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TRANSLATIONAL PHYSIOLOGY

Thioredoxin liquefies and decreases the viscoelasticity of cystic fibrosis sputum

¹Department of Pediatrics, National Jewish Medical and Research Center, Denver 80206; ³The Mike McMorris Cystic Fibrosis Research and Treatment Center, Department of Pediatrics, University of Colorado School of Medicine; and ⁴The Children's Hospital, Denver, Colorado 80218; and ²Pulmonary Research Group, University of Alberta, Edmonton, Canada T6G 2S2

Submitted 2 October 2003 ; accepted in final form 22 December 2003

The persistent and viscous nature of airway secretions in cystic fibrosis (CF) disease leads to airway obstruction, opportunistic infection, and deterioration of lung function. Thioredoxin (Trx) is a protein disulfide reductase that catalyzes numerous thiol-dependent cellular reductive processes. To determine whether Trx can alter the rheological properties of mucus, sputum obtained from CF patients was treated with TRX and its reducing system (0.1 µM thioredoxin reductase + 2 mM NADPH), and liquid phase-gel phase ratio (percent liquid phase) was assessed by compaction assay. Exposure to low Trx concentrations (1 µM) caused significant increases in the percentage of liquid phase of sputum. Maximal increases in percent liquid phase occurred with 30 µM Trx. Additional measurements revealed that sputum liquefaction by the Trx reducing system is dependent on NADPH concentration. The relative potency of the Trx reducing system also was compared with other disulfide-reducing agents. In contrast with Trx, glutathione and N-acetylcysteine were ineffective in liquefying sputum when used at concentrations <1 mM. Sputum viscoelasticity, measured by magnetic microrheometry, also was diminished significantly following 20-min treatment with 3, 10, or 30 µM Trx. Similarly, this reduction in viscoelasticty also was dependent on NADPH concentration. Further investigation has indicated that Trx treatment increases the solubility of high-molecular-weight glycoproteins and causes redistribution of extracellular DNA into the liquid phase of sputum. Recognizing that mucins are the major gel-forming glycoproteins in mucus, we suggest that Trx alters sputum rheology by enzymatic reduction of glycoprotein polymers present in sputum.

sputum viscoelasticity; mucin; mucus; glutathione; N-acetylcysteine; deoxyribonucleic acid

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				R. L. Lee, R. C. Rancourt, G. del Val, K. Pack, C. Pardee, F. J. Accurso, and C. W. White Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L875 - L882. [Abstract] [Full Text] [PDF]