Abstract

The body's response to injury and surgical stress involves the coordinated elaboration of a number of pro-inflammatory and anti-inflammatory mediators which function to prevent the spread of invading organisms, minimize tissue injury, repair damaged tissues, and restore homeostasis and vital organ function. Among the earliest mediators produced in response to injury and infection are catecholamines, corticosteroids, and glucagon. The mechanisms by which glucagon regulates glucose homeostasis have been well characterized, while the ability of glucagon to alter other metabolic pathways has not been extensively studied. The expression of nitric oxide synthase in hepatocytes is important in the response of the liver to infection because NO from the inducible nitric oxide synthase (iNOS) contributes to sepsis-induced hepatic injury and hepatic dysfunction. Our preliminary data demonstrate that glucagon inhibits hepatocyte nitric oxide (NO) synthesis by inhibiting the expression of iNOS in response to pro-inflammatory stimuli in both in vitro and in vivo models of sepsis. The reduction in iNOS expression with glucagon is associated with decreased LPS-mediated hepatic injury and decreased LPS-mediated hepatic dysfunction. In this proposal, we will identify the mechanisms responsible for the regulation of this critical hepatocyte pathway by glucagon. We will identify the mechanisms involved in the transcriptional regulation of iNOS by glucagon (AIM D, the regulation by glucagon of post-transcriptional effects on iNOS expression (AIM II), and the second messenger signal transduction systems responsible for these events (AIM III). By defining the mechanisms involved in the regulation of iNOS expression by glucagon, we will enhance our understanding of the cellular events that constitute the body's response to injury, stress, and infection. These insights will contribute to uncovering the basic cellular mechanisms involved in multiple organ dysfunction and may lead to potential therapeutic approaches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK055664-01A2
Application #
6286569
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Serrano, Jose
Project Start
2001-02-15
Project End
2005-11-30
Budget Start
2001-02-15
Budget End
2001-11-30
Support Year
1
Fiscal Year
2001
Total Cost
$213,117
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Kimbrough, Charles W; Lakshmanan, Jaganathan; Matheson, Paul J et al. (2015) Resveratrol decreases nitric oxide production by hepatocytes during inflammation. Surgery 158:1095-101; discussion 1101
Lakshmanan, Jaganathan; Zhang, Baochun; Nweze, Ikenna C et al. (2015) Glycogen synthase kinase 3 regulates IL-1? mediated iNOS expression in hepatocytes by down-regulating c-Jun. J Cell Biochem 116:133-41
Zhang, Baochun; Crankshaw, Will; Nesemeier, Ryan et al. (2015) Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression. J Surg Res 193:795-801
Zhang, Baochun; Nweze, Ikenna; Lakshmanan, Jaganathan et al. (2013) Activation of a cyclic amp-guanine exchange factor in hepatocytes decreases nitric oxide synthase expression. Shock 39:70-6
Harbrecht, Brian G; Nweze, Ikenna; Smith, Jason W et al. (2012) Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 302:G116-22
Nweze, Ikenna C; Smith, Jason W; Zhang, Baochun et al. (2012) 17?-Estradiol attenuates cytokine-induced nitric oxide production in rat hepatocyte. J Trauma Acute Care Surg 73:408-12
Miller, Keith R; Lawson, Christy M; Smith, Vance L et al. (2011) Carbohydrate provision in the era of tight glucose control. Curr Gastroenterol Rep 13:388-94
Smith, Jason W; Garrison, R Neal; Matheson, Paul J et al. (2010) Direct peritoneal resuscitation accelerates primary abdominal wall closure after damage control surgery. J Am Coll Surg 210:658-64, 664-7
Hong, Guiying; Zhang, Baochun; Harbrecht, Brian G (2010) Cyclic AMP inhibits IL-1beta plus IFNgamma-induced NF-kappaB translocation in hepatocytes by a PKA independent mechanism. J Surg Res 159:565-71
Leggett, Maya; Harbrecht, Brian G (2009) Glucose control and its implications for the general surgeon. Am Surg 75:1031-5

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