Ysebaert Dirk K, De Greef Kathleen E, Vercauteren Sven R, Verhulst Anja, Kockx Marc, Verpooten Gert A, De Broe Marc E
Department of Experimental Surgery, University of Antwerp, Belgium.
Kidney Int. 2003 Sep;64(3):864-73. doi: 10.1046/j.1523-1755.2003.00150.x.
Post-ischemia/reperfusion (I/R) damage, accompanied by leukocyte infiltration, is unavoidable in renal transplantation, as is the need for immunosuppressive treatment. Influence of immunosuppressive treatment on post-I/R renal damage, nonalloimmune cellular infiltration, and regeneration is not well studied.
Uninephrectomized inbred LEW rats were submitted to warm renal ischemia of 45 minutes/60 minutes, and received different immunosuppressive regimens: cyclosporine (CsA) 10 mg/kg/day subcutaneously in the neck daily, or mycophenolate mofetil (MMF) 20 mg/kg/day by daily oral gavage. Control animals underwent sham operation (unilateral nephrectomy) with immunosuppressive treatment or ischemia with vehicle administration. In addition the effect of MMF/mycophenolic acid (MPA) on renal tubule cell proliferation in culture was studied with bromodeoxyuridine incorporation.
The post-I/R interstitial cellular infiltration/proliferation consisted mainly of mononuclear leukocytes [first monocytes/macrophages (Mo/MPhi) followed by CD4+ cells]. This mononuclear cell infiltration became apparent 24 hours after injury at the time of acute tubular necrosis, and was most prominent during the phase of regeneration. Severe I/R combined with CsA aggravated morphologic damage and dysfunction, without effect on tubular cell proliferation and tubular regeneration. Early leukocyte infiltration was qualitatively and quantitatively comparable to control animals, yet decreased moderately later in time. In contrast, MMF in combination with severe I/R did not influence initial morphologic damage and dysfunction. Although the initial leukocyte infiltration was comparable to control animals, the subsequent mononuclear cell accumulation, especially CD4 T cells decreased dramatically during MMF treatment. This was concomitant with a decrease of tubular cell proliferation and hence tubular regeneration. Increasing MPA concentrations in renal tubular cell culture caused a significant decrease in total cell number, and an almost arrest of bromodeoxyuridine incorporation, as measurement of cell proliferation.
Immunosuppressive treatment with CsA or MMF affected significantly and in a different manner post-I/R renal morphologic damage, interstitial leukocyte, accumulation and regeneration.
缺血/再灌注（I/R）损伤伴有白细胞浸润，在肾移植中不可避免，免疫抑制治疗也同样必要。免疫抑制治疗对I/R后肾损伤、非同种免疫细胞浸润及再生的影响尚未得到充分研究。
对切除一侧肾脏的近交系LEW大鼠进行45分钟/60分钟的热缺血处理，并给予不同的免疫抑制方案：环孢素（CsA）10毫克/千克/天，每日颈部皮下注射；或霉酚酸酯（MMF）20毫克/千克/天，每日经口灌胃。对照动物接受假手术（单侧肾切除术）并进行免疫抑制治疗，或接受缺血处理并给予赋形剂。此外，通过溴脱氧尿苷掺入法研究了MMF/霉酚酸（MPA）对培养的肾小管细胞增殖的影响。
I/R后的间质细胞浸润/增殖主要由单核白细胞组成[首先是单核细胞/巨噬细胞（Mo/MPhi），随后是CD4+细胞]。这种单核细胞浸润在急性肾小管坏死时损伤后24小时变得明显，并在再生阶段最为突出。严重I/R联合CsA加重了形态学损伤和功能障碍，但对肾小管细胞增殖和肾小管再生无影响。早期白细胞浸润在定性和定量上与对照动物相当，但在后期适度减少。相比之下，MMF联合严重I/R并不影响初始形态学损伤和功能障碍。虽然初始白细胞浸润与对照动物相当，但在MMF治疗期间，随后的单核细胞积聚，尤其是CD4 T细胞显著减少。这与肾小管细胞增殖减少以及肾小管再生减少同时发生。在肾小管细胞培养中增加MPA浓度导致总细胞数显著减少，并且作为细胞增殖测量指标的溴脱氧尿苷掺入几乎停止。
CsA或MMF免疫抑制治疗对I/R后肾形态学损伤、间质白细胞积聚和再生有显著且不同的影响。
