Adjuvant Activity of Ambient Particulate Matter in Macrophage Activity-Suppressed,N-Acetylcysteine-Treated, iNOS- and IL-4-Deficient Mice

Abstract

In previous studies, we have shown strong adjuvant activity for Ottawa dust (EHC-93) after coexposure of the BALB/c mouse to EHC-93 and ovalbumin. Mice were intranasally sensitized at days 0 and 14 with 200 microg ovalbumin and 150 microg EHC-93, and challenged with ovalbumin at days 35, 38, and 41 with 200 microg ovalbumin. Mice were autopsied at day 42. This adjuvant activity was shown for the antibody response to ovalbumin (immunoglobulins E, G1, and G2a), histopathological lesions in the lung, cytokines, and the numbers of eosinophils in lung lavages. To study the mechanisms of this adjuvant activity, mice (BALB/cC.D2-Vil6) with natural-resistance-associated macrophage protein (Nramp1s), BALB/c mice pretreated with the antioxidant N-acetylcysteine (NAC), mice (B6.129P2-Nos2tmLau) deficient in inducible nitric oxide synthase (iNOS), and mice with interleukin-4 (IL-4) deficiency (BALB/cIl4< tm2Nnt) were coexposed to ovalbumin and EHC-93. Our studies have shown that the adjuvant activity induced after such coexposure does not change if the macrophage activation of the mice is disturbed or if the mice have been pretreated with N-acetylcysteine. In addition, the adjuvant activity does not develop through the pathway in which inducible nitric oxide synthase is involved. Because the histopathological lesions are statistically significant less in the IL-4 knockout strain in comparison with the wild type, we conclude that interleukin-4 might play an important role in the adjuvant activity caused by EHC-93.

Preexposure to Amorphous Silica Particles Attenuates but also Enhances Allergic Reactions in Trimellitic Anhydride-Sensitized Brown Norway Rats

“…In this study, the 6-day exposure regimen of SAS, which was considered comparable to the 5-day exposure period as used previously (Arts et al, 2007), did not affect body weights; it induced transient changes in breathing parameters without other indications of distress, but it increased levels of ALP, GGT, LDH, and NAG, increased numbers of neutrophils and macrophages in BAL fluid, increased relative lung weight, and induced a mild granulomatous (neutrophilic) inflammation (Table 4). We used inhalation as a more physiological route of exposure than the intranasal, intratracheal, or intraperitoneal routes of administration used in several other studies studying the effects of coexposure or preexposure to particles in respiratory allergy (Lambert et al, 1999(Lambert et al, , 2000Ma & Ma, 2002;Steerenberg et al, 2003aSteerenberg et al, , 2003bSteerenberg et al, , 2004aSteerenberg et al, , 2004bSiegel et al, 2004).…”

“…However, although particles may act as an adjuvant for allergic sensitization (Lambert et al, 1999(Lambert et al, , 2000Steerenberg et al, 1999Steerenberg et al, , 2003aSteerenberg et al, , 2003bSteerenberg et al, , 2004aSteerenberg et al, , 2004bSteerenberg et al, , 2005Hamada et al, 2000;Ma & Ma, 2002;Siegel et al, 2004;Dong et al, 2005a), this is a delayed 936 J. H. E. ARTS ET AL. response and does not explain acute particle effects on airway hyperreactivity during episodes of high air pollution.…”

“…Particulate compounds such as diesel exhaust particles (DEP), residual oil fly ash (ROFA), and crystalline silica may also act as irritants, by exerting toxic effects on macrophages (Allison & Ferluga, 1977;Asherson et al, 1977;Tansey & Brosnan, 1982;Rao & Frey, 1998;Ma & Ma, 2002). This has resulted in a large number of studies examining the adjuvant properties of particles such as DEP and ROFA during sensitization in animal models of ovalbumin, pollen, or house dust mite allergy (Lambert et al, 1999(Lambert et al, , 2000Steerenberg et al, 1999Steerenberg et al, , 2003aSteerenberg et al, , 2003bSteerenberg et al, , 2004aSteerenberg et al, , 2004bSteerenberg et al, , 2005Hamada et al, 2000;Ma & Ma, 2002;Siegel et al, 2004;Dong et al, 2005aDong et al, , 2005b.…”

Role of oxidative stress on diesel-enhanced influenza infection in mice

“…The toxic particles and gases may singly or in combination have a multitude of effects including reducing mucociliary clearance [49], decreasing alveolar macrophage function [50], diminishing production of antiviral defenses [13] as well as having more broad systemic immuntoxicity affecting both the myeloid and lymphatic systems [10]. Recently we demonstrated that exposure to DE decreased expression and production of host defense molecules including surfactant protein A (SP-A), SP-D, and clara cell secretory protein (CCSP) [51], and this was associated with increased proliferation of influenza virus in both in vitro [52] and vivo systems [13,53-55].…”

N-acetylcysteine Effects on Inflammatory Markers in Animal Models Exposed to Air Pollutants

“…Moreover, NAC pretreatment was correlated with the downregulation of inflammatory markers. Steerenberg et al (2004) used mice with natural resistance-associated macrophage protein activity, with NAC pre-treatment, deficient inducible nitric oxide synthase, and deficient IL-4 expression, which were co-exposed to OVA and Ottawa dust. This experiment showed no differences in histological inflammation or immunoglobulin formation.…”