Lung infections account for a tremendous burden of disease worldwide, representing the most frequent cause of infection-related deaths and a leading cause of acute lung injury. Overcoming lower respiratory tract infection requires a critica yet dangerous innate immune response, typified by robust inflammation. The biological signals eliciting innate immunity must be delicately balanced by mechanisms maintaining tissue integrity and homeostasis. How these pathways converge to promote adequate host defense while limiting inflammatory injury is poorly understood. We have recently shown that during bacterial pneumonia, the cytokine leukemia inhibitory factor (LIF) is critical for activation of the transcription factor STAT3, which has emerged as an important signaling hub for both antimicrobial defense and tissue protection in the lungs and other mucosal tissue sites. However, the regulation and functional significance of LIF during lung infection is virtually unknown. Preliminary results indicate that LIF neutralization causes a profound increase in lung injury in pneumonic mice, suggesting that LIF serves to offset inflammatory injury in response to infectious microbes. By pursuing the following aims, we will test the central hypothesis that LIF is a critical determinant of tissue protection during pneumonia:
Aim 1) Test the hypothesis that LIF is necessary and sufficient for STAT3- mediated protection against lung injury during pneumonia;
Aim 2) Test the hypothesis that during pneumonia neutrophils elaborate LIF in a RelA-dependent manner to counter inflammatory lung injury;
and Aim 3) Test the hypothesis that the soluble variant of the LIF receptor is a negative acute phase protein regulating LIF biological activity during pneumonia. By elucidating the biology of this understudied and poorly understood pathway, pursuit of these aims will provide novel insights regarding the cellular and molecular mechanisms of tissue protection during pneumonia. Moreover, dissection of the LIF-STAT3 pathway during lung infection has clear potential for future translational directions, as it is anticipated to reveal candidate molecular targets for better identifying and/or treating patient with or at risk for acute lung injury.

Public Health Relevance

Lung infections are a major public health concern, accounting for the greatest burden of disease in both poor and wealthy communities. However, the immune response to this important disease often results in acute lung injury. The goal of our laboratory and this proposal is to identify biological pathways that balance the consequences of infection and immunity during pneumonia, possibly revealing novel targets for clinical intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111449-02
Application #
8526540
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Eu, Jerry Pc
Project Start
2012-08-15
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$389,606
Indirect Cost
$151,606
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Quinton, Lee J (2018) C-rac-king the Code of Smoke-induced Pneumonia Susceptibility. Am J Respir Crit Care Med 198:1246-1248
Smith, N Ms; Wasserman, G A; Coleman, F T et al. (2018) Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol 11:220-235
Quinton, Lee J; Walkey, Allan J; Mizgerd, Joseph P (2018) Integrative Physiology of Pneumonia. Physiol Rev 98:1417-1464
Wasserman, Gregory A; Szymaniak, Aleksander D; Hinds, Anne C et al. (2017) Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells. J Clin Invest 127:3866-3876
Traber, Katrina E; Symer, Elise M; Allen, Eri et al. (2017) Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol 313:L548-L558
Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10
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

Showing the most recent 10 out of 19 publications