2/6/2013 10:30:00 AM
OXYGEN-DEPENDENT DEPOLYMERIZATION OF SICKLE CELL HEMOGLOBIN POLYMERS IN THE LUNGS: KINETIC MECHANISMS AND THEIR SIGNIFICANCE FOR PATHOGENESIS AND ITS PREVENTION
Robin W. Briehl
, Jiang Cheng Wang
, Hacene Boukari
, Zakaria Mrah
, Suzanna Kwong
, W. David Appel
, Thomas K. Aldrich
Albert Einstein College of Medicine, Bronx, NY, USA,
Delaware State University, Dover, DE, USA.
Our kinetic studies have characterized the mechanisms of deoxyhemoglobin S polymer depolymerization when exposed to CO (used as a model for oxygen because rates can be controlled photolytically). Fibers dissolve slowly, losing monomers from their ends at low partial pressure, and very rapidly at higher partial pressures that induce fiber fracture and therefore many new ends. Slow dissolution that is not complete in the time red cells traverse the pulmonary microvasculature will generate residual arterial polymers (RAPs), enhancing pathogenesis by seeding nucleation of new polymers, accelerating repolymerization and increasing its extent.
We now demonstrate, to the best of our knowledge for the first time by direct observation, that anaerobically drawn arterial blood of sickle patients shows birefringence in many red cells and therefore RAPs exist, which we confirm by EM observation of aligned polymers. RAPs exist not only under hypoxemic conditions, when they can be explained by limited solubility due to the presence of deoxyHbS, but also when hypoxemia is absent. RAPs without hypoxemia imply that slow depolymerization kinetics are responsible. One minute of voluntary hyperventilation and (separately) brief nasal oxygen greatly decrease RAPs. RAPs increase during sleep. We attribute these results to accelerated depolymerization at increasing levels of oxygen that cooperatively induce polymer fracture (fracture, using CO, exhibits a 4.7 power dependence on pCO). These results and the interdependent progress of oxygen saturation, partial pressure, fracture rate and remaining polymer that we model bear on pathogenesis and particularly on vaso-occlusive crises, which result from red cell rigidification and from cellular adhesion due to polymer-dependent cellular damage. Under these mechanisms, the lungs may play an important role in initiating pathology; and remediation of dysfunction by breathing assists is potentially prophylactic.
Technical Support Help Desk
11400 Rockville Pike, Suite 800
Rockville, MD 20852
The Online Abstract Submission and Invitation System
© 1996 - 2013 Coe-Truman Technologies, Inc. All rights reserved.