Sunlight, the sole source of energy for all living organisms, has profound effects on life. The current biological evidence suggests that light profoundly influences the physiologic capacity with which an organism responds to stress. However, whether an acute light exposure can modify the biology of disease remains to be determined. We now show using murine models of kidney and liver ischemia and reperfusion (I/R) that acute exposure to blue spectrum light prior to I/R reduces by more than 50% the magnitude of organ injury by comparison to red or ambient white fluorescent light. Blue light reduces HMGB1 release and neutrophil influx, both key mediators of I/R damage. The mechanism involves an optic pathway, as mice experiencing optic nerve degeneration are not protected. Thus, we propose that the spectrum of light is a critical determinant of its effect on health, and that blue spectrum light of optimal photoperiod (i.e., duration) and illuminance (i.e., brightness) can be used therapeutically to favorably modify the biology of critical illness in humans. We now propose to examine the biological mechanisms underlying our observation that blue light is protective. We hypothesize that a single exposure to a short (8 hours) photoperiod of high illuminance (1700 lux), blue (peak 442nm) spectrum light functions through an optic pathway to reduce neutrophil- mediated cellular/organ injury and preserve cellular bioenergetics and ATP during I/R.
In Aim 1 we will determine the neurophysiologic mechanisms through which blue light attenuates organ injury, using murine models of hepatic and renal I/R. We focus upon an optic pathway that leads to a withdrawal of sympathetic (adrenergic) and an enhancement in parasympathetic (cholinergic) tone that mediates adaptive changes in peripheral tissue circadian clock proteins to reduce organ injury. Furthermore we will determine whether an 8 hour or a 24 hour photoperiod of blue light is optimally protective.
In Aim 2 : we will explore the cellular mechanisms by which blue light attenuates organ injury, focusing upon a reduction in neutrophil recruitment and oxidant damage to the kidney and liver and an enhancement in mitochondrial health that preserves cellular bioenergetics and a critical threshold of ATP. And finally in Aim 3, we translate the results of Aims 1 and 2 into a translational trial to determine whether blue light reduces organ injury in patients undergoing liver resection and cardiopulmonary bypass; two procedures characterized by a period of I/R. The ramifications of light on health and disease remain to be convincingly defined, but are likely profound. This proposal will define the biological mechanisms through which blue light beneficially alters the adaptive response to I/R. We will define the dimensions of blue light that are optimally protective and then confirm the therapeutic value of blue light therapy in translational trials of patients undergoing surgery. The significance and potential impact of our work and this proposal lie in the very real potential to influence health by harnessing a ubiquitous medium, light, and determining how and when to turn it `on' or turn it `off'.
The current biological evidence suggests that light profoundly influences the physiologic capacity with which an organism responds to stress. However, the ramifications of light on human health and disease remain to be convincingly defined. Our data highlight that a short duration (24 hours) of bright blue spectrum light can be used therapeutically to favorably modify the biology of ischemia and reperfusion (I/R). We now propose to examine the biological mechanisms underlying our observation that acute exposure to high illuminance blue light prior to I/R protects against organ injury. We will further define the characteristics and dimensions of blue light that are optimally protective and then confirm the therapeutic value of blue light therapy in a trial of patients undergoing hepatectomy or cardiopulmonary bypass, operations characterized by I/R. The knowledge gained by these studies may further help in developing therapeutic interventions equally relevant to other ischemic diseases, which burden global health, including myocardial infarction and stroke.
| Lewis, Anthony J; Rosengart, Matthew R (2018) Bench-to-Bedside: A Translational Perspective on Murine Models of Sepsis. Surg Infect (Larchmt) 19:137-141 |
| Lewis, Anthony J; Griepentrog, John E; Zhang, Xianghong et al. (2018) Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial. Crit Care Med 46:e426-e434 |
| Lewis, Anthony J; Zhang, Xianghong; Griepentrog, John E et al. (2018) Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis. Crit Care Med 46:e779-e787 |
| Lewis, Anthony J; Lee, Janet S; Rosengart, Matthew R (2018) Translational Sepsis Research: Spanning the Divide. Crit Care Med 46:1497-1505 |
| Lewis, Anthony; Zuckerbraun, Brian; Griepentrog, John et al. (2017) Reducing Animal Use with a Biotelemetry-Enhanced Murine Model of Sepsis. Sci Rep 7:6622 |
| Lewis, Anthony J; Seymour, Christopher W; Rosengart, Matthew R (2016) Current Murine Models of Sepsis. Surg Infect (Larchmt) 17:385-93 |
| Yuan, Du; Collage, Richard D; Huang, Hai et al. (2016) Blue light reduces organ injury from ischemia and reperfusion. Proc Natl Acad Sci U S A 113:5239-44 |
| Lewis, Anthony J; Yuan, Du; Zhang, Xianghong et al. (2016) Use of Biotelemetry to Define Physiology-Based Deterioration Thresholds in a Murine Cecal Ligation and Puncture Model of Sepsis. Crit Care Med 44:e420-31 |
| Lewis, Anthony J; Billiar, Timothy R; Rosengart, Matthew R (2016) Biology and Metabolism of Sepsis: Innate Immunity, Bioenergetics, and Autophagy. Surg Infect (Larchmt) 17:286-93 |
