Pneumonia is a leading cause of morbidity and mortality across the socioeconomic spectrum. It is also the most frequent cause of acute respiratory distress syndrome (ARDS), due in large part to a harmful imbalance of biological pathways promoting antimicrobial resistance and tissue resilience. The latter is essential for maintaining barrier integrity and limiting alveolar flooding, but host mechanisms protecting the delicate air-liquid interface during pneumonia remain poorly understood. We have previously shown that the IL-6 family cytokine leukemia inhibitory factor (LIF) is critical for limiting acute lung injury in response to infection, and its protective properties do not appear to influence host immunity. A more complete understanding of the biological signals up- and downstream of this cytoprotective factor, which are currently unclear, may provide a unique and important window into pathways that dictate tissue homeostasis without compromising antimicrobial defense. Our published and preliminary results suggest that lung epithelium is both the source and target of LIF during pneumonia, serving as a mechanism of inducible resilience. Initial results also suggest that this response is macrophage-mediated, and that it may involve LIF-dependent changes in the cytoprotective transcriptional co- activator Yes-associated protein (YAP), as well as regulation of the low-density lipoprotein receptor-1 (LOX-1), which can promote injury and cell death. Here we propose the central hypothesis that epithelial integrity is maintained in pneumonic lungs by a macrophage-dependent paracrine LIF axis that promotes tissue resilience. This hypothesis will be tested by pursuing the following 3 aims:
Aim 1) Test the hypothesis that LIFR? signaling in lung epithelium prevents acute lung injury during pneumonia;
Aim 2) Test the hypothesis that macrophage-epithelial communication initiates the tissue protective circuit mediated by LIF;
and Aim 3) Test the hypothesis that LOX-1 induction sensitizes epithelial cells to pneumonic lung injury, and is countered by LIF to fortify tissue resilience. Studies designed to address these aims will employ complementary in vivo and ex vivo strategies to reveal novel pathways of tissue protection in the setting of lung infection. We anticipate that these findings will be leveraged for the development of novel clinical interventions in patients with or at risk for pneumonia and ARDS.

Public Health Relevance

Lung infections, which represent the leading cause of acute respiratory distress syndrome (ARDS), are a leading cause of morbidity and mortality worldwide. The goal of our laboratory and this proposal is to identify biological pathways that limit tissue injury in response to invading pathogens, possibly revealing novel targets for clinical intervention in patients with or at risk for pneumonia and ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111449-08
Application #
9730539
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Zhou, Guofei
Project Start
2012-08-15
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
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