Do organs hibernate during prolonged sepsis? Study of ATP turnover and mitochondrial biogenesis in patients & lab models

Lead Research Organisation: University College London
Department Name: The Wolfson Inst for Biomedical Research

Abstract

UCL have a Media Office that is very proactive in alerting the media to interesting discoveries and ideas. For example, they communiqued a recent UCL Lecture given by Professor Singer which attracted intense TV, radio and press coverage both nationally and internationally, ranging from China to South Africa to North America. Many of the applicants are experienced in communicating to the lay public through television and radio programmes, e.g. the 9 o?clock News, Newsround, Medicine Now and Woman?s Hour, and being interviewed for various newspaper articles.

Technical Summary

Sepsis frequently results in multi-organ failure through mechanisms that remain ill-defined. Intriguingly, cell death is a minor feature of this condition and, with resolution of the critical illness, recovery of organ function generally occurs within days-to-weeks, i.e. far in excess of their usual regenerative capacity. We and others have found that mitochondrial dysfunction occurs both in septic patients and in animal and in-vitro laboratory models, despite the ready availability of cellular oxygen. We therefore hypothesize that the consequent reduction in energy supply leads to a cellular metabolic shutdown, with a resulting decrease in biochemical and physiological function. On disease resolution the bioenergetic pathway recovers, with restoration of normal organ performance. Paradoxically, and despite the diminished ability to generate energy, cellular ATP concentrations are often elevated and only fall in eventual non-survivors. We thus suggest this process is directly analogous to hibernation or aestivation, for which a precedent in humans is recognised within the heart during prolonged ischaemia.
We propose to examine this hypothesis further by evaluating ATP turnover and other measurables during the successive phases (acute inflammation, organ failure, resolution) of a prolonged septic illness. We will use a 3-day rodent model of faecal peritonitis that mimics many aspects of the human condition, measuring ATP turnover in skeletal muscle and kidney both in-vivo using saturation transfer magnetic resonance spectroscopy (MRS), and ex-vivo using cells from kidney, muscle and liver freshly isolated from septic animals, in which oxygen consumption will also be measured. Comparison will be made against (i) muscle biopsies from septic patients and (ii) in-vitro stimulation of primary myoblast, hepatocyte and renal proximal tubule cultures to assess the validity of the in-vitro model relative to the in-vivo situation. Evidence of concurrent mitochondrial biogenesis will be sought in both patients and laboratory models by assessing changes in respiratory enzyme complex activities and protein levels, expression of activators and coactivators of mitochondrial biogenesis, and alterations in mitochondrial density and morphometry.
Confirmation of this hibernation-like process will open up an exciting new avenue of therapeutic research, with the possibility of accelerating the recovery phase once inflammation has abated, thus shortening the duration of organ failure and improving patient outcome.

Publications

10 25 50
 
Description Basic Science Award /European Society of Intensive Care
Amount £18,000 (GBP)
Organisation European Society of Intensive Care Medicine (ESICM) 
Sector Charity/Non Profit
Country European Union (EU)
Start 10/2010 
End 09/2011
 
Description ESICM, Basic Science Award
Amount £20,000 (GBP)
Organisation European Society of Intensive Care Medicine (ESICM) 
Sector Charity/Non Profit
Country European Union (EU)
Start 10/2007 
End 09/2008
 
Description Collaboration with German group 
Organisation Duke University
Department Department of Anesthesiology
Country United States 
Sector Academic/University 
PI Contribution Contributed intellectually through discussion and interpretation of data
Collaborator Contribution Assisted with transcriptomics and bioinformatics.Useful assistance with measurement of transcription factors
Impact With the Jena group we have performed additional work in liver dysfunction in sepsis. One of their postdocs spent a year in my lab in London
Start Year 2008
 
Description Collaboration with German group 
Organisation University Hospital Jena
Department Department of Anesthesiology and Intensive Care Medicine
Country Germany 
Sector Academic/University 
PI Contribution Contributed intellectually through discussion and interpretation of data
Collaborator Contribution Assisted with transcriptomics and bioinformatics.Useful assistance with measurement of transcription factors
Impact With the Jena group we have performed additional work in liver dysfunction in sepsis. One of their postdocs spent a year in my lab in London
Start Year 2008