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Immune-to-brain communication driven by sterile lung injury

Litvin, David Gregory, Litvin
http://orcid.org/0000-0001-7688-5894
http://rave.ohiolink.edu/etdc/view?acc_num=case1528469492924001

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Peripheral organ injuries serve as potent stimuli for the immune system, triggering local inflammatory activation that can become increasingly amplified as the injury progresses, this in turn can lead to a severe systemic immune activation, which wreaks havoc over physiologic function. This is exemplified by lung injury, which can induce failure of multiple organ systems, or cause profound disruptions to brain function. When lung injury occurs in perinatal settings it may induce developmental impairments that last into adulthood. Here, using an experimental model of lung injury I investigated the mechanisms responsible for altering brainstem control of cardiorespiratory function in neonatal and adult rats. In neonatal rats, I determined that when lung injury is induced just before a transition period for the neural control of breathing (spanning P11-15), it promotes: i) an increase to the number of apnea directly preceded by a sigh, and ii) depression of viscerosensory synaptic transmission to 2nd-order neurons located in the nucleus tractus solitarii (nTS). This depression occurs through a postsynaptic mechanism that increases the contribution of Ca2+-impermeable (CI) AMPA receptors, and is mediated by the immune response to lung injury; minocycline, an inhibitor of microglia/macrophage activation, prevented the lung injury dependent increase in post-sigh apnea and the CI-AMPAR mediated synaptic depression. In rat-pups that were injured just after the transition period, viscerosensory synaptic transmission was also depressed, but occurred in a CI-AMPAR independent manner that contrastingly was presynaptically mediated. Thus, discrete mechanisms are responsible for these synaptic changes. In adult rats, where lung injury also increased the frequency of post-sigh apnea, I determined a novel immune-to-brain communication (I¿Bc) pathway utilized by the injury, which involves the glial-barrier separating the area postrema (a circumventricular organ) from the immune-privileged nTS. Transmission of this immune response occurred via increased expression of the proinflammatory cytokine Interleukin-1ß (IL-1ß) and its downstream transcriptional target Cyclooxygenase-2 (COX-2) within radial-glia projecting basolaterally into the nTS. Both the post-sigh apnea and the radial-glial IL-1ß increase could be prevented by continuous intracerebroventricular infusion of the COX inhibitor Indomethacin, indicating as others have that COX may also act upstream on the mechanisms that govern its transcription. Together this demonstrates that the immune response to lung injury exerts changes to brainstem physiology that can be observed at the level of the synapse and centrally mediated respiratory function.
Frank Jacono, M.D. (Advisor)
George Dubyak, Ph.D. (Committee Chair)
Corey Smith, Ph.D. (Committee Member)
Thomas Dick, Ph.D. (Committee Member)
Roberto Galan, Ph.D. (Committee Member)
216 p.
Biophysics; Neurobiology; Physiology
Viscerosensory, Microglia, Neuroinflammation, Developmental Plasticity, Lung Injury, GluR2, Calcium Impermeable AMPA Receptor, Nucleus Tractus Solitarii, Bleomycin, Area Postrema, Funiculus Separans, Interleukin-1 beta, Radial-glia

Recommended Citations

Citations

  • Litvin, Litvin, D. G. (2018). Immune-to-brain communication driven by sterile lung injury [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1528469492924001

    APA Style (7th edition)

  • Litvin, Litvin, David. Immune-to-brain communication driven by sterile lung injury. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1528469492924001.

    MLA Style (8th edition)

  • Litvin, Litvin, David. "Immune-to-brain communication driven by sterile lung injury." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1528469492924001

    Chicago Manual of Style (17th edition)

case1528469492924001
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© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.