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First published online September 14, 2007
Journal of Experimental Biology 210, 3451-3460 (2007)
Published by The Company of Biologists 2007
doi: 10.1242/jeb.008524

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In vivo red blood cell sickling and mechanism of recovery in whiting, Merlangius merlangus

Pia Koldkjær^* and Michael Berenbrink

School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK

^* Author for correspondence (e-mail: piak{at}liv.ac.uk)

Accepted 17 July 2007

Haemoglobin concentrations in vertebrate red blood cells are so high that in human sickle cell disease a single surface amino acid mutation can result in formation of large insoluble haemoglobin aggregates at low oxygen levels, causing peculiar cell deformations or `sickling'. This may cause vascular occlusion and thereby severe pain, organ failure and death. Here, using light and transmission electron microscopy, we demonstrate extensive in vivo sickling of whiting red blood cells after capture stress without any apparent haemolysis and show its subsequent recovery. We show exceptionally high cooperative proton binding during the sickling process in vitro and identify the reduction of extracellular pH below resting values as the primary cause for in vivo sickling, although the response is modulated to a lesser extent also by oxygen tension. Using isotope tracer fluxes, we further show that ß-adrenergic hormones, which are released under capture stress, activate a powerful endogenous Na/H exchanger in these fish red blood cells, which is known to elevate intracellular pH. ß-adrenergic treatment further leads to a marked reduction of acid-induced in vitro sickling, which is impaired when Na/H exchange is inhibited by amiloride. We propose that this mechanism protects red blood cells of some fishes against the problem of haemoglobin aggregation and red blood cell sickling, except under most severe acidosis. This system offers a unique example of how, over evolutionary time, nature may have overcome what is still a deadly disease in humans.

Key words: Merlangius merlangus, sickle cell disease, Na/H exchanger, red blood cell, haemoglobin, Hb polymerisation, fish

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