Pneumonia is the leading cause of infectious deaths in the U.S. and the most common factor underlying acute lung injury. Community acquired pneumonias are most often caused by Streptococcus pneumoniae, whereas nosocomial pneumonias are commonly caused by Gram-negative enteric bacteria such as Escherichia coli. Fighting bacteria while preventing lung injury requires precisely regulated gene expression mediated by cytokine-transcription factor networks. Our long-term goals are to elucidate these signaling networks so that cytokines and transcription factors may be manipulated to improve host defense and prevent lung injury. The cytokine IL-6 is essential to neutrophil recruitment and bacterial clearance during bacterial pneumonia. The transcription factor STAT3 can be activated by IL-6, and is critical to preventing lung injury after hyperoxia. Our broad objectives are to determine whether STAT3 is activated in the lungs during pneumonia, to decipher the upstream pathways regulating STAT3 activation during pneumonia, and to determine whether increasing STAT3 activity protects the lungs during pneumonia. Based on results from our preliminary studies, we have formulated the central hypothesis that STAT3 is activated by different upstream cytokine pathways during E. coli and S. pneumoniae pneumonias to increase neutrophil recruitment and prevent lung injury. To test this central hypothesis, we have developed strategies for studying gene induction and transcription factor function in the lungs in vivo, using plasmid transfection, and for identifying transcription factors activated in the lungs in vivo, using proteomics. With these approaches, we will pursue the following specific aims: (1) to test the hypothesis that STAT3 activation requires IL-6 during E. coli pneumonia, (2) to test the hypothesis that, during S. pneumoniae pneumonia, STAT3 is activated by multiple IL-6 family cytokines whose expression requires NF-KappaB activation from receptors for TNFalpha and IL-1, (3) to test the hypothesis that STAT3 activity in the lungs increases neutrophil recruitment and decreases lung injury during pneumonia, and (4) to identify transcriptional regulators other than STAT3 that depend on IL-6 during pneumonia. Elucidating the regulation and function of IL-6 and STAT3 during pneumonia will provide molecular targets for improving host defense and preventing lung injury in patients with or at risk for lung infections.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079392-01A1
Application #
6968007
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Reynolds, Herbert Y
Project Start
2005-07-14
Project End
2010-05-31
Budget Start
2005-07-14
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$410,000
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
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Mizgerd, Joseph P (2017) Pathogenesis of severe pneumonia: advances and knowledge gaps. Curr Opin Pulm Med 23:193-197
Coleman, Fadie T; Blahna, Matthew T; Kamata, Hirofumi et al. (2017) Capacity of Pneumococci to Activate Macrophage Nuclear Factor ?B: Influence on Necroptosis and Pneumonia Severity. J Infect Dis 216:425-435
Kamata, Hirofumi; Yamamoto, Kazuko; Wasserman, Gregory A et al. (2016) Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia. Am J Respir Cell Mol Biol 55:407-18
Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia. Infect Immun 83:4015-27
Hilliard, Kristie L; Allen, Eri; Traber, Katrina E et al. (2015) The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia. Am J Respir Cell Mol Biol 53:378-90
Quinton, Lee J; Mizgerd, Joseph P (2015) Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling. Annu Rev Physiol 77:407-30
Traber, Katrina E; Hilliard, Kristie L; Allen, Eri et al. (2015) Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia. Am J Respir Cell Mol Biol 53:479-88
Ubags, Niki D; Vernooy, Juanita H; Burg, Elianne et al. (2014) The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury. Crit Care Med 42:e143-51
Mizgerd, Joseph P (2014) The infant nose. Introducing the respiratory tract to the world. Am J Respir Crit Care Med 190:1206-7

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