Acute lung injury (ALl) is frequently associated with sepsis. Activation of procoagulant and fibrinolytic cascades occurs in ALl, and includes increased expression of urokinase plasminogen activator (uPA) and its inhibitors, such as plasminogen activator inhibitor (PAl-1), in the lungs. ALl is also characterized by the accumulation of large numbers of activated neutrophils in the lungs. Our preliminary data demonstrate a novel pro-inflammatory role for uPA. These results show that uPA contributes to acute lung injury produced by endotoxemia and also potentiates LPS and PGN induced neutrophil activation. Determination of the molecular mechanisms and receptors through which uPA enhances neutrophil activation and contributes to the development of ALl is the major goal of the proposed experiments. Our hypothesis is that processes involving the balance between uPA and its inhibitors contribute to neutrophil activation and pulmonary inflammation in sepsis induced ALl.
The specific aims of this project are: 1) To elucidate the effects of uPA and the kringle domain of uPA on neutrophil activation, the receptors involved in uPA induced potentiation of neutrophil activation, and the role of uPA in contributing to the development of LPS and P. aeruginosa induced ALl; 2) To determine the importance of uPA generated plasmin in contributing to neutrophil activation and to the development of ALl; and 3) To examine how interactions between uPA and PAl modulate neutrophil activation and development of ALl. Our goal is to characterize mechanisms involved in neutrophil activation that are modulated by exposure to uPA, plasmin, and PAl-1, and that contribute to the development and severity of ALl. Delineation of such uPA dependent pro-inflammatory mechanisms, that may not involve proteolytic properties of uPA, will provide novel insights into interactions between fibrinolytic cascades and neutrophil activation, particularly in the setting of neutrophil dependent inflammatory responses, such as ALl. The proposed experiments are likely to suggest new therapeutic approaches to improve outcome from important clinical conditions, such as sepsis induced acute lung injury in which both fibrinolytic and neutrophil dependent pathways play major roles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076206-03
Application #
7211466
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$327,644
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Cui, Huachun; Banerjee, Sami; Xie, Na et al. (2016) MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation. Am J Respir Cell Mol Biol 54:843-52
Tan, Zheng; Xie, Na; Cui, Huachun et al. (2015) Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194:6082-9
Xie, Na; Tan, Zheng; Banerjee, Sami et al. (2015) Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis. Am J Respir Crit Care Med 192:1462-74
Xie, Na; Liu, Gang (2015) ncRNA-regulated immune response and its role in inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol 309:L1076-87
Huang, Shengping; Liu, Shufeng; Fu, Jia J et al. (2015) Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem 290:20782-92
Tan, Zheng; Xie, Na; Banerjee, Sami et al. (2015) The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages. J Biol Chem 290:46-55
Cui, Huachun; Xie, Na; Thannickal, Victor J et al. (2015) The code of non-coding RNAs in lung fibrosis. Cell Mol Life Sci 72:3507-19
Cui, Huachun; Xie, Na; Tan, Zheng et al. (2014) The human long noncoding RNA lnc-IL7R regulates the inflammatory response. Eur J Immunol 44:2085-95
Armstead, William M; Riley, John; Cines, Douglas B et al. (2014) PAI-1-derived peptide EEIIMD prevents hypoxia/ischemia-induced aggravation of endothelin- and thromboxane-induced cerebrovasoconstriction. Neurocrit Care 20:111-8
Xie, Na; Cui, Huachun; Banerjee, Sami et al. (2014) miR-27a regulates inflammatory response of macrophages by targeting IL-10. J Immunol 193:327-334

Showing the most recent 10 out of 84 publications