Systemic inflammatory response injury (SIRS) and sepsis are the principal causes of death in trauma patients in the USA. The diagnosis of sepsis requires confirmation of bacterial growth in blood cultures, as well as the presence of two or more of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea and leukocytopenia or leukocytosis. However, only about one-third to one half of patients meeting these criteria are subsequently diagnosed with an infection. Accordingly, all remaining patients are diagnosed with SIRS. The major pathophysiological characteristic of SIRS and sepsis is vascular collapse. Breakdown of the endothelial barrier function results in the loss of fluid into the extravascular space and may lead to edema in several tissues, including the kidneys. Therefore, a frequent complication that affects more than 35% of patients with SIRS is the development of acute kidney injury (AKI). There is a lack of knowledge about the pathogenesis of AKI during SIRS, specifically as there is no study showing whether intrarenal arteries play a role in the genesis and/or maintenance of AKI during trauma-induced SIRS. Several studies have proposed that renal vasoconstriction and reduced renal blood flow (RBF) are the major causes of AKI in SIRS. However, recent observations have showed that improvements in cardiac index as well as blood pressure did not result in improved renal function and prevention of death. This implies that poor forward flow alone does not account for the development of AKI. Although it has been well established that AKI is a unifying factor of SIRS and sepsis in trauma patients, a common mediator to the many types of sepsis and SIRS has not been discovered. Also, the mechanism by which traumatic injury leads to SIRS is not fully understood. It has been proposed that cell components from traumatized tissue, called damage-associated molecular patterns (DAMPs), are the primary instigators of SIRS in trauma patients. For evolutionary reasons, mitochondria share several characteristics with bacteria and N-formyl peptides are common molecular signatures of both bacteria and mitochondria. We have observed that mitochondrial N-formyl peptides (F-MIT) induce vascular leakage, exacerbated vasodilatation and inflammation in resistance arteries via formyl peptide receptor activation. In a preliminary study, it was observed for the first time that sterile trauma induces the release of F-MIT into the circulation of patients with SIRS. Also, it was observed that F-MIT leads to SIRS, intrarenal artery dysfunction and kidney injury via FPR activation. Therefore, based on our preliminary data, it is clear that F-MIT plays a role in SIRS. However, it is unclear whether these peptides are responsible for the development of AKI due to intrarenal arteries dysfunction (e.g. exacerbated vasodilatation associated with vascular leakage, inflammation and local edema). We propose the novel and intriguing hypothesis that higher levels of F-MIT in the circulation after trauma/ischemia activate FPR leading to intrarenal artery dysfunction, AKI and SIRS. The objective of this K99/R00 application is to reveal an intrinsic factor released after cell damage initiates SIRS and acute inflammation of intrarenal arteries which results in AKI with or without hemodynamic changes. This application will also facilitate the transition of my research career towards an independent investigator position. The training (K99) phase of this award will be mentored by Dr. Clinton Webb, who is internationally recognized leader in the fields of vascular physiology and will be co- mentored by Dr. Paul OConnor, who has devoted his career to studying whole animal renal physiology and is an expert in kidney injury. Also, during the mentored phase, I will pursue addition training in the laboratory of Dr. Grisk at University of Greifswald, Germany. It is with Dr. Grisk where I plan to learn in vivo techniques for investigating simultaneous recordings of renal perfusion and I will learn how to isolate human intrarenal arteries. These experiences will play a vital role for the completion of the independent phase of this award. My visit to the Dr. Grisk's laboratory not only will expand my technical skill and experience with different models, but it will also initiate collaboration with an expert in the renal field. Such interaction would expand the scope of my current research and improve the potential for success in gaining further independent funding as I establish my own independent research program. My short- term goal is to become an independent investigator in the field of renal vascular physiology and pathophysiology of trauma and SIRS. As an expert in these fields, I hope to obtain a tenure-track faculty position in an academic institution that promotes interdisciplinary biomedical science and has an emphasis on translational research. My long-term career goal is to establish a strong research program using integrative approaches to study the effects of injury-associated vascular dysfunction on renal physiology.
Systemic inflammatory response syndrome (SIRS) is one of the principal causes of death in intensive care units in the USA. Acute kidney injury (AKI) is a common symptom of SIRS. This research presents the intriguing hypothesis that fragments from damaged mitochondria, released into the circulation after trauma, are recognized by the vessels of the kidney as an infection. Understanding this will help develop new treatments aimed at inhibiting the devastating interaction between mitochondrial fragments and the renal vascular system.
