Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma

Abstract

The pathogenesis of bronchial asthma is chronic airway inflammation caused by immune cells such as T lymphocytes and eosinophils. Eosinophils release cytotoxic products including reactive oxygen species at the site of inflammation, leading to epithelial damage. Human thioredoxin (TRX), a redox-regulating protein with antioxidant activity, is induced and secreted from cells by oxidative stress. This study was undertaken to investigate the clinical significance of TRX in the pathogenesis of asthma. We collected blood samples from 48 patients with bronchial asthma with or without attack, and measured serum ECP and pulmonary function as well as serum TRX. The serum TRX levels in patients with asthma were significantly increased in patients with mild (34.63 [28.40–42.73] ng/ml, medians with 25 and 75% interquartiles, P=0.0064) and moderate (38.83 [35.14–50.80] ng/ml, P=0.0017) asthma attacks compared with those during the asymptomatic period. The serum TRX levels were inversely correlated with FEV_1.0% (r=−0.44, P=0.039) and %PEF (r=−0.49, P=0.020) during attack. There was a significant correlation between the serum TRX and the serum eosinophil cationic protein (rs=0.32, P=0.016). These findings suggest that serum TRX is related to the state of asthma exacerbation and allergic inflammation.

Introduction

The pathogenesis of bronchial asthma is chronic airway inflammation caused by immune cells, involving T lymphocytes and eosinophils [1], [2]. The activation of eosinophils by cytokines and chemoattractants is a critical event in the allergic inflammatory response. Eosinophils are recruited from the circulation into inflammatory foci by chemoattractants such as C5a, platelet-activating factor, and C-C chemokines. IL-5 prolongs eosinophil survival and primes other functions in the tissue. At the site of inflammation, eosinophils release cytotoxic products including eosinophil granule proteins and reactive oxygen species (ROS) causing epithelial damage [1], [2]. We and others have shown that eosinophil-active cytokines and chemoattractants elicit the production of ROS from eosinophils [3], [4], [5]. Consistent with the aforementioned findings, eosinophils in bronchoalveolar lavage fluid (BALF) from subjects who underwent allergen challenge spontaneously produce prominent amounts of superoxide anions [6]. The quantity of oxidants appears to be increased at the inflammatory sites of asthma, leading to the formation of antioxidant defenses that neutralize the effect of oxidants [7]. One example of this phenomenon is the enhanced glutathione level in BALF obtained from patients with asthma [8].

Thioredoxin (TRX) containing a redox-active disulfide (-Cys-Gly-Pro-Cys-) was originally discovered in Escherichia coli as a hydrogen donor for ribonucleotide reductase [9]. Human TRX produced by human T-cell leukemia virus-1 (HTLV-1) transformed T-cells was cloned as adult T-cell leukemia-derived factor (ADF) [10]. By thorough investigations accomplished during more than a decade, TRX is currently known to possess both intracellular and extracellular activities. The former includes antioxidant activity which regulates redox-sensitive molecules such as NF-κB, AP-1, and glucocorticoid receptors. In contrast, TRX exhibits extracellular cytokine-like activity similar to IL-2Rα chain induction [11]. Recent studies have shown that TRX is a potent chemoattractant for neutrophils, monocytes, T-cells, and eosinophils [12], [13]. Clinically, TRX appears to play a crucial role in the control of oxidative stress in many diseases. TRX is involved in infection by various viruses as well as HTLV-1, and in a variety of human cancers [14], [15], [16], [17]. Autoimmune diseases including rheumatoid arthritis (RA) and Sjögren's syndrome are associated with increased levels of TRX [18], [19]. In addition, acutely elevated circulating TRX appears to be beneficial to reduce inflammation. For example, circulating TRX markedly blocks migration of neutrophils into the lipopolysaccharide-stimulated air pouch in mice with elevated TRX levels [20].

In this study, we measured the serum levels of TRX in asthmatic patients to investigate its clinical roles. Increased serum TRX levels were observed in patients with asthma attacks and associated with loss of lung functions and eosinophil activation.