Activation of clotting & cell adhesion: gas embolism

Summary

Principal Investigator: David Eckmann
Abstract: Vascular gas embolism contributes to cerebral dysfunction in over 300,000 cardiopulmonary bypass patients in the US annually. Transient and permanent brain abnormalities occur. These include reduced cognitive function, speech and speech processing impairment, and diminished or lost orientation. All are consistent with episodes of therapy-induced stroke. Gas embolism is pervasive in medicine, with at least two unavoidable key triggers associated with bypass: bubble nucleation in oxygenator membranes and blood degassing triggered by rapid warming of cooled patient blood. Our research is first directed at developing an understanding of the key, as yet undefined, molecular mechanisms inciting injury, including the initiation of pathological processes in response to blood and blood vessel contact with gas bubbles. Embolism bubbles induce derangements of endothelial cell barrier function, calcium homeostasis and cell death. Bubbles promote clot formation, cellular activation, and adhesion events. Identification of the molecular basis of pathophysiological responses provides insights and opportunities for therapy. Our second research goal is to develop chemical interventions to reduce tissue injury from gas embolism. By identifying chemical agents that attenuate or eliminate these pathological processes, the risks of unregulated stroke events after extracorporeal blood oxygenation may be better prevented or controlled. Four specific aims are proposed: Aim 1 In vivo experiments with rats having gas embolism-induced brain injury to evaluate dose-dependent neuroprotection using a surfactant as a chemical based intervention. Aim 2 In vitro experiments with cells (endothelium, platelets) to identify the molecular basis of gas embolism-induced changes in cellular function in human blood and blood vessels and to quantitate effects of a chemical based intervention to reduce pathophysiological responses associated with brain injury (Aim 1). Aim 3 In vitro investigation of a chemical based intervention in competition with proteins for macromolecular surface occupancy of gas emboli-blood interfaces under controlled and defined biomimetic conditions. Aim 4 Computationally model chemical reaction dynamics of intravascular gas embolism. We seek to provide fundamental insights into the molecular-mechanical basis of gas embolism related injury as well as protection by pharmacological intervention. This work is the basis for neuroprotection in gas embolism-induced stroke, a persistent, growing health threat without treatment.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Dextran functionalized surfaces via reductive amination: morphology, wetting, and adhesion
    Davide Miksa
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, 19104, USA
    Biomacromolecules 7:557-64. 2006
  2. pmc Air bubble contact with endothelial cells causes a calcium-independent loss in mitochondrial membrane potential
    Peter Sobolewski
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e47254. 2012
  3. pmc Surfactant reduction of cerebral infarct size and behavioral deficit in a rat model of cerebrovascular arterial gas embolism
    David M Eckmann
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania
    J Appl Physiol (1985) 115:868-76. 2013
  4. pmc Finite-sized gas bubble motion in a blood vessel: non-Newtonian effects
    Karthik Mukundakrishnan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 78:036303. 2008
  5. pmc Numerical study of wall effects on buoyant gas-bubble rise in a liquid-filled finite cylinder
    Karthik Mukundakrishnan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 76:036308. 2007
  6. ncbi Dose- and time-dependent liquid sclerosant effects on endothelial cell death
    Shunji Kobayashi
    Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
    Dermatol Surg 32:1444-52. 2006
  7. ncbi A guest molecule-host cavity fitting algorithm to mine PDB for small molecule targets
    William C Byrem
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Biochim Biophys Acta 1764:1320-4. 2006
  8. ncbi Gas embolism and surfactant-based intervention: implications for long-duration space-based activity
    David M Eckmann
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Ann N Y Acad Sci 1077:256-69. 2006
  9. ncbi Numerical modeling of the transport to an intravascular bubble in a tube with a soluble/insoluble surfactant
    Portonovo S Ayyaswamy
    Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA 19104 6315, USA
    Ann N Y Acad Sci 1077:270-87. 2006
  10. pmc Computational simulation of hematocrit effects on arterial gas embolism dynamics
    Karthik Mukundakrishnan
    Dassault Systemes Simulia Corp, Rising Sun Mills, RI, USA
    Aviat Space Environ Med 83:92-101. 2012

Scientific Experts

  • David Eckmann
  • Karthik Mukundakrishnan
  • Portonovo S Ayyaswamy
  • Peter Sobolewski
  • Shunji Kobayashi
  • Alexandra L Klinger
  • Zhengzheng Liao
  • Joshua W Lampe
  • Judith Kandel
  • Ivan J Dmochowski
  • T N Swaminathan
  • P S Ayyaswamy
  • Davide Miksa
  • William C Byrem
  • Steven D Crooks
  • Benjamin Pichette
  • Shaoping Quan
  • Elizabeth R Irish
  • Roderic G Eckenhoff
  • Steven Crooks
  • Stephen C Armstead
  • Russell J Composto
  • Dwayne Chen
  • Jie Zhang

Detail Information

Publications20

  1. ncbi Dextran functionalized surfaces via reductive amination: morphology, wetting, and adhesion
    Davide Miksa
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, 19104, USA
    Biomacromolecules 7:557-64. 2006
    ..Overall, film morphology and wetting behavior were relatively invariant with grafting density, confirming the method's robustness for preparing biomimetic coatings with consistent properties...
  2. pmc Air bubble contact with endothelial cells causes a calcium-independent loss in mitochondrial membrane potential
    Peter Sobolewski
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e47254. 2012
    ..Here, we investigate the mitochondrial consequences of air bubble contact with endothelial cells...
  3. pmc Surfactant reduction of cerebral infarct size and behavioral deficit in a rat model of cerebrovascular arterial gas embolism
    David M Eckmann
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania
    J Appl Physiol (1985) 115:868-76. 2013
    ....
  4. pmc Finite-sized gas bubble motion in a blood vessel: non-Newtonian effects
    Karthik Mukundakrishnan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 78:036303. 2008
    ....
  5. pmc Numerical study of wall effects on buoyant gas-bubble rise in a liquid-filled finite cylinder
    Karthik Mukundakrishnan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 76:036308. 2007
    ..The paper includes figures of bubble shape regimes for various values of R*, Eo, Mo, and ReT. Our predictions agree with existing results reported in the literature...
  6. ncbi Dose- and time-dependent liquid sclerosant effects on endothelial cell death
    Shunji Kobayashi
    Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
    Dermatol Surg 32:1444-52. 2006
    ..Intravenous sclerotherapy solutions can induce endothelial cell death...
  7. ncbi A guest molecule-host cavity fitting algorithm to mine PDB for small molecule targets
    William C Byrem
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA, 19104, USA
    Biochim Biophys Acta 1764:1320-4. 2006
    ..Proteins with large numbers of such cavities are more likely to be functionally altered by halothane...
  8. ncbi Gas embolism and surfactant-based intervention: implications for long-duration space-based activity
    David M Eckmann
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Ann N Y Acad Sci 1077:256-69. 2006
    ..Special consideration is given to modeling the transport and hydrodynamic interactions associated with surfactant-based intervention...
  9. ncbi Numerical modeling of the transport to an intravascular bubble in a tube with a soluble/insoluble surfactant
    Portonovo S Ayyaswamy
    Department of Mechanical Engineering and Applied Mechanics, University of Pennsylvania, Philadelphia, PA 19104 6315, USA
    Ann N Y Acad Sci 1077:270-87. 2006
    ..For identical surface concentrations of the surfactant, the effect of the presence of a soluble surfactant is more severe on the retardation of the bubble motion than that of an insoluble surfactant...
  10. pmc Computational simulation of hematocrit effects on arterial gas embolism dynamics
    Karthik Mukundakrishnan
    Dassault Systemes Simulia Corp, Rising Sun Mills, RI, USA
    Aviat Space Environ Med 83:92-101. 2012
    ..Other recent studies have suggested that variations in hematocrit level may play an important role in determining the severity of neurological complications due to decompression sickness associated with gas embolism...
  11. pmc Protein assembly at the air-water interface studied by fluorescence microscopy
    Zhengzheng Liao
    Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
    Langmuir 27:12775-81. 2011
    ..Protein domains were observed to coalesce during this competitive adsorption process...
  12. pmc Mechanotransductional basis of endothelial cell response to intravascular bubbles
    Alexandra L Klinger
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, PA 19104, USA
    Integr Biol (Camb) 3:1033-42. 2011
    ....
  13. pmc Air bubble contact with endothelial cells in vitro induces calcium influx and IP3-dependent release of calcium stores
    Peter Sobolewski
    Dept of Anesthesiology and Critical Care, Univ of Pennsylvania, Philadelphia, 19104 4283, USA
    Am J Physiol Cell Physiol 301:C679-86. 2011
    ....
  14. pmc In vitro surfactant mitigation of gas bubble contact-induced endothelial cell death
    Shunji Kobayashi
    Department of Anesthesiology and Resuscitation, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
    Undersea Hyperb Med 38:27-39. 2011
    ..The surfactant findings provide a cytoprotective approach to mitigate this form of mechanical injury...
  15. pmc Surfactant properties differentially influence intravascular gas embolism mechanics
    T N Swaminathan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, USA
    Ann Biomed Eng 38:3649-63. 2010
    ..These observations could form a basis for choosing surfactants in treating gas embolism related illnesses...
  16. pmc Imaging macromolecular interactions at an interface
    Joshua W Lampe
    Center for Resuscitation Science, Department of Emergency Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Langmuir 26:2452-9. 2010
    ....
  17. pmc Polidocanol for endovenous microfoam sclerosant therapy
    David M Eckmann
    University of Pennsylvania, 331 John Morgan Building 6112, 3620 Hamilton Walk, Philadelphia, PA 19104 4215, USA
    Expert Opin Investig Drugs 18:1919-27. 2009
    ..Polidocanol is a liquid surfactant having endothelial cell lytic properties. In the form of a controlled, dispensed microfoam it is administered endovenously as a sclerosing agent in the treatment of varicose veins...
  18. pmc Bubble motion through a generalized power-law fluid flowing in a vertical tube
    Karthik Mukundakrishnan
    Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Ann N Y Acad Sci 1161:256-67. 2009
    ..Results show that at low shear rates, for a given pressure gradient the residence time for a non-Newtonian flow is higher than that for a Newtonian flow...