T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia

Singbartl, Kai; Bockhorn, Susanne Grosse; Zarbock, Alexander; Schmolke, Mirco; Aken, Hugo Van

doi:10.1681/asn.2004050381

Cited by 31 publications

(29 citation statements)

References 37 publications

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“…Kidney MPO levels were increased in both WT and nu/nu mice after cisplatin; however, this increase was reduced in nu/nu mice. Thus, T cell-mediated phagocyte infiltration is a potential mode of action and is consistent with recent publications on the mechanisms of T cells in ischemic tissue injury (17,27). Given that recent data have demonstrated a significant role for TNF-␣ in cisplatin nephrotoxicity, we measured several cytokine/chemokine protein expressions in both cisplatin-treated nu/nu and WT mouse kidneys as potential mediators of the T cell's role in cisplatin nephrotoxicity.…”

Section: Discussionsupporting

confidence: 83%

A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity

Liu¹,

Chien²,

Burne-Taney³

et al. 2006

Journal of the American Society of Nephrology

166

151

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Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4-or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2 ؎ 0.5 versus 0.8 ؎ 0.1 mg/dl; P ‫؍‬ 0.007), kidney tubular injury (scores 1.44 ؎ 0.15 versus 0.22 ؎ 0.08; P < 0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-␣, IL-1␤, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4-and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.

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Section: Discussionsupporting

confidence: 83%

A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity

Liu¹,

Chien²,

Burne-Taney³

et al. 2006

Journal of the American Society of Nephrology

166

151

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“…The decreased TNF production observed in the T cell-deficient mice with associated protection from cisplatin nephrotoxicity is also consistent with the reported role for TNF as a mediator of cisplatin injury (18). Lymphocytes have also recently been demonstrated to mediate sepsis-induced AKI (19).…”

supporting

confidence: 84%

Immune Modulation of Acute Kidney Injury

Rabb¹

2006

Journal of the American Society of Nephrology

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“…The present study demonstrated that ICAM-1 was significantly induced in the kidney at 16 h after LPS injection and it was markedly attenuated by pretreatment of pentoxifylline. The role of ICAM in PMN accumulation has been incriminated in endotoxemic ARF (7,22,37), but ICAM-1 can moderate renal injury independent of PMN accumulation (31). Although detectable PMN accumulation has been observed at 16 h with this endotoxemic mouse model of ARF (44), other mechanisms may be involved.…”

Section: Discussionmentioning

confidence: 99%

Pentoxifylline protects against endotoxin-induced acute renal failure in mice

Wang¹,

Zolty²,

Falk³

et al. 2006

American Journal of Physiology-Renal Physiology

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. Pentoxifylline protects against endotoxin-induced acute renal failure in mice. Am J Physiol Renal Physiol 291: F1090 -F1095, 2006; doi:10.1152/ajprenal.00517.2005.-Acute renal failure (ARF) in septic patients drastically increases the mortality to 50 -80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-␣ (TNF-␣), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-␣ and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-␣ and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 Ϯ 6.6 vs. 50.2 Ϯ 6.6 l/min, P Ͻ 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-␣ (1.00 Ϯ 0.55 vs. 7.02 Ϯ 2.40 pg/ml, P Ͻ 0.05) and serum IL-1␤ (31.3 Ϯ 3.6 vs. 53.3 Ϯ 5.9 pg/ml, P Ͻ 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 Ϯ 18.0 vs. 44.5 Ϯ 16.2 l/min, P Ͻ 0.05) and renal blood flow (0.86 Ϯ 0.08 vs. 0.59 Ϯ 0.05 ml/min, P Ͻ 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 Ϯ 5.8 vs. 178.0 Ϯ 7.6 mmHg ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-␣, IL-1␤, and NO as well as a decrease in renal iNOS and ICAM-1. sepsis; tumor necrosis factor SEPSIS IS KNOWN TO OCCUR annually in 751,000 Americans and accounts for 215,000 deaths, a number equivalent to the overall deaths due to myocardial infarction (1). Moreover, sepsis is a major cause of acute renal failure (ARF) in intensive care units; sepsis-related ARF is associated with a 70 -80% mortality (33,34).Both inflammatory and vasoactive mediators are involved in the pathophysiology of sepsis-related ARF. TNF-␣ plays a central role in this process. Serum levels of TNF-␣ are induced early in endotoxemia in humans (25). Moreover, elevated serum levels of the type I and type II receptors for TNF-␣ are shown to be predictive factors for ARF in patients with septic shock (12). The role of TNF-␣ as a pathogenetic factor in experimental ARF was supported by the observation that pretreatment with a TNF-soluble receptor (TNF s R p55 ) significantly attenuated endotoxemia-related ARF (19). It has also been shown that endotoxemic ARF is caused by TNF acting directly on TNF receptor-1 in the kidney (6). TNF-␣ participates in the magnification of the response mediated by the release of other cytokines and active substan...

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T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia

Cited by 31 publications

References 37 publications

A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity

A Pathophysiologic Role for T Lymphocytes in Murine Acute Cisplatin Nephrotoxicity

Immune Modulation of Acute Kidney Injury

Pentoxifylline protects against endotoxin-induced acute renal failure in mice

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