplanted. After 2 hours of reperfusion, lungs were flushed with trypan blue and fixed. TUNEL staining was used for the detection of apoptosis. This combined staining technique allows one to determine the mode of cell death by distinguishing apoptotic dead cells from necrotic dead cells.Results: Lung function was superior in the interleukin-10 group (P = .0001) vs the EV and VD group (Pao(2): 240 +/- 31 mm Hg vs 98 +/- 17 mm Hg vs 129 +/- 11 mm Hg, respectively). Although the total number of dead cells (as percent of total cells) was similar in all groups (32.7% +/- 3.2%, 30.2% +/- 2.5%, and 30.3% +/- 3.8%), interestingly, apoptosis was highest in interieukin-10 lungs (9.7 +/- 1.9 vs 2 +/- 1.9 and 1.8 +/- 2, P = .0001), and necrosis was lowest in the interleukin-10 group (20.6 +/- 5.7 vs 28.3 +/- 3.1 and 30.3 +/- 4.2, P = .01).Conclusions: AdhIL-10 gene transfection improves function of transplanted lungs. Although the total number of cells dying as a result of the transplant process did not change, the mode of cell death appears to have been modified. It is possible that AdhIL-10, by decreasing proinflammatory cytokine production, ameliorates the overall injury and preserves the ability of damaged cells to undergo a more quiescent and less tissue-damaging mode of cell death-apoptosis, rather than necrosis.