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      Influence of TH1/TH2 Switched Immune Response on Renal Ischemia-Reperfusion Injury

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          Background/Aims: Recent evidence shows a critical role of the CD4+ T cell with the Th1/Th2 paradigm as a possible effector mechanism in ischemia and reperfusion injury. We hypothesize that a polarized Th1 activation response may negatively influence the renal IRI through its relationship with chemokine production (MCP-1) and with a protective tissue response (HO-1). Methods: We subjected mice to renal ischemia for 45 min using IL-4 and IL-12 knockout C57BL/6. We then measured serum urea levels, performed histomorphometric analysis for tubular necrosis and regeneration, and evaluated the mRNA expression of HO-1, t-bet, Gata-3 and MCP-1 by real-time PCR at 24, 48 and 120 h after surgery. Results/Conclusions: The IL-4 knockout mice had a statistically significant rise in serum urea levels post IRI compared with control animals. The IL-12-deficient mice were not affected. The IL-4-deficient mice had a statistically significant increase in tubular injury and impairment in cell regeneration. The IRI in IL-4-deficient mice was accompanied by higher levels of HO-1, t-bet and later up-regulation of MCP-1. These findings suggest that the deleterious effects of the Th1 cell involve increased production of chemokines such as MCP-1.

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          Most cited references 34

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          Ischemic acute renal failure: an inflammatory disease?

          Inflammation plays a major role in the pathophysiology of acute renal failure resulting from ischemia. In this review, we discuss the contribution of endothelial and epithelial cells and leukocytes to this inflammatory response. The roles of cytokines/chemokines in the injury and recovery phase are reviewed. The ability of the mouse kidney to be protected by prior exposure to ischemia or urinary tract obstruction is discussed as a potential model to emulate as we search for pharmacologic agents that will serve to protect the kidney against injury. Understanding the inflammatory response prevalent in ischemic kidney injury will facilitate identification of molecular targets for therapeutic intervention.
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            Heme oxygenase-1 expression inhibits dendritic cell maturation and proinflammatory function but conserves IL-10 expression.

            Heme oxygenase-1 (HO-1) is an intracellular enzyme that degrades heme and inhibits immune responses and inflammation in vivo. In most cell types, HO-1 is inducible by inflammatory stimuli and oxidative stress. Here we demonstrate that human monocyte-derived immature dendritic cells (iDCs) and several but not all freshly isolated rat splenic DC subsets and rat bone marrow-derived iDCs, spontaneously express HO-1. HO-1 expression drastically decreases during human and rat DC maturation induced in vitro. In human tissues, iDCs also express HO-1, whereas mature DCs do not. Induction of HO-1 expression with cobalt protoporphyrin (CoPP) in human and rat DCs inhibits lipopolysaccharide (LPS)-induced phenotypic maturation and secretion of proinflammatory cytokines, resulting in the inhibition of alloreactive T-cell proliferation. CoPP-treated DCs, however, retain the ability to produce the anti-inflammatory cytokine interleukin 10 (IL-10). Reactive oxygen species induced by LPS in DCs were inhibited by induction of HO-1. In conclusion, we identify, for the first time, the capacity of HO-1 to block maturation of DCs and to inhibit proinflammatory and allogeneic immune responses while preserving IL-10 production. This novel immune function for HO-1 may be of interest for the inhibition of immune responses in autoimmune diseases, transplantation, and other conditions involving activation of the immune system.
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              Inflammatory cells in ischemic acute renal failure.

              Ischemic acute renal failure (ARF) is increasingly recognized as involving a complex cascade of mechanisms with both acute and chronic consequences. Attention to nontraditional mediators of ARF such as inflammatory pathways and microvascular events has yielded new paradigms and avenues of research. The initiation phase of renal ischemia/reperfusion (I/R) injury damage involves microvascular hemodynamic changes characterized by red blood cell sludging with platelets and leukocytes. Blocking leukocyte-endothelial interactions has yielded significant protection from renal I/R injury in experimental models. However, experiments focusing on the role of the neutrophil have led to a modest expectation of its role in ARF. Recent studies have found that T cells directly mediate renal injury in experimental I/R injury. The CD4+ T cell, working both via interferon-gamma (IFN-gamma) and costimulatory molecules appears to be an important modulator of ARF. The B cell has recently been implicated in ARF. Little is known about the role for the macrophage. Finally, resident kidney cells likely contribute to the inflammatory pathogenesis of I/R damage and protection/repair, but how, and to what extent they are involved is not known. New tools to modulate inflammatory cells, particularly mononuclear leukocytes, hold promise for clinical trials in ARF.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                August 2006
                02 June 2006
                : 104
                : 1
                : e48-e56
                aLaboratório de Imunologia Clínica e Experimental, Division of Nephrology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, bDepartment of Pathology, Universidade Federal do Triangulo Mineiro, Uberaba, and cDivision of Nephrology, Universidade Federal de Juiz de Fora, Minas Gerais, and dDepartment of Immunology, Universidade de São Paulo, São Paulo, Brazil
                93676 Nephron Exp Nephrol 2006;104:e48–e56
                © 2006 S. Karger AG, Basel

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                Page count
                References: 53, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/93676


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