Targeting RBC-neutrophil interactions for the treatment of sepsis associated kidney injury.

Context Sepsis is a common and life-threatening response to infection which frequently leads to multiple organ failure. The kidney is particularly vulnerable, however the mechanisms for damage are not well understood. This means there are currently no specific treatments for kidney damage in sepsis, which often leads to kidney failure. Challenge The oxygen carrying cells of the blood (red blood cells RBCs) have a delicate jelly like outer layer called the glycocalyx (Glx). The human Glx is very fragile and not easily detectable by standard laboratory techniques. However, we have developed a blood test which can detect RBC Glx damage. Results from my pilot study suggests the RBC Glx is broken down in patients with sepsis and kidney failure. Healthy RBCs are known to prevent immune cells called neutrophils from activating excessively in the bloodstream. Regulation of neutrophils is essential for health, and vital to combat infections. In sepsis, excessive neutrophil activity damages organs and tissues, including the kidney. I believe that a healthy RBC Glx is important for limiting excessive activation of neutrophils. When this layer becomes damaged in sepsis, RBC are no longer able to prevent neutrophils from activating excessively causing damage to the blood vessels within the kidney. Aims Firstly, I will confirm RBC Glx damage in patients with sepsis using our blood test. Then I will see whether RBC Glx can be used as a marker or predictor of organ damage in sepsis. Next, I will investigate whether damaged RBC Glx (using enzymes) change the behaviour of human neutrophils in test tubes. I will perform this work in collaboration with world leading neutrophil experts at the University of Bristol to assist me with specialist tests of neutrophil activity. Finally, I will investigate treatment strategies to protect RBC Glx to see whether this reduces human neutrophil activation. I will test these treatments in mice to see whether we can reduce the severity of their sepsis and kidney damage. By collaborating with experts at the University of Southern California, I can use a highly sophisticated technique (multiphoton microscopy) to image blood vessels deep inside anaesthetised mice. Multiphoton microscopy will help me determine whether protecting the RBC Glx affects the number of neutrophils entering the kidney and time spent in the blood vessels of the kidney. This work will progress our understanding of organ damage in sepsis, highlighting the previously neglected role of the RBC Glx. Potential benefits Using RBC Glx as a marker of kidney damage will allow us to identify patients at high risk of developing organ failure, facilitating their early risk assessment. These patients can be monitored more closely and treated earlier with the limited therapies currently available. Ultimately, this project aims to uncover a new pathway leading to new treatments which effectively reduce organ damage in sepsis. By reducing kidney damage, patients with sepsis have a much greater chance of recovery and are much less likely to develop long term health problems such as chronic kidney disease, and complications of kidney disease such as heart attacks and strokes. Beyond sepsis, regulating neutrophils by protecting RBC Glx has the potential to lead to treatments for other conditions where there is excessive neutrophil activity such as in malaria, cancer, autoimmune and cardiovascular disease.