A Novel Large Animal Model of ARDS induced by Mitochondrial Products

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Presentation transcript:

A Novel Large Animal Model of ARDS induced by Mitochondrial Products Pablo Sanchez, MD PhD AATS 2015 Seattle

No Disclosures

Acute Respiratory Distress Syndrome -Morbidity and Mortality modest decline -Treatment remains primarily supportive -Pharmacologic therapies not effectively translated -Need for animal models to test new hypotheses

ARDS: Pathogenesis -Dysregulated Inflammation *Activation Innate Immune System Pathogens PAMPs Cell injury molecules DAMPs *Uncontrolled Activation of Coagulation -Alveolar Barrier Disruption * Altered alveolar and endothelial permeability

Eukaryotic Cell Sepsis Cell Injury Neutrophil Activation Bacteria Evolution Mitochondria Sepsis Cell Injury Molecular Products PAMPs Molecular Products DAMPs TLR Neutrophil Activation

Rat lung: sham Rat lung : MTD NATURE March 2010 Mice lung: sham Mice lung : Histones Am J Respir Crit Care Med Jan 2013

Hypothesis Injection of Mitochondrial Products in swine activates the innate immune system resulting in SIRS and ARDS. This response is clinically similar to models of “infectious sepsis”.

Methods Isolated Mitochondria Disrupted by sonication 35-45 Kg Male Yorkshire 35-45 Kg Male Yorkshire

Methods Control Group n=3 LPS Group n=3 50ng/kg mt-DAMPs n=6 15 µg/ ml of blood volume Animals received supportive treatment according to Surviving Sepsis Guidelines

Results: Clinical Signs of SIRS * * * NS WBC (cells/mcL) *p<0.05 mt-DAMPs and LPS developed clinical signs of SIRS mt-DAMPs led to leukocytosis LPS led to leukopenia

Results: Clinical Signs of ARDS * * * NS NS Final PaO2/FiO2 Oxygenation Index Wet/Dry ratio *p<0.05 mt-DAMPs and LPS showed decreased P/F ratios mt-DAMPs and LPS showed increased Oxygenation Index

Results: Histology quantification of ARDS * H & E Myeloperoxidase NS Control LPS DAMPs Lung Injury Score * * MMP-8 protein expression *p<0.05

Results: Lung and Systemic Inflammation * * NS NS LPS DAMPS mRNA fold increase from Controls Lung IL-6 pg/mg protein Serum IL-6 (pg/ml) IL-6 TNF-α Procalcitonin BL HR6 BL HR6 BL HR6 Control LPS DAMPs *p<0.05 No differences chemokine levels between mt-DAMPs and LPS

Conclusions Our data demonstrates that the release of mitochondrial products to the circulation leads to SIRS and ARDS. In its acute phase, this response is indistinguishable from LPS induced sepsis. There were subtle differences between the models which require further investigation.

Thank you! Division of Cardiac Surgery University of Maryland SOM Bartley Griffith James Gammie Si Pham Keshava Rajagopal Chetan Pasrija Matthew Mulligan Diana Pratt Division of Cardiac Surgery University of Maryland SOM Artificial Organs Laboratory Mandheer Wadhwa Tieluo Li Thank you!