Oxygen and perioperative organ injury

Project Summary/Abstract
More than 20% of patients undergoing major surgery experience acute kidney, brain, and heart injury,
and these perioperative complications lead to persistent organ dysfunction, long-term morbidity, and death. My
research program is investigating and manipulating mechanisms of perioperative organ injury in order to
identify therapeutic targets and develop novel therapies. We are currently focused on the critical impact of
oxygen tension on organ injury, because perioperative oxygen administration is inconsistent, unguided, often
excessive, and potentially harmful. Both hypoxia and hyperoxia can be harmful to surgical patients, yet both
occur frequently, despite the ease with which the fraction of inspired oxygen (FiO2) can be manipulated in the
perioperative period. Our laboratory is focused on identifying and investigating molecular pathways and
therapeutic targets that a) impact oxygen tension in tissues during surgery and b) impact hypoxia- and
hyperoxia-mediated organ injury. We target these molecular pathways to reduce organ injury.
We have recently demonstrated that: 1) perioperative oxidative damage increases acute kidney, brain,
and heart injury; 2) intraoperative normoxia improves vascular reactivity compared to hyperoxia possibly by
reducing intraoperative oxidation of the heme moiety of vascular smooth muscle soluble guanylyl cyclase; 3)
normoxia upregulates hypoxia inducible factor (HIF)-regulated transcription and reduces circulating markers of
oxidative damage; and 4) increased circulating cell-free hemoglobin (Hb) oxidizes lipids and is independently
associated with postoperative kidney, lung, and brain injury. In the next 5 years we will investigate the effects
of oxygen tension on mechanisms of organ injury, including oxidative damage, vascular function, HIF signaling,
and cell free Hb-mediated organ injury, using a multifaceted translational approach. Our program combines
laboratory experiments in human tissues and preclinical models with prospective cohort studies and
mechanistic trials in patients having major surgery. We perform experiments on arterioles and arteries isolated
from patients during surgery to study the effects of hypoxic, normoxic, and hyperoxic treatments on vascular
function. We investigate the impact of oxygen treatments during preclinical models of acute kidney injury in
genetically engineered mice in collaboration with oxygen biologist nephrologist Volker Haase, and we are
measuring the effect of intraoperative hyperoxia vs. normoxia treatment in samples biobanked from the
NIGMS-supported ROCS clinical trial. Examples of these experiments include the measurement of HIF-
regulated transcripts in atrial myocardium and the oxidation state of the heme group in plasma cell-free Hb. We
will complement these hypothesis-driven experiments with unbiased approaches to measure the transcriptome
and protein responses in vascular and murine tissues to identify and support new paths of investigation.
This rigorous multimodal strategy provides the framework to advance the understanding of perioperative
organ injury and guide the development of therapies for hundreds of thousands of surgical patients.

Grant Number: 5R35GM145375-04
NIH Institute/Center: NIH
Principal Investigator: Frederic Billings