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University of Kentucky, M.D.
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.
(For a comprehensive list of Dr. Arndt's recent publications, refer to PubMed, a service provided by the National Library of Medicine)