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Thymosin ß4 Sequesters Actin in Cystic Fibrosis Sputum and Decreases Sputum Cohesivity in Vitro^*

Bruce K. Rubin, MEngr, MD, MBA, FCCP; Arnon P. Kater, MD, PhD and Allan L. Goldstein, PhD

^* From the Department of Pediatrics (Drs. Rubin and Kater), Wake Forest University School of Medicine, Winston-Salem, NC; and the Department of Biochemistry and Molecular Biology (Drs. Kater and Goldstein), The George Washington University School of Medicine and Health Sciences, Washington, DC. Currently at the Department of Hematology, Academic Medical Center, University of Amsterdam, the Netherlands.

Correspondence to: Bruce K. Rubin, MEngr, MD, MBA, FCCP, Professor and Vice Chair, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1081; e-mail: brubin{at}wfubmc.edu

Abstract

Background: Filamentous actin (F-actin) forms polymers that contribute to the abnormal biophysical properties of sputum. Thymosin ß4 (Tß4) is the major monomeric actin-sequestering peptide in cells and can depolymerize F-actin. Tß4 could potentially decrease sputum viscoelasticity and adhesivity and improve sputum clearance.

Methods: Sputum was collected during pulmonary function testing from 17 subjects during a cystic fibrosis (CF) center visit. Sputum rheology, cough and ciliary transportability, and interfacial tension were measured before and after the addition of dornase alfa at 30 µg/mL; Tß4 at 0.3, 3, 30, and 150 µg/mL; and Tß4 with dornase alfa at 1.5 µg/mL each. Sputum was separately incubated with Tß4 at 30 µg/mL for 0, 10, 20, or 60 min.

Results: There was a direct relationship between actin filament length and sputum cohesivity. There was a dose-dependent threshold decrease in cohesivity with Tß4 and a time-dependent decrease in cohesivity over 60 min at 30 µg/mL. With the combination of dornase alfa and Tß4 at 1.5 µg/mL each, there was a 70% decrease in G*s and a 65% decrease in G' at 1 rad/s (p = 0.013). There was a 44% increase in cough transportability of sputum in vitro (p = 0.037) and a 71% increase in mucociliary transportability of sputum in vitro (p = 0.013) relative to control with the combination of dornase alfa and Tß4, but no significant change with dornase alfa or Tß4 alone at any concentration.

Conclusions: Actin polymer filament length is correlated with sputum cohesivity. Tß4 depolymerizes CF sputum actin in both a dose-dependent and a time-dependent manner. An apparent synergy of Tß4 on actin and dornase on DNA may be explained by the combined effect of actin depolymerization and DNA filament severing or by virtue of actin depolymerization increasing the effectiveness of dornase alfa.

Key Words: actin • cystic fibrosis • dornase alfa • sputum • thymosins • viscoelasticity

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				R. R. Kempainen, C. B. Williams, A. Hazelwood, B. K. Rubin, and C. E. Milla Comparison of High-Frequency Chest Wall Oscillation With Differing Waveforms for Airway Clearance in Cystic Fibrosis Chest, October 1, 2007; 132(4): 1227 - 1232. [Abstract] [Full Text] [PDF]