Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) is a major cause of sepsis-induced mortality in the ICU. Patients who initially survive may subsequently die with immune paralysis characterized by poorly understood mechanisms involving the over-expression of counter-regulatory cytokines that suppress NF-KB-dependent pro-Inflammatory cytokine synthesis. Sepsis induces heme oxygenase-1 (HO-1;Hmox1), which has specific anti-inflammatory effects, e.g. via carbon monoxide (CO) mediated IL-10 production, and exerts powerful control over the transcriptional network of mitochondrial biogenesis, which safeguards energy metabolism by improving mitochondrial mass and promoting clearance of damaged organelles {mitophagy). Our preliminary data demonstrate that HO-1/CO up-regulates the suppressor of cytokine signaling-3 (S0CS3), the inflammasome inhibitor/anti-apoptotic protein BCIXL, DNA damage regulated autophagy modulator protein 1 (Dram1), and the mitophagy genes NIX and BNIP3. This information suggests that the H0-1/C0 system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving S0CS3, BCIXL and Dram1. We hypothesize that the transcriptional network of mitochondrial biogenesis regulates the anti-inflammatory response through HO-1/CO-dependent NFE2I2 and NRF-1 activation, leading to up-regulation of IL10 and S0CS3, activation of mitophagy. and suppression of inflammasome-mediated IL-1 B production and suppression of apoptosis. Using Staphylococcal aureus (S. aureus) sepsis and pneumonia in mice and relevant cell models in two mechanistic molecular Aims, and through a translational third Aim, we will address how this integrated process of mitochondrial quality control mitigates lung and liver inflammation and hastens the resolution of sepsis. Completion of these Aims and a successful test of this hypothesis would allow a paradigm shift in our understanding and approach to sepsis-induced organ failure both experimentally and clinically, as well as test CO pre-clinically as a way to improve mitochondrial quality control in ALI and MODS.

Public Health Relevance

Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) in sepsis is a major cause of death in ICU patients. Patients who initially survive may subsequently die with so-called immune paralysis, which is poorly understood. The induction of heme oxygenase-1 (HO-1;Hmox1) and endogenous CO production has powerful anti-inflammatory effects and exerts control over mitochondrial biogenesis, which improves mitochondrial mass and promotes the clearance of damaged organelles (mitophagy). We propose that gene regulation for mitochondrial biogenesis cross-talks with the anti-Inflammatory response through HO-1/CO, increasing the expression of anti-inflammatory IL10 and S0CS3, activating mitophagy and preventing cell death. Using experimental models of S. aureus pneumonia and sepsis, we will address how this integrated process of mitochondrial quality control mitigates inflammation in the lungs and liver and hastens the resolution of sepsis, thereby greatly improving our understanding and approach to sepsis-induced MODS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108801-03
Application #
8526533
Study Section
Special Emphasis Panel (ZHL1-PPG-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$425,889
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Ryter, Stefan W; Choi, Augustine M K (2016) Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation. Transl Res 167:7-34
Lee, Seonmin; Suh, Gee-Young; Ryter, Stefan W et al. (2016) Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. Am J Respir Cell Mol Biol 54:151-60
Piantadosi, Claude A (2016) Cardioprotective role of S-nitrosylated hemoglobin from rbc. J Clin Invest 126:4402-4403
Liu, Fei; Haeger, Christina Mallarino; Dieffenbach, Paul B et al. (2016) Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension. JCI Insight 1:
Tsoyi, Konstantin; Hall, Sean R R; Dalli, Jesmond et al. (2016) Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators. Crit Care Med 44:e1236-e1245
Suliman, Hagir B; Zobi, Fabio; Piantadosi, Claude A (2016) Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes. Antioxid Redox Signal 24:345-60
Ghanta, Sailaja; Tsoyi, Konstantin; Liu, Xiaoli et al. (2016) Mesenchymal Stromal Cells Deficient in Autophagy Proteins are Susceptible to Oxidative Injury and Mitochondrial Dysfunction. Am J Respir Cell Mol Biol :
Nakahira, Kiichi; Pabon Porras, Maria Angelica; Choi, Augustine M K (2016) Autophagy in Pulmonary Diseases. Am J Respir Crit Care Med 194:1196-1207
Moon, Jong-Seok; Nakahira, Kiichi; Chung, Kuei-Pin et al. (2016) NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages. Nat Med 22:1002-12
Zhang, Ruoyu; Nakahira, Kiichi; Guo, Xiaoxian et al. (2016) Very Short Mitochondrial DNA Fragments and Heteroplasmy in Human Plasma. Sci Rep 6:36097

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