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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Brigham and Women's Hospital
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Beitler, Jeremy R; Schoenfeld, David A; Thompson, B Taylor (2014) Preventing ARDS: progress, promise, and pitfalls. Chest 146:1102-13
Siempos, Ilias I; Lam, Hilaire C; Ding, Yan et al. (2014) Cecal ligation and puncture-induced sepsis as a model to study autophagy in mice. J Vis Exp :e51066
Suliman, Hagir B; Piantadosi, Claude A (2014) Mitochondrial biogenesis: regulation by endogenous gases during inflammation and organ stress. Curr Pharm Des 20:5653-62
Agrawal, Pankaj B; Pierson, Christopher R; Joshi, Mugdha et al. (2014) SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 95:218-26
Nakahira, Kiichi; Cloonan, Suzanne M; Mizumura, Kenji et al. (2014) Autophagy: a crucial moderator of redox balance, inflammation, and apoptosis in lung disease. Antioxid Redox Signal 20:474-94
Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74
Colas, Romain A; Shinohara, Masakazu; Dalli, Jesmond et al. (2014) Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol 307:C39-54
Shinohara, Masakazu; Kibi, Megumi; Riley, Ian R et al. (2014) Cell-cell interactions and bronchoconstrictor eicosanoid reduction with inhaled carbon monoxide and resolvin D1. Am J Physiol Lung Cell Mol Physiol 307:L746-57
Ryter, Stefan W; Koo, Ja Kun; Choi, Augustine M K (2014) Molecular regulation of autophagy and its implications for metabolic diseases. Curr Opin Clin Nutr Metab Care 17:329-37
Kraft, Bryan D; Piantadosi, Claude A; Benjamin, Ashlee M et al. (2014) Development of a novel preclinical model of pneumococcal pneumonia in nonhuman primates. Am J Respir Cell Mol Biol 50:995-1004

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