Acute lung injury is an event that occurs as a consequence of a variety of disease states which share a common pathobiological process, neutrophilic lung inflammation (NLI). NLI likely results from increased production of inflammatory cytokines and endothelial-leukocyte adhesion molecules, many of which are regulated by the ubiquitous transcription factor complex, NF-kappaB. Although NF-kappaB is necessary for directing high level transcription of many cytokines, adhesion molecules, and other pro-inflammatory genes in tissue culture, the extent to which NF-kappaB controls specific biological processes in vivo remains unanswered. Systemic inflammation induced by injection of bacterial lipopolysaccharide (LPS) results in a reproducible pattern of NF-kappaB activation in lung tissue, gene expression of several NF- kappaB-dependent cytokines, and NLI. At present, the proximate stimulus for NF-kappaB activation in the lung following LPS injection is unknown. NF-kappaB activation could occur as a result of direct stimulation of lung cells by LPS. Conversely, other mediators, such as TNFalpha or IL-1, could be primarily responsible for lung NF-kappaB activation in this setting. Another uncertainty is whether NF-kappaB is activated diffusely and simultaneously in all lung cells, or whether the timing and intensity of NF-kappaB activation differs among subpopulations of lung cells. The larger question concerns the extent to which NF-kappaB activation regulates production of cytokines and other pro-inflammatory molecules in vivo. It is uncertain whether NF-kappaB activation is merely a marker of significant acute inflammation. The following hypotheses are proposed to address these issues: 1) systemic LPS induces NF-kappaB activation in the lung through both direct stimulation of lung cells and action of the LPS-induced cytokines TNFalpha and IL-1,2) specific subsets of lung cells are differentially activated following LPS injection, and 3) targeting NF-kappaB in lung cells for molecular intervention will result in attenuation of LPS-induced neutrophilic lung inflammation. We have four specific aims to address these hypotheses using a murine model system of NLI following intraperitoneal injection of LPS. The first is to define the characteristic pattern of NF-kappaB activation in lung (compared to other organs) following intraperitoneal injection of LPS and relate NF-kappaB activation to expression of NF- kappaB dependent cytokine genes and NLI. The second specific aim is to investigate the specific cell types in the lung which respond to intraperitoneal LPS injection by activating NF-kappaB. The third specific aim is to modulate LPS-induced activation of NF-kappaB in the lungs by inhibiting the cytokine cascade or blocking IKappaB degradation. The last specific aim is to specifically target the NF- kappaB complex in the lung for molecular intervention using a trans- dominant inhibitor of the NF-kappaB complex. These studies should lead to a better understanding of the role of NF-kappaB in the molecular regulation of NLI, and may ultimately lead to better treatment strategies for the adult respiratory distress syndrome and other inflammatory lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061419-02
Application #
6125974
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1999-01-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$190,608
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Saxon, Jamie A; Cheng, Dong-Sheng; Han, Wei et al. (2016) p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment. J Immunol 196:1891-9
Giannou, Anastasios D; Marazioti, Antonia; Spella, Magda et al. (2015) Mast cells mediate malignant pleural effusion formation. J Clin Invest 125:2317-34
Han, Wei; Li, Hui; Cai, Jiyang et al. (2013) NADPH oxidase limits lipopolysaccharide-induced lung inflammation and injury in mice through reduction-oxidation regulation of NF-?B activity. J Immunol 190:4786-94
Li, Hui; Luo, Yi-Feng; Williams, Bryan J et al. (2012) Structure and function of OprD protein in Pseudomonas aeruginosa: from antibiotic resistance to novel therapies. Int J Med Microbiol 302:63-8
Karabela, Sophia P; Psallidas, Ioannis; Sherrill, Taylor P et al. (2012) Opposing effects of bortezomib-induced nuclear factor-?B inhibition on chemical lung carcinogenesis. Carcinogenesis 33:859-67
Zaynagetdinov, Rinat; Sherrill, Taylor P; Polosukhin, Vasiliy V et al. (2011) A critical role for macrophages in promotion of urethane-induced lung carcinogenesis. J Immunol 187:5703-11
Segal, Brahm H; Han, Wei; Bushey, Jennifer J et al. (2010) NADPH oxidase limits innate immune responses in the lungs in mice. PLoS One 5:e9631
Williams, Bryan J; Du, Rui-Hong; Calcutt, M Wade et al. (2010) Discovery of an operon that participates in agmatine metabolism and regulates biofilm formation in Pseudomonas aeruginosa. Mol Microbiol 76:104-19
Stathopoulos, Georgios T; Sherrill, Taylor P; Karabela, Sophia P et al. (2010) Host-derived interleukin-5 promotes adenocarcinoma-induced malignant pleural effusion. Am J Respir Crit Care Med 182:1273-81
Joo, Myungsoo; Kwon, Minjae; Cho, Yong-Jig et al. (2009) Lipopolysaccharide-dependent interaction between PU.1 and c-Jun determines production of lipocalin-type prostaglandin D synthase and prostaglandin D2 in macrophages. Am J Physiol Lung Cell Mol Physiol 296:L771-9

Showing the most recent 10 out of 47 publications