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Alteration of pulmonary immunity to Listeria monocytogenes by diesel exhaust particles . I. Effects of DEPs on early pulmonary responses
Environmental Health Perspectives, Nov, 2002 by Xue-Jun Yin, Rosana Schafer, Jane Y.C. Ma, James M. Antonini, David D. Weissman, Paul D. Siegel, Mark W. Berger, Jenny R. Roberts, Joseph K.-H. Ma
It has been hypothesized that diesel exhaust particles (DEPs) aggravate pulmonary bacterial infection by both innate and cell-mediated immune mechanisms. To test this hypothesis, we investigated the effects of DEP exposure on the functions of alveolar macrophages (AMs) and lymphocytes from lung-draining lymph nodes using a rat Listeria monocytogenes infection model. In the present study, we focused on the effects of DEP exposure on AM functions, including phagocytic activity and secretion of proinflammatory cytokines. The Listeria infection model was characterized by an increase neutrophil count, albumin content, and acellular lactate dehydrogenase activity in the bronchoalveolar lavage (BAL) fluid at 3 and 7 days postinfection. Short-term DEP inhalation (50 and 100 mg/[m.sup.3], 4 hr) resulted in a dose-dependent suppression of lung clearance of Listeria, with the highest bacteria count occurring at day 3. This aggravated bacterial infection was consistent with the inhibitory effect of DEPs on macrophage functions. DEPs suppressed pressed phagocytosis and Listeria-induced basal secretion of interleukin-1[beta] (IL-1[beta]) and IL-12 by AMs in a dose-dependent manner. The amount of IL-1[beta] and IL-12 in the BAL fluid was also reduced by DEP exposure In addition, DEPs decreased Listeria-induced lipopolysaccharide-stimulated secretion of tumor necrosis factor-[alpha] (TNF-[alpha]), IL-1[beta], and IL-12 from AMs. These results suggest that DEPs retard bacterial clearance by inhibiting AM phagocytosis and weaken the innate immunity by inhibiting AM secretion of IL-1[beta] and TNF-[alpha]. DEPs may also suppress cell-mediated immunity by inhibiting ANJ secretion of IL-12, a key cytokine for the initiation of T helper type 1 cell development in Listeria infection. Key words: alveolar macrophages, cytokine production, diesel exhaust particles, inhalation exposure, Listeria monocytogenes, occupational exposure, phagocytosis. Environ Health Perspect 110:1105-1111 (2002). [Online 17 September 2002]
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http://ehpnet.niehs.nig.gov/docs/2002/110p1105-1111yin/abstract.html
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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 [micro]m, 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 [micro]g/[m.sup.3], with maximum measurements as high as 3,650 [micro]g/[m.sup.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-or (TNF-[alpha]), 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 CD[4.sup.+] 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 infection (14) and depressing immune responsiveness to bacterial antigenic stimulation (15,16). In addition, DEPs were also shown to be capable of potentiating antigen sensitization with increased production of antigen-specific immunoglobulin E (17-19). In a recent study, we further demonstrated that exposure to DEPs, but not to carbon black, decreased pulmonary bacterial clearance in rats, suggesting that DEPs may have an adverse influence on both the innate and the T-cell-mediated immune responses (20). Although we have previously shown that AMs from DEP-exposed rats were less responsive to ex vivo challenge with lipopolysaccharide (LPS) in the production of IL-1 and TNF-[alpha] (16), how DEPs impair pulmonary host defense mechanisms is not yet well understood. Whether the cytokine production by AMs is indeed decreased during a bacterial infection after DEP exposure remains to be determined.
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