Patrick Arndt

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Credentials

MD

Bio

Administrator Info
Name: Helen Rieger
Phone: 612-624-0999
Email: riege002@umn.edu
Fax: 612-625-2174

Summary
My research focuses on innate immunity and in particular the response of neutrophils to exogenous bacterial components or endogenous stress signals. Our main focus of disease is acute lung injury and the acute respiratory distress syndrome (ARDS) with our overall goal to improve patient outcomes in ARDS, a disease still associated with significant morbidity and mortality. Through examination of cell signaling pathways utilized by neutrophils in their response to stress mediators, we hope to identify targets that may be useful in dampening the response of neutrophils and accordingly decrease the severity of lung injury and the development of acute respiratory failure. Our major area of focus has been dissecting the pathways used by the mitogen activated protein kinase family of cell signaling molecules in order to better understand their upstream and downstream signaling components that induce and regulate the cellular activation of neutrophils. These identified components can then be assessed for their potential as modifiable targets for the treatment of ARDS at the bedside by drug or genetic approaches with the ultimate goal of improving patient outcomes.

Research Summary

Cell signaling, acute lung inflammation
The neutrophil is crucial to the inflammatory response and in particular to the pathophysiology of the acute respiratory distress syndrome (ARDS). Although neutrophil recruitment to sites of acute inflammation is beneficial, an over-exuberant influx of neutrophils results in tissue damage that is detrimental to the patient. Accordingly, limiting neutrophil recruitment or neutrophil activation in the lung may benefit patients with ARDS, thereby improving outcomes. Our laboratory is interested in the signaling pathways that are activated in neutrophils during acute inflammation. One such pathway is the evolutionary conserved mitogen activated protein kinase (MAPK) cascade. Exposure of neutrophils to inflammatory mediators, such as lipopolysaccharide (LPS) or chemokines (e.g. Interleukin 8--IL-8), activates components of the MAPK cascade leading to the expression and release of pro-inflammatory proteins. Our laboratory has previously examined the signaling pathways by which LPS activates the MAPK c-Jun NH2-terminal kinase (JNK) in neutrophils and have shown that JNK regulates neutrophil recruitment to the lung after exposure to LPS. Although we continue to examine pathways leading to JNK activation in LPS-stimulated neutrophils, our laboratory is currently focusing on the role of the proteoglycan syndecan-4 in regulating the activation of JNK in neutrophils exposed to the chemokine IL-8. IL-8 is a major attractant for neutrophil migration and is highly expressed at sites of acute inflammation. In addition, IL-8 binds to syndecan-4 suggesting that syndecan-4 is uniquely positioned to regulate IL-8-induced signaling in neutrophils. We plan to examine the upstream signaling events that are regulated by syndecan-4 in the IL-8-induced pathway leading to JNK activation using biochemical and in vitro and in vivo genetic knockdown strategies. Our hopes are that these studies will further elucidate the mechanisms by which IL-8 activates JNK in neutrophils, and therefore neutrophil migration, and will provide potential modalities to control the inflammatory response. In addition, the lab is beginning to examine the mechanisms by which the renin angiotenisn system regulates neutrophil influx during acute inflammation. Currently, angiotensin converting enzyme inhibitors (ACE inhibitors) are widely used and are effective in patients with cardiovascular disease. In addition to their effect on blood pressure and cardiac function, however, ACE inhibitors decrease neutrophil recruitment to inflammatory sites. The goal of this project is to determine the mechanisms by which ACE-I decrease neutrophil recruitment and specifically the signaling pathways that are regulated by the RAS in neutrophils.

Clinical Summary

General Pulmonary, Pulmonary complications after hematopoietic stem cell transplant