There is increasing evidence that liver injury can precipitate or exaggerate lung injury. Cytokines produced in the liver and lungs, including tumor necrosis factor alpha (TNF-alpha) and interleukin-1(IL- 1), are implicated in the pathogenesis of Systemic Inflammatory Response Syndrome (SIRS). Animal experiments have demonstrated them capable of precipitating acute lung injury. Increased expression of the genes encoding these cytokines involves activation of two transcription factors, nuclear factor kappa B (NF-kappa B) and CCAAT enhancer binding protein beta (C/EBPbeta, also known as NF-IL6) and activation is well-documented in several inflammatory states. Hepatic cryoablation, a non-resectional surgical technique used to eliminated primary and metastatic liver tumors, is associated with ARDS when more than 30-35% is ablated. The mechanisms of this response remain undefined. Previous studies have shown that liver injury produced by cryoablation in experimental animals caused an early activation of NF- kappaB, followed by TNF-alpha release in the liver and then NF-kappaB activation in the lungs with histologic findings similar to those seen in Adult Respiratory Distress Syndrome; none of these events follows hepatic resection.
The specific aims are to: 1) To determine the role of the proximal cytokines, TNF-alpha and IL-1 in the response to hepatic cryoablation using TNF-alpha, IL-1, and TNF-alpha/IL-1 receptor knockout transgenic mice. 2) To determine if altering NF-kappaB or C/EBP (P20) activation in the liver affects the response to cryoablation. Results of these studies should lead to enhanced understanding of the liver's role in propagation of SIRS in response to direct liver injury and may permit mediator specific strategies to ameliorate deleterious events in the setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK010160-02
Application #
6516948
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Podskalny, Judith M,
Project Start
2002-03-01
Project End
2003-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$18,278
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212