Hepatic changes in systemic infection

Srivastava, Brijesh; Gimson, Alexander

doi:10.1016/j.bpg.2013.06.011

Cited by 15 publications

(10 citation statements)

References 59 publications

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“…This was seen in conjunction with a hepatic increase in inflammatory myeloid and Kupffer cell populations (Figure 5A). Similar hepatic innate immune activation is also seen during other non-hepatic systemic infections: sinusoidal dilatation combined with an influx of inflammatory cells, primarily Kupffer cells [43].…”

Section: Discussionmentioning

confidence: 93%

Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza

Тарасенко

Singh

Chatterji-Len

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.

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Section: Discussionmentioning

confidence: 93%

Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza

Тарасенко

Singh

Chatterji-Len

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In addition to local immune responses, Kupffer cells also play a role in systemic immunity. During systemic infection, blood supply to the liver is increased and hepatic sinusoids dilate, leading to prolonged exposure to blood borne pathogens by Kupffer cells [37]. The importance of Kupffer cells in combating systemic infections is highlighted by depletion studies.…”

Section: Kupffer Cells Play a Role In Systemic And Local Immune Reactmentioning

confidence: 99%

The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM)

Тарасенко

McGuire

2017

Molecular Genetics and Metabolism

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Metabolic decompensation in inborn errors of metabolism (IEM) is characterized by a rapid deterioration in metabolic status leading to life-threatening biochemical perturbations (e.g. hypoglycemia, hyperammonemia, acidosis, organ failure). Infection is the major cause of metabolic decompensation in patients with IEM. We hypothesized that activation of the immune system during infection leads to further perturbations in end-organ metabolism resulting in increased morbidity. To address this, we established model systems of metabolic decompensation due to infection. Using these systems, we have described the pathologic mechanisms of metabolic decompensation as well as changes in hepatic metabolic reserve associated with infection. First and foremost, our studies have demonstrated that the liver experiences a significant local innate immune response during influenza infection that modulates hepatic metabolism. Based on these findings, we are the first to suggest that the role of the liver as a metabolic and immunologic organ is central in the pathophysiology of metabolic decompensation due to infection in IEM. The dual function of the liver as a major metabolic regulator and a lymphoid organ responsible for immunosurveillance places this organ at risk for hepatotoxicity. Mobilization of hepatic reserve and the regenerative capacity of a healthy liver compensates for this calculated risk. However, activation of the hepatic innate immune system may be deleterious in IEM. Based on this assertion, strategies aimed at modulating the innate immune response may be a viable target for intervention in the treatment of hepatic metabolic decompensation.

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“…The liver plays a central role in the systemic response to critical illness both through the clearance of pathogenic microorganisms and toxins from the circulation and through the APR and release of liver‐derived cytokines, inflammatory mediators, and coagulation cascade components . These mediators and bacterial or endotoxin “spillover” from impaired hepatic clearance may have important systemic effects and contribute to the pathogenesis of multiple organ failure …”

Section: Normal Physiological Responsementioning

confidence: 99%