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Home > Faculty > Patrick Arndt, MD
Patrick Arndt, MD
Assistant Professor of Medicine
arndt108@umn.edu
Office: 612-626-4871
Pager: 612-899-7680
Clinical Interests
My clinical interests are the acute respiratory distress syndrome, respiratory failure, mechanical ventilation, chronic ventilatory support, and general pulmonary medicine.
Research
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.
Current and Recent Grant Support
Principal Investigator: NIH RO1. "The role of syndecan-4 in the regulation of JNK activation in human neutrophils." (2007-2012)
Principal Investigator: Minnesota Medical Foundation Research Grant. "The regulation of neutrophil migration by angiotensin converting enzyme inhibitors." (2006-2008)
Principal Investigator: NIH KO8. "LPS responsiveness of TLR2 and TLR4 in the neutrophil." (2001-2006)
Selected Recent Publications
Fessler MB, Young SK, Jeyaseelan S, Lieber JG, Arndt PG, Nick JA, and Worthen GS. A role for hydroxy-methyglutaryl coenzyme A reductase in pulmonary inflammation and host defense. Am J Resp Crit Care Med. 2005 Mar 15, 171(6):606-615.
Arndt PG, Young SK, Lieber JG, Fessler MB, Nick JA, Worthen GS. Inhibition of c-Jun-N-terminal kinase limits lipopolysaccaride-induced pulmonary neutrophil influx. Am J Resp Crit Care Med. 2005 May 1, 171(9)978-86.
Arndt PG, Young SK, and Worthen GS. Regulation of lipopolysaccharide-induced lung inflammation by plasminogen activator inhibitor-1 through a c-Jun N-terminal kinase mediated pathway. J Immunol 2005 Sept 15, 175(6):4049-59.
Jeyaseelan S, Young SK, Yamamoto M, Arndt PG, Akira S, Kolls JK, and Worthen GS. Toll/IL-1R domain-containing adaptor protein (TIRAP) is a critical mediator of antibacterial defense in the lung against Klebsiella pneumoniae but not Pseuodomonas aeruginosa. J Immunol 2006 Jul 1, 177(1): 538-47.
Arndt PG, Young SK, Poch, KR, Nick JA, Falk S, Schrier RW, Worthen GS. Systemic inhibition of the angiotensin-converting enzyme limits lipopolysaccaride-induced lung neutrophil recruitment through both bradykinin and angiotensin II-regulated pathways. J Immunol 2006 Nov 15, 177(10):7233-7241.
Fessler, MB, Arndt PG, Just I, Nick JA, Malcolm KC, Worthen GS. Dual role for RhoA in suppression and induction of cytokines in the human neutrophil. Blood 2007, Feb 1, 109(3):1248-1256.
Arndt PG, Young SK, Worthen GS. Regulation of ongoing lipopolysaccharide-induced pulmonary inflammation via c-Jun N-terminal kinase. Submitted for publication.
Zemans RS, Navuluri L, Worthen GS, Arndt PG. Regulation of lipopolysaccharide-induced c-Jun N-Terminal kinase activation by Tec kinase in human neutrophils. Submitted for publication.
Last Update 4/8/2008
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