title: A possible role for integrin signaling in diffuse axonal injury.
abstract: Over the past decade, investigators have attempted to establish the pathophysiological mechanisms by which non-penetrating injuries damage the brain. Several studies have implicated either membrane poration or ion channel dysfunction pursuant to neuronal cell death as the primary mechanism of injury. We hypothesized that traumatic stimulation of integrins may be an important etiological contributor to mild Traumatic Brain Injury. In order to study the effects of forces at the cellular level, we utilized two hierarchical, in vitro systems to mimic traumatic injury to rat cortical neurons: a high velocity stretcher and a magnetic tweezer system. In one system, we controlled focal adhesion formation in neurons cultured on a stretchable substrate loaded with an abrupt, one dimensional strain. With the second system, we used magnetic tweezers to directly simulate the abrupt injury forces endured by a focal adhesion on the neurite. Both systems revealed variations in the rate and nature of neuronal injury as a function of focal adhesion density and direct integrin stimulation without membrane poration. Pharmacological inhibition of calpains did not mitigate the injury yet the inhibition of Rho-kinase immediately after injury reduced axonal injury. These data suggest that integrin-mediated activation of Rho may be a contributor to the diffuse axonal injury reported in mild Traumatic Brain Injury.
authors.affiliation: Disease Biophysics Group, School of Engineering and Applied Sciences, Wyss Institute of Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hemphill
authors.forename: Borna E
authors.initials: BE
authors.lastname: Dabiri
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gabriele
authors.forename: Lucas
authors.initials: L
authors.lastname: Kerscher
authors.forename: Christian
authors.initials: C
authors.lastname: Franck
authors.forename: Josue A
authors.initials: JA
authors.lastname: Goss
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Alford
authors.forename: Kevin Kit
authors.initials: KK
authors.lastname: Parker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D020833:Diffuse Axonal Injury / Q000378:metabolism / Q000473:pathology*; D005353:Fibronectins / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects; D016023:Integrins / Q000378:metabolism*; D060526:Magnetic Fields; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D005353:Fibronectins; D016023:Integrins; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases