Shappell S B, Gurpinar T, Lechago J, Suki W N, Truong L D
Department of Pathology, Methodist Hospital, Houston, TX 77030, USA.
J Am Soc Nephrol. 1998 Jun;9(6):1008-17. doi: 10.1681/ASN.V961008.
Progressive renal injury in humans and experimental animal models is characterized by tubular atrophy, infiltration of mononuclear inflammatory cells, and interstitial fibrosis. Permanent unilateral ureter ligation represents a reproducible model for investigating mechanisms of progressive kidney injury, and in the rat is characterized by tubular epithelial cell proliferation followed by apoptosis and progressive infiltration of monocytes and lymphocytes. Nevertheless, whether monocytes or lymphocytes play a dominant role in causing tubulointerstitial damage remains to be elucidated. In the current study, a model of chronic obstructive uropathy in the mouse is established and the role of lymphocyte infiltration in the evolution of the tubule and interstitial alterations is investigated. Permanent ligation of the left ureter in wild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 30-d period. Immunoperoxidase studies on frozen sections taken from kidneys at 0, 3, 10, 20, and 30 d after ureter ligation showed that the tubulointerstitial injury was accompanied by a marked and progressive increase in interstitial macrophages and T lymphocytes, with no appreciable increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same time frame. The significance of T lymphocyte infiltration was examined by comparing the degree of tubular atrophy and interstitial fibrosis and the nature and quantity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Scid/J (SCID) mice subjected to permanent left ureter ligation. SCID mice have genetic defects in immunoglobulin and T cell receptor gene rearrangements and are devoid of circulating mature B and T lymphocytes. Wild-type and SCID mice developed tubular atrophy and interstitial volume expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage infiltrate in the ligated kidney, which was essentially equal to that in wild-type mice. In contrast, consistent with the known absence of mature lymphocytes in SCID mice, there was essentially no T lymphocyte infiltration into the ligated kidney of SCID mice. These results demonstrate the effective establishment of the model of maintained unilateral ureter ligation in mice, which is readily applicable to genetic mutant strains thus allowing for specific investigation of the role of individual components of the inflammatory response in progressive tubulointerstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and increased interstitial fibrosis after maintained unilateral ureter ligation.
人类和实验动物模型中的进行性肾损伤的特征为肾小管萎缩、单核炎性细胞浸润和间质纤维化。永久性单侧输尿管结扎是一种用于研究进行性肾损伤机制的可重复模型，在大鼠中其特征为肾小管上皮细胞增殖，随后发生凋亡以及单核细胞和淋巴细胞的进行性浸润。然而，单核细胞或淋巴细胞在导致肾小管间质损伤中是否起主导作用仍有待阐明。在本研究中，建立了小鼠慢性梗阻性尿路病模型，并研究了淋巴细胞浸润在肾小管和间质改变演变过程中的作用。与对侧肾脏相比，野生型（C3H/HeJ）小鼠左侧输尿管的永久性结扎在30天内导致肾小管进行性萎缩和间质纤维化。对输尿管结扎后0、3、10、20和30天取自肾脏的冰冻切片进行免疫过氧化物酶研究显示，肾小管间质损伤伴随着间质巨噬细胞和T淋巴细胞显著且进行性增加，而B淋巴细胞没有明显增加。在同一时间范围内，对侧肾脏未检测到炎性细胞增加。通过比较野生型小鼠和接受永久性左侧输尿管结扎的C3HSMn.C-Scid/J（SCID）小鼠的肾小管萎缩程度、间质纤维化程度以及炎性浸润的性质和数量，研究了T淋巴细胞浸润的意义。SCID小鼠在免疫球蛋白和T细胞受体基因重排方面存在遗传缺陷，缺乏循环成熟的B和T淋巴细胞。野生型和SCID小鼠结扎肾脏中的肾小管萎缩和间质容积扩大程度相同、速率相同。SCID小鼠结扎肾脏中出现显著的单核细胞/巨噬细胞浸润，其程度与野生型小鼠基本相同。相比之下，与已知SCID小鼠缺乏成熟淋巴细胞一致，SCID小鼠结扎肾脏中基本没有T淋巴细胞浸润。这些结果证明成功建立了小鼠持续性单侧输尿管结扎模型，该模型易于应用于基因变异株，从而能够特异性研究炎症反应的各个成分在进行性肾小管间质损伤中的作用。这些研究进一步证明，持续性单侧输尿管结扎后进行性肾小管萎缩和间质纤维化增加并不需要淋巴细胞浸润。
