Metabolic Function of the Isolated Perfused Rat Liver in Chronic Sepsis

Dahn, Michael S.; Lange, M.; McCurdy, Brenda; Mahaffey, Susan

doi:10.1006/jsre.1995.1166

Cited by 12 publications

(3 citation statements)

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“…Some short-term studies have demonstrated increased oxygen consumption and enhanced mitochondrial function in septic models [18][19][20][21]. The study by Dawson et al [21] involved rats injected with a large dose of intravenous endotoxin (70 mg/kg) and observed until death (mean duration of 4 hours).…”

Section: Enhanced Mitochondrial Functionmentioning

confidence: 97%

Mitochondrial dysfunction in sepsis

Brealey¹,

Singer

2003

Curr Infect Dis Rep

138

101

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Sepsis is an increasingly common problem, particularly among critically ill patients. Mechanisms by which sepsis induces organ dysfunction have not been elucidated. The coexisting findings (unique to sepsis) of metabolic acidosis yet increased tissue oxygen tensions suggest cellular availability but decreased use of oxygen (tissue dysoxia). Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels. These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsis-associated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.

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Section: Enhanced Mitochondrial Functionmentioning

confidence: 97%

Mitochondrial dysfunction in sepsis

Brealey¹,

Singer

2003

Curr Infect Dis Rep

138

101

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show abstract

“…For instance, in a rat cecal ligation and puncture model, Kantrow et al demonstrated reduced hepatocyte oxygen consumption after 16 hours of sepsis, but the further investigation of respiration rate of isolated hepatocytes from the septic animals evidenced an increase in both complex I and II mediated respiration in states 3 and 4 [5]. Perfused livers isolated from a rat model of fecal peritonitis demonstrated enhanced oxygen consumption at rest [9] and, in a rat model of massive endotoxemia, skeletal muscle and cardiac mitochondria showed an early rise in respiratory control ratio compared to controls [10]. The mixed findings of these studies may be related to the technique of measuring mitochondrial respiration in isolated mitochondria, as described previously.…”

Section: Laboratory and Clinical Evidence Of Mitochondrial Dysfunctiomentioning

confidence: 99%

Mitochondrial Dysfunction during Sepsis

Azevedo

2010

EMIDDT

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Sepsis and multiple organ failure remain leading causes of death in intensive care patients. Recent advances in our understanding of the pathophysiology of these syndromes include a likely prominent role for mitochondria. Patient studies have shown that the degree of mitochondrial dysfunction is related to the eventual outcome. Associated mechanisms include damage to mitochondria or inhibition of the electron transport chain enzymes by nitric oxide and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia), hormonal influences that decrease mitochondrial activity, and downregulation of mitochondrial protein expression. Notably, despite these findings, there is minimal cell death seen in most affected organs, and these organs generally regain reasonably normal function should the patient survive. It is thus plausible that multiple organ failure following sepsis may actually represent an adaptive state whereby the organs temporarily 'shut down' their normal metabolic functions in order to protect themselves from an overwhelming and prolonged insult. A decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration. Data from animal studies show histological recovery of mitochondria after a septic insult that precedes clinical improvement. Stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in multi-organ failure. This review will cover basic aspects of mitochondrial function, mechanisms of mitochondrial dysfunction in sepsis, and approaches to prevent, mitigate or speed recovery from mitochondrial injury.

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“…The extent to which mitochondrial ROS contribute to oxidative stress during sepsis is less clear. A few animal studies have reported enhanced mitochondrial function early during sepsis [206][207][208] , which could possibly contribute to the observed oxidative stress seen in human patients with ARDS or sepsis 146,209,210 . One study showed that this increase in mitochondrial metabolism could be induced with a bolus of TNF-α and IL-1β, cytokines which peak early during inflammation 211 .…”

Section: Ggmentioning

confidence: 99%

Neutrophil priming and host inflammation

Whitmore¹

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have provided me with insightful feedback in lab meetings and have always made themselves available to answer questions, share their expertise, or proofread my writing. It has been a privilege to participate in the Molecular and Cellular Biology Program and the Biosciences Program at The University of Iowa. I would like to thank Rick Domann, Jackie Bickenbach, Paulette Villhauer, Joshua Lobb, and Jodi Graff for overseeing and coordinating these programs and supporting the students in them. I would especially like to thank my parents, Craig and Kathleen Heise, my parents-inlaw, Steve and Esther Whitmore, and all my siblings for their love and support during many years of graduate school. Finally, I want to thank Scott, my husband and fellow graduate student for all six years of our marriage. Scott has provided daily love, encouragement, and laughter and has been an amazing example for me to follow.

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Metabolic Function of the Isolated Perfused Rat Liver in Chronic Sepsis

Cited by 12 publications

References 0 publications

Mitochondrial dysfunction in sepsis

Mitochondrial dysfunction in sepsis

Mitochondrial Dysfunction during Sepsis

Neutrophil priming and host inflammation

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