A problem as simple as a ruptured appendix can quickly become a life-threatening event for a child. Even with prompt surgery and excellent post-operative care, children occasionally develop sepsis syndrome, a complex systemic inflammatory condition which can complicate an otherwise treatable infection. In the United States, children who develop sepsis syndrome have a 1 in 10 chance of dying, accounting for about 4,300 preventable deaths annually.
“Despite all we can do, we still don’t understand why this inflammatory condition is unleashed in some children but not in others,” says Dr. Allan Doctor, Critical Care Director at St. Louis Children’s Hospital and a researcher at Washington University School of Medicine. In 2007, Dr. Doctor received a Children’s Discovery Institute grant to study the issue.
Researchers agree that sepsis syndrome is not the direct result of germs that may be present, but rather how the patient responds. Any localized infection such as a ruptured appendix or severe burn invariably produces inflammation and the release of harsh, germ killing chemicals to the area of injury.
Inflammation is a protective response aimed at destroying the injurious agent. In doing its job, however, inflammation may actually injure the patient’s own tissue. Because of this destructive power, inflammation must be sequestered to the affected site in order to limit ‘collateral damage’ to surrounding normal tissue.
The body normally does this by restricting the range of molecules that promote inflammation to the area of injury, permitting resolution - rather than progression, of the destructive inflammation deployed to address the original infection or injury. In the case of a ruptured appendix, the response would be limited to a specific region in the abdomen.
Occasionally, however, the body’s inflammation containment system fails, opening the way for sepsis syndrome, and potentially leading to a cascade in which organs, frequently starting with the lungs, begin to shut down.
For decades, medical researchers have tried to understand what happens to cause containment failures by looking at the spread of signals from the local area of inflammation. These efforts have focused principally upon the spread of inflammatory, rather than vascular signaling cells and molecules. While scientists have gained a greater understanding of the biology involved, unfortunately, new therapies or preventive strategies remain elusive.
A few years ago, Dr. Doctor decided to approach the problem from a totally different perspective — to examine the hypothesis that red blood cells (RBC) initiated the breach in containment that precedes cascading organ failure and shock.
“Ten years ago, nobody knew that red blood cells could do anything other than haul oxygen and carbon dioxide,” said Doctor. “Then, a researcher at Duke University showed that red blood cells govern the distribution of blood flow within the vascular system by controlling the availability of the molecules which determine blood vessel diameter. This discovery has led to a fundamental change in our understanding of vascular physiology and has opened an entirely new field of inquiry.”
That led Doctor to consider red blood cells as a possible link between remote inflammation and loss of vascular control in the lungs.
A single drop of blood contains millions of red blood cells, the donut shaped cells, which package the hemoglobin molecules that deliver oxygen to, and remove carbon dioxide from, body tissues.
It takes less than a minute for a red blood cell to circulate through the body, and, given the average 120-day functioning life time of a red blood cell, a single one will make nearly two million round trips before dying.
“Our data has led us to propose that when red blood cells flow through areas of severe inflammation or infection during their journey through the circulatory system, some of the red cells sustain the equivalent of a “chemical burn” that damages critical signaling proteins on the red cell membrane,” said Doctor.
These proteins, when functioning normally, act like thermostats to optimize oxygen delivery to body tissues. They sense the oxygen needs of tissue and either dispense or sequester the molecule nitric oxide, which, in turn, governs the caliber of blood vessels.
For example, during exercise red cells sense an oxygen lack and release nitric oxide, which dilates vessels to increase blood flow to the muscles being used – matching blood flow to the regional requirements. This happens quickly, in millisecond by millisecond changes in local metabolic demand.
When the membrane proteins of red blood cells are damaged, they lose this ability to regulate nitric oxide in accordance with metabolic demand for oxygen. And, because red blood cells lack a nucleus, they don’t have the ability to synthesize new proteins to replace damaged ones.
“The damaged red blood cells then carry a signal that was proper for the area of infection, but inappropriate for the normal lung, the first organ downstream from foci of infection or inflammation in the body” said Doctor. “They have lost the ability to respond appropriately to the environment, and the result is a disruption of normal gas exchange in previously uninjured lungs. Our findings have identified a novel mechanism through which the body’s containment system may fail and explains why vascular disruption in the lung is a sentinel event in cascading organ failure and shock.”
Dr. Doctor’s current research focus is to understand how the red blood cells become damaged when they traverse harsh environments in the body such as areas of infection. “Red blood cells are continuously exposed to stresses in the form of oxidizing compounds from food or drugs or generated by the body, and have elaborate anti-oxidant defense systems,” said Doctor. “We want to find out what makes this protective system fail. What makes red blood cells more vulnerable to injury? What tips the balance?”
To carry out his investigation, Dr. Doctor has created a mock circulatory system to mimic the oxygen gradients of harsh environments that red blood cells might traverse, as well as an isolated lung system and methods for mapping chemical changes produced. He has further developed methods to relate chemical anomalies to changes in the actual physiology of mouse lungs. Exciting early data suggests that a disruption of glucose metabolism in red blood cells is the key to their lost defenses. Doctor’s CDI funded work is aggressively exploring this possibility.
“Our goal is to identify what tips the balance in favor of injury so that, in time, we can devise ways to either prevent or reverse the problem,” said Doctor.