Diesel exhaust particles (DEPs), generated by heavy-duty diesel engines in various industries, can adsorb over 450 different organic compounds, including mutagenic and carcinogenic polycyclic aromatic hydrocarbons (1). With diameters < 2 µm, these fine respirable particles can remain airborne for long periods of time and deposit in great numbers deeply in the lungs. For these reasons, exposure of truckers, railroad and construction workers, and engine mechanics to DEPs is an occupational health concern. A report from the U.S. Department of Labor showed that the worst-case mean exposures to DEPs in underground metal and nonmetal mines are about 2,000 µg/m 3 , with maximum measurements as high as 3,650 µg/m 3 (2). Epidemiologic studies have also shown a consistent association between elevated levels of particulate matter in ambient air and increased incidence of pulmonary infections (3) or increased respiratory mortality and morbidity in high-risk groups (4,5). Because DEPs are a major component of particulate air pollution in most industrialized urban areas, their effect on pulmonary infections is of great environmental and occupational concern.The principal function of pulmonary host defense mechanisms is to clear inhaled particles or microorganisms from the lungs and prevent infections. Among the various cell types involved in the innate immune system, alveolar macrophages (AMs) are responsible for the clearance of inhaled particles and/or microorganisms from the distal airways and alveolar spaces. These cells engulf inhaled particles or microorganisms and become activated to release reactive oxygen species (ROS), cytokines, and a variety of mediators that are capable of killing microorganisms (6,7). It has been well documented that AM-derived proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), provide innate resistance to bacterial infection, promote the inflammatory process by recruiting neutrophils into the air spaces, and stimulate these phagocytes to release ROS and enzymes (7,8). A successful pulmonary host defense, on the other hand, also needs specific cell-mediated immunity (9). In this aspect, studies have already shown that AMs, through their secretion of cytokines in response to specific antigen exposure, provide a critical link between these two systems. For example, Hsieh et al. (10) showed that the production of IL-12 by macrophages is a key process for the development of the appropriate CD4 + T helper (Th) subset during the immune response to Listeria monocytogenes infection. IL-12, in fact, not only initiates but also plays an important role in maintaining the Th1 response (11). This cytokine is produced very rapidly after infection, thus serving as an early marker for the study of DEP effect(s) on cell-mediated immunity.Studies from our laboratory as well as from others have suggested that DEPs may suppress host immunity by suppressing mucociliary clearance and the phagocytic activity of AMs (12,13), reducing interferon production in response to viral ...

Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of pro-antiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extract (DEPE)-mediated inflammatory responses and evaluated the interaction of inducible NO synthase (iNOS) and cytochrome P450 1A1 (CYP1A1). Male Sprague-Dawley rats were intratracheally (IT) instilled with saline, DEPs (35 mg/kg), or DEPEs (equivalent to 35 mg DEP/kg), with or without further treatment with an iNOS inhibitor, aminoguanidine (AG; 100 mg/kg), by intraperitoneal injection 30 min before and 3, 6, and 9 hr after IT exposure. At 1 day postexposure, both DEPs and DEPEs induced iNOS expression and NO production by AMs. AG significantly lowered DEP- and DEPE-induced iNOS activity but not the protein level while attenuating DEPE- but not DEP-mediated pulmonary inflammation, airway damage, and oxidant generation by AMs. DEP or DEPE exposure resulted in elevated secretion of both interleukin (IL)-12 and IL-10 by AMs. AG significantly reduced DEP- and DEPE-activated AMs in IL-12 production. In comparison, AG inhibited IL-10 production by DEPE-exposed AMs but markedly increased its production by DEP-exposed AMs, suggesting that NO differentially regulates the pro- and antiinflammatory cytokine balance in the lung. Both DEPs and DEPEs induced CYP1A1 expression. AG strongly inhibited CYP1A1 activity and lung S9 activity-dependent 2-aminoanthracene mutagenicity. These studies show that NO plays a major role in DEPE-induced lung inflammation and CYP-dependent mutagen activation but a lesser role in particulate-induced inflammatory damage.

No abstract

No abstract

No abstract