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 HO-1/CO system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving SOCS3, 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 SOCS3, 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.
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 SOCS3, 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.
| Ma, Kevin C; Schenck, Edward J; Pabon, Maria A et al. (2018) The Role of Danger Signals in the Pathogenesis and Perpetuation of Critical Illness. Am J Respir Crit Care Med 197:300-309 |
| Schenck, Edward J; Oromendia, Clara; Torres, Lisa K et al. (2018) Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. Chest : |
| Schenck, Edward J; Ma, Kevin C; Murthy, Santosh B et al. (2018) Danger Signals in the ICU. Crit Care Med 46:791-798 |
| Ghanta, Sailaja; Kwon, Min-Young; Rosas, Ivan O et al. (2018) Mesenchymal Stromal Cell Therapy: Does the Source Matter? Crit Care Med 46:343-345 |
| Baron, Rebecca M; Kwon, Min-Young; Castano, Ana P et al. (2018) Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis. J Leukoc Biol 104:677-689 |
| Shu, Chang; Huang, He; Xu, Ying et al. (2018) Pressure Overload in Mice With Haploinsufficiency of Striated Preferentially Expressed Gene Leads to Decompensated Heart Failure. Front Physiol 9:863 |
| Harrington, John S; Schenck, Edward J; Oromendia, Clara et al. (2018) Acute respiratory distress syndrome without identifiable risk factors: A secondary analysis of the ARDS network trials. J Crit Care 47:49-54 |
| Siempos, Ilias I; Ma, Kevin C; Imamura, Mitsuru et al. (2018) RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. JCI Insight 3: |
| Rosas, Ivan O; Goldberg, Hilary J; Collard, Harold R et al. (2018) A Phase II Clinical Trial of Low-Dose Inhaled Carbon Monoxide in Idiopathic Pulmonary Fibrosis. Chest 153:94-104 |
| Suliman, Hagir B; Keenan, Jeffrey E; Piantadosi, Claude A (2017) Mitochondrial quality-control dysregulation in conditional HO-1-/- mice. JCI Insight 2:e89676 |
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