Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis
Persistent rejection of peritubular capillaries and tubules is associated with progressive interstitial fibrosis
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DOI：
10.1046/j.1523-1755.2002.00309.x
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发表时间：
2002-05-01
影响因子：
19.6
通讯作者：
Colvin, RB
中科院分区：
文献类型：
--
作者：
Shimizu, A;Yamada, K;Colvin, RB
背景资料。我们曾报道，大剂量环孢素A治疗胸腺切除的小型猪的主要组织相容性复合体(MHC-I类不相合的同种异体肾移植)12天的疗程会导致一过性急性排斥，随后是慢性排斥(进展组)或移植物接受(恢复组)。在这里，我们研究了两组患者肾小管周围毛细血管(PTCs)和肾小管的不同特征，以阐明慢性排斥反应中进行性间质纤维化的发病机制。对两组患者的连续肾活检(0-100天)进行形态计量学和免疫组织化学研究，重点观察细胞浸润性病变、PTCs和肾小管的排斥反应、肌成纤维细胞积聚和进行性间质纤维化。进展组在第8天发生急性排斥反应，在第100天进展为慢性排斥反应，并伴有间质纤维化。与CD3+细胞浸润相关的PTC内皮细胞和肾小管上皮细胞死亡明显，由缺口末端标记(TUNEL)证实，从第8天开始，此后一直持续。在急性排斥反应中，PTCs和小管的破坏伴随着基底膜(BM)的破坏，并伴有毛细管炎或小管炎，在细胞浸润性较强的区域。在慢性排斥反应的发展过程中，PTCs的毛细管炎和小管炎持续到100d，并伴有持续的T细胞浸润，其余的PTCs和小管呈进行性萎缩，并伴有BM增厚和/或板层。在第100天，间质纤维化区可辨认的PTC和小管丢失。增殖(增殖细胞核抗原+)α-肌动蛋白+肌成纤维细胞聚集在PTCs、小管和间质周围，并在第100天发展为广泛的间质纤维化。相反，在恢复组，根据急性排斥反应的解决，受损的PTCs和小管在100d恢复，100d时PTCs和小管明显减少，间质纤维化也很少。针对PTCs和小管的持续性排斥反应和肌成纤维细胞的增殖是慢性排斥反应中进行性间质纤维化的显著特征，可能是其发病机制中的关键事件。
Background. We have reported that a 12-day course of high dose cyclosporine A treatment in thymectomized miniature swine with major histocompatibility complex (MHC class I-mismatched renal allografts results in transient acute rejection followed by either in chronic rejection (progression group) or graft acceptance (recovery group). Here, we examined the differential features between both groups in the peritubular capillaries (PTCs) and tubules to clarify the pathogenesis of the progressive interstitial fibrosis in chronic rejection.Methods. Morphometric and immunohistochemical studies were performed on serial renal biopsies (days 0 to 100) obtained from both groups, focusing on the cellular infiltrate, rejection of PTCs and tubules, myofibroblast accumulation, and progressive interstitial fibrosis.Results. In the progression group, acute rejection occurred by day 8 and progressed to chronic rejection by day 100, with the development of interstitial fibrosis. PTC endothelial cell and tubular epithelial cell death associated with CD3+ cell infiltration was evident, confirmed by nick end-labeling (TUNEL), commencing by day 8 and continuing thereafter. In acute rejection, destruction of PTCs and tubules accompanied by disruption of basement membrane (BM) occurred with capillaritis or tubulitis in areas with a severe cellular infiltrate. During the development of chronic rejection, capillaritis of PTCs and tubulitis continued by day 100, accompanied by persistent T cell infiltration, and the remaining PTCs and tubules exhibited progressive atrophy with thickening and/or lamination of BM. On day 100, identifiable PTCs and tubules were lost in areas of interstitial fibrosis. Proliferating (PCNA+) alpha-actin+ myofibroblasts accumulated around PTCs, tubules and in interstitium, and widespread interstitial fibrosis developed by day 100. In contrast, in the recovery group, injured PTCs and tubules recovered by day 100 based on the resolution of acute rejection, and minimal loss of PTCs and tubules was evident by day 100 with minimal interstitial fibrosis.Conclusions. Persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts are prominent features in the progressive interstitial fibrosis in chronic rejection, and are probably key events in its pathogenesis.