The long-term objective of our research is to determine the mechanisms by which mast cells regulate the host response to bacterial lung infections and to be able to modify how mast cells coordinate this response in ways that benefit the host. Recently, we made the discovery that the mast cell protease dipeptidyl peptidase I (DPPI) contributes to death of the host from septic peritonitis and that it appears to do so by regulating levels of mast cell IL-6. This suggests that mast cell DPPI, or other mast cell proteins regulated by DPPI, modify the host response to bacterial infection in ways that harm the host. Our central hypothesis is that: Mast cell proteases and cytokines coordinate lung defense against bacterial infections. While coordinating this defense, some of these mediators protect the host and improve survival while others harm the host and worsen survival.
Specific aims are: #1. To determine the mechanism by which mast cell DPPI modulates the host response and survival from bacterial lung infections. This will be accomplished by applying a new method for creating mast cell-specific knockout mice and determining the physiologic mechanism for survival following inoculation with Klebsiella pneumoniae. #2. To define mechanisms by which mast cell proteases regulate cytokine levels during bacterial infections. We will test whether mast cell proteases hydrolyze cytokines by incubating cytokines with purified DPPI, tryptase or chymase and identifying cleavage products. Protease mediated cytokine production will be studied by measuring cytokines released by specific lung cells in response to DPPI, tryptase or chymase. #3. To determine whether mast cell TNF-alpha, IL-6, or IL-10 modulate the host response and survival from bacterial lung infections. We will use mast cell-specific-TNF-alpha, -IL-6, or -IL-10 knockout mice to test if mast cell sources of these cytokines play important roles in host defense. By understanding how specific mast cell mediators regulate host defense, we will gain greater insight into how these cells influence host survival. This knowledge can then be applied to the development of new treatments for bacterial pneumonia that modulate the activity of specific mast cells proteins in ways that improve survival.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075026-01A1
Application #
6820426
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Reynolds, Herbert Y
Project Start
2004-07-02
Project End
2008-06-30
Budget Start
2004-07-02
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$378,750
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sutherland, Rachel E; Barry, Sophia S; Olsen, Joanna S et al. (2014) Dipeptidyl peptidase I controls survival from Klebsiella pneumoniae lung infection by processing surfactant protein D. Biochem Biophys Res Commun 450:818-823
Seeley, Eric J; Barry, Sophia S; Narala, Saisindhu et al. (2013) Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice. J Immunol 190:4717-24
Sutherland, Rachel E; Xu, Xiang; Kim, Sophia S et al. (2011) Parasitic infection improves survival from septic peritonitis by enhancing mast cell responses to bacteria in mice. PLoS One 6:e27564
Seeley, Eric J; Sutherland, Rachel E; Kim, Sophia S et al. (2011) Systemic mast cell degranulation increases mortality during polymicrobial septic peritonitis in mice. J Leukoc Biol 90:591-7
Liu, Jian; Divoux, Adeline; Sun, Jiusong et al. (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940-5
Wolters, Paul J; Wray, Charlie; Sutherland, Rachel E et al. (2009) Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury. J Immunol 182:8056-62
Sutherland, Rachel E; Olsen, Joanna S; McKinstry, Andrew et al. (2008) Mast cell IL-6 improves survival from Klebsiella pneumonia and sepsis by enhancing neutrophil killing. J Immunol 181:5598-605
Sun, Jiusong; Sukhova, Galina K; Yang, Min et al. (2007) Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. J Clin Invest 117:3359-68
Sun, Jiusong; Sukhova, Galina K; Wolters, Paul J et al. (2007) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 13:719-24
Mallen-St Clair, Jon; Shi, Guo-Ping; Sutherland, Rachel E et al. (2006) Cathepsins L and S are not required for activation of dipeptidyl peptidase I (cathepsin C) in mice. Biol Chem 387:1143-6

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