An essential component of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that injury of the endothelial barrier of pulmonary microvessels results in persistent increase in lung vascular permeability to protein and intractable protein-rich edema formation. Compared to young patients, the incidence of ALI/ARDS resulting from sepsis in elderly patients is as much as 19-fold greater and the mortality rate is up to 10-fold greater. However, the underlying causes are poorly understood. Also crucially little is known how aging influences mechanisms of endothelial regeneration and restoration of vascular homeostasis following sepsis challenge. We have recently shown that the Forkhead transcription factor FoxM1 is a key reparative factor responsible for endothelial regeneration. However, our new Supporting Data presented here show that FoxM1 expression and the endogenous endothelial regeneration program were severely impaired in aged lungs following inflammatory lung injury. We observed that endothelial hypoxia-inducible factor HIF-1? is the critical mediator of FoxM1 expression through transcriptional control of SDF-1? which activates CXCR4 receptor leading to activation of the GPCR-dependent p110gamma isoform of PI3K, and that inhibition of the oxygen sensors HIF prolyl hydroxylase (PHDs) re-induced FoxM1 expression and activated the endothelial regeneration program in aged lungs. Thus, we hypothesize that impaired HIF- 1?->FoxM1 signaling secondary to activation of PHD2 in aged lungs is responsible for the severely defective endothelial regeneration in these lungs, and activation of this fundamental reparative pathway through PHD2 inhibition and CXCR4 activation is a potential novel therapeutic approach for reversing lung microvessel leakiness and improving survival of elderly ALI/ARDS patients. The proposed studies address the following Specific Aims.
In Aim #1, we will address the role of impaired HIF-1?->FoxM1 signaling in aged lungs as a crucial factor responsible for severely impaired endothelial regeneration and restoration of lung vascular homeostasis following sepsis challenge.
In Aim #2, we will delineate the signaling mechanisms underlying severely defective endothelial regeneration in aged lungs following sepsis challenge.
In Aim #3, we will determine the role of HIF-1? stabilization through PHD inhibition in activating endothelial regeneration in aged lungs. We will also address the potential clinical relevance of our findings in animal models to humans; thereby determine the therapeutic implications of inhibition of PHD2 and activation of CXCR4 in treatment of ALI/ARDS of elderly patients. With these comprehensive studies, we will delineate the fundamental signaling mechanisms of impaired endothelial regeneration in aged lungs, and identify therapeutic targets to activate this fundamental intrinsic HIF-1?->FoxM1-dependent mechanisms to repair leaky lung microvessels for the treatment of ALI/ARDS in elderly patients.

Public Health Relevance

Acute lung injury (ALI) and in its more severe form, acute respiratory distress syndrome (ARDS) bears the hallmark of inflammatory infiltration and protein-rich lung edema due to severe disruption of lung vascular endothelial barrier. Compared to young patients, the incidence of ALI/ARDS resulting from sepsis in elderly patients is as much as 19-fold greater, and the mortality rate of elderly ALI/ARDS patients is up to 10-fold greater. The central objective of the proposed studies is to delineate the molecular mechanisms of defective endothelial regeneration in aged lungs, and thereby provide novel therapeutic strategies by which the dormant endothelial regeneration program can be activated in these lungs to restore lung fluid balance and improve survival of elderly ALI/ARDS patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL123957-05
Application #
9618476
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Lin, Sara
Project Start
2014-08-15
Project End
2019-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension. Am J Respir Crit Care Med 198:788-802
Dai, Zhiyu; Zhao, You-Yang (2017) Discovery of a murine model of clinical PAH: Mission impossible? Trends Cardiovasc Med 27:229-236
Du, Xueke; Jiang, Chunling; Lv, Yang et al. (2017) Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling. PLoS One 12:e0180213
Evans, Colin E; Zhao, You-Yang (2017) Impact of thrombosis on pulmonary endothelial injury and repair following sepsis. Am J Physiol Lung Cell Mol Physiol 312:L441-L451
Soni, Dheeraj; Regmi, Sushil C; Wang, Dong-Mei et al. (2017) Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions. Am J Physiol Lung Cell Mol Physiol 312:L1003-L1017
Evans, Colin E; Zhao, You-Yang (2017) Molecular Basis of Nitrative Stress in the Pathogenesis of Pulmonary Hypertension. Adv Exp Med Biol 967:33-45
Li, Liping; Sheng, Yue; Li, Wenshu et al. (2017) ?-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q). Cancer Res 77:4116-4126
Chen, Qian; Suresh Kumar, Varsha; Finn, Johanna et al. (2017) CD44high alveolar type II cells show stem cell properties during steady-state alveolar homeostasis. Am J Physiol Lung Cell Mol Physiol 313:L41-L51
Wu, Chaomin; Evans, Colin E; Dai, Zhiyu et al. (2017) Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome. PLoS One 12:e0174327
Dai, Zhiyu; Li, Ming; Wharton, John et al. (2016) Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2?. Circulation 133:2447-58

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