Formaldehyde exposure induces airway inflammation by increasing eosinophil infiltrations through the regulation of reactive oxygen species production

Abstract

Formaldehyde (FA) is a well-known cytotoxic irritant to the airways, but the mechanism of airway inflammation due to FA has not been clarified. In the present study, C57BL/6 mice were exposed to two concentrations (5 and 10 ppm) of FA for 6 h/day, 5 days/week, for 2 weeks. The FA-exposed mice had much higher number of CCR3⁺ eosinophils than control mice, and showed upregulated gene expression of CC-chemokine receptor-3 (CCR3), eotaxin and intercellular adhesion molecules-1 (ICAM-1) as well as an increased expression of proinflammatory and Th2 cytokines, such as interleukin (IL)-1β, IL-4 and IL-5. In addition, FA exposure revealed a considerable increase in the serum levels of IgG1, IgG3, IgA and IgE compared to controls. Histopathological analysis of the lung tissues demonstrated eosinophils and mononuclear cell infiltration of the alveolar cell walls and alveolar spaces. Gene expression of thioredoxin (TRX), redox-regulating antioxidant proteins, was markedly suppressed in FA-exposed mice, and thereby intracellular ROS levels were increased along with increased FA concentration. These results were consistent with an increase in the number of CCR3-expressing eosinophils, and indicate that FA-induced ROS was generated from eosinophils recruited to the inflammatory sites of the airways.

Introduction

Formaldehyde (FA) has been considered an airway-sensitizing agent, which may also cause or exacerbate respiratory distress in individuals with a preexisting or FA-induced bronchial hyperreactivity (Bernstein et al., 1984). Common sources of FA exposure in the environment include renovation and remodeling materials such as paints, carpets, flooring, insulation materials, adhesives, office supplies, cleaning products, and office machines (Redlich et al., 1997). Further, it has been reported that FA exposure at high concentrations is an irritant to the eyes and mucous membranes of the respiratory tract but the effects are completely reversible (Bardana, 1997). FA is also known as a key component causing sick building syndrome (SBS), which refers to the non-specific complaints of respiratory irritation symptom, headache, fatigue, and rash (Redlich et al., 1997, Kim et al., 2002, Saijo et al., 2004, Nakazawa et al., 2005). However, it remains unclear that FA exposure is capable of aggravating existing allergic diseases and a variety of respiratory symptoms that are induced through chemical sensitivities (Ziem and McTamney, 1997, Rowat, 1998, Kita et al., 2003, Fujimaki et al., 2004).

FA has been suspected of acting as a modulating factor of cutaneous inflammation by affecting the ability of keratinocytes to release pro-inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α) and IL-8 (Bardana and Montanara, 1991, Ushio et al., 1999). Meanwhile, the development of airway inflammation and bronchial asthma is associated with eosinophilia in the airways due to the predominant expression of the Th2 cytokines, including IL-4 and IL-5 (Foster et al., 1996, Rothenberg, 1999, Yazdanbakhsh et al., 2002, Maddox and Schwartz, 2002, Lewis, 2002). IL-4 and IL-5 are known to promote airway eosinophilia by suppressing the production of IFN-γ (Foster et al., 1996, Cohn et al., 2001). In addition to pre-formed cytokines, such as IL-4, the eosinophils contain the CC chemokine eotaxin within specific granules and cytoplasmic vesicles (Gonzalo et al., 1996, Pope et al., 2005, Bandeira-Melo and Weller, 2005). Eotaxin binds selectively to its receptor CCR3, which is functionally expressed on T lymphocytes co-localizing with eosinophils at sites of allergic inflammation (Gerber et al., 1997). Indeed, airway eosinophil related inflammation is reduced in an ovalbumin (OVA)-induced experimental asthma model using eotaxin and CCR3-deficient mice (Pope et al., 2005).

In airway inflammation, the NADPH-oxidase in the membranes of inflammatory cells is activated to produce oxygen, which are then reduced to the superoxide anion by receiving an electron from NADPH, and dismutated to hydrogen peroxide. Thus, these reactive oxygen species (ROS) are involved in the pathogenesis of airway inflammation through the induction of tissue damage at the inflammation site. Eotaxin is capable of inducing production of ROS from eosinophils in a dose-dependent manner (Honda and Chihara, 1999) and in addition, ROS can be scavenged by thioredoxin (TRX), a redox-active protein. The administration of TRX strongly suppresses airway hyperresponsiveness and airway inflammation in the lungs of OVA-sensitized mice, and the serum TRX has been shown to relate to the state of asthma exacerbation and allergic inflammation (Ichiki et al., 2005, Yamada et al., 2003). It has recently become apparent that the cell adhesion molecules are another key factor involved in inflammatory cell infiltration. Mice that congenitally lack the intercellular adhesion molecule-1 (ICAM-1) and the vascular cell adhesion molecule-1 (VCAM-1) failed to develop pulmonary eosinophilia (Gonzalo et al., 1996). Despite the association of FA with the increasing incidence of allergic inflammation that has been reported, a well defined and understood molecular mechanism for airway inflammation as a result of FA exposure remains to be elucidated.

In this study, we have investigated the effects of FA on airway inflammation, and herein report our findings on the association between the results of the changes in immune related factors with respect to airway inflammation in FA-exposed mice.