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Experimental data suggesting that inflammation mediated rat liver mitochondrial dysfunction results from secondary hypoxia rather than from direct effects of inflammatory mediators.

ABSTRACT: Systemic inflammatory response (SIR) comprises both direct effects of inflammatory mediators (IM) and indirect effects, such as secondary circulatory failure which results in tissue hypoxia (HOX). These two key components, SIR and HOX, cause multiple organ failure (MOF). Since HOX and IM occur and interact simultaneously in vivo, it is difficult to clarify their individual pathological impact. To eliminate this interaction, precision cut liver slices (PCLS) were used in this study aiming to dissect the effects of HOX and IM on mitochondrial function, integrity of cellular membrane, and the expression of genes associated with inflammation. HOX was induced by incubating PCLS or rat liver mitochondria at pO2 < 1% followed by reoxygenation (HOX/ROX model). Inflammatory injury was stimulated by incubating PCLS with IM (IM model). We found upregulation of inducible nitric oxide synthase (iNOS) expression only in the IM model, while heme oxygenase 1 (HO-1) expression was upregulated only in the HOX/ROX model. Elevated expression of interleukin 6 (IL-6) was found in both models reflecting converging pathways regulating the expression of this gene. Both models caused damage to hepatocytes resulting in the release of alanine aminotransferase (ALT). The leakage of aspartate aminotransferase (AST) was observed only during the hypoxic phase in the HOX/ROX model. The ROX phase of HOX, but not IM, drastically impaired mitochondrial electron supply via complex I and II. Additional experiments performed with isolated mitochondria showed that free iron, released during HOX, is likely a key prerequisite of mitochondrial dysfunction induced during the ROX phase. Our data suggests that mitochondrial dysfunction, previously observed in in vivo SIR-models, is the result of secondary circulatory failure inducing HOX rather than the result of a direct interaction of IM with liver cells.

SUBMITTER: Weidinger A

PROVIDER: S-EPMC3675332 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Experimental data suggesting that inflammation mediated rat liver mitochondrial dysfunction results from secondary hypoxia rather than from direct effects of inflammatory mediators.

Weidinger Adelheid A Dungel Peter P Perlinger Martin M Singer Katharina K Ghebes Corina C Duvigneau J Catharina JC Müllebner Andrea A Schäfer Ute U Redl Heinz H Kozlov Andrey V AV

Frontiers in physiology 20130607

Systemic inflammatory response (SIR) comprises both direct effects of inflammatory mediators (IM) and indirect effects, such as secondary circulatory failure which results in tissue hypoxia (HOX). These two key components, SIR and HOX, cause multiple organ failure (MOF). Since HOX and IM occur and interact simultaneously in vivo, it is difficult to clarify their individual pathological impact. To eliminate this interaction, precision cut liver slices (PCLS) were used in this study aiming to diss ...[more]

PMID: 23760194

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Project description:Background:Bacterial infection and inflammation of the testis impairs fertility, yet an understanding of inflammatory responses of the testis is incomplete. We are interested in identifying gene pathways involved in the detection and clearance of infectious microbes in the male reproductive tract. In previous studies in our lab focused on hypoxia-responsive genes of the testis, preliminary experiments suggested that genes classically categorized as hypoxia genes are also activated during antimicrobial responses. The purpose of this study was to identify hypoxia and inflammatory gene pathways that contribute to antimicrobial protection of the testis and to consider possible cross-talk and interactions between these pathways. Inflammation was induced in Sprague-Dawley rats using P. aeruginosa or E. coli lipopolysaccharide (LPS). Levels of hypoxia-inducible factor-1 (HIF-1?) protein and nuclear factor kappa B (NF-?B) were measured, and hypoxia and inflammatory gene expression patterns in testis were analyzed by gene expression profiling using real-time quantitative PCR arrays. Results:In LPS-treated rats, HIF-1? protein increased with no change in Hif-1? mRNA. Western Blot analysis also demonstrated no change in NF-?B and inhibitory NFKB alpha (I?B?) protein levels following LPS treatment. Five hypoxia pathway genes (Angptl4, Egr1, Ier3, Pai1, and Glut1), and 11 inflammatory pathway genes (Ccl12, Cc13, Cd14, Cxcl10, Icam1, Il10, Il1b, Il6, Nfkbia, Tlr2, Tnf) up-regulated after 3 h of inflammation. Angptl4, Ccl12, Cc13, Cd14, Egr1, Nfkbia, Tlr2, and Tnf remained elevated at 6 h. Six genes were up-regulated at 6 h only (Bhlhe40, C3, Jak2, Nlrp3, Slc11a1, Tlr1). One gene (Tlr5) was down-regulated after 3 h and no genes at 6 h. Electrophoretic mobility shift assay results suggest a decrease in NF-?B binding activity following LPS treatment. Conclusions:Testicular HIF-1? is up-regulated following LPS-induced inflammation. In contrast to other tissues, in which HIF-1? is up-regulated through transcriptional activation via NF-?B, we conclude that HIF-1? in the testis is not up-regulated through an increase in Hif-1? mRNA or through NF-?B-dependent mechanisms. Hypoxia pathway genes and genes involved in Toll-like receptor (TLR) and cytokine-mediated signaling comprise major functional categories of up-regulated genes, demonstrating that both hypoxia and classic inflammatory pathways are involved in inflammatory responses of the testis.

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Experimental data suggesting that inflammation mediated rat liver mitochondrial dysfunction results from secondary hypoxia rather than from direct effects of inflammatory mediators.

Publications

Experimental data suggesting that inflammation mediated rat liver mitochondrial dysfunction results from secondary hypoxia rather than from direct effects of inflammatory mediators.

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