In this study, we tested the hypothesis that exposure to diesel exhaust particles (DEP) may increase susceptibility of the host to pulmonary infection. Male Sprague-Dawley rats received a single dose of DEP (5 mg/kg), carbon black (CB, 5 mg/kg), or saline intratracheally. Three days later, the rats were inoculated intratracheally with approximately 5,000 Listeria monocytogenes and sacrificed at 3, 5, and 7 days postinfection, and we determined the number of viable Listeria in the left lobe of lungs. The remaining lungs underwent bronchoalveolar lavage (BAL) and the retrieved BAL cells were identified and counted. Luminol-dependent chemiluminescence, a measure of reactive oxygen species (ROS) formation, generated by BAL cells was monitored and the levels of nitric oxide and tumor necrosis factor (TNF)-[alpha] produced by macrophages in culture were determined. At 7 days postinfection, we excised the lung-draining lymph nodes and phenotyped the lymphocyte subpopulations. Exposure of rats to DEP, but not to CB, decreased the clearance of Listeria from the lungs. Listeria-induced generation of luminol-dependent chemiluminescence by pulmonary phagocytes decreased by exposure to DEP but not CB. Similarly, Listeria-induced production of NO by alveolar macrophages was negated at 3, 5, and 7 days after inoculation in DEP-exposed rats. In contrast, CB exposure had no effect on Listeria-induced NO production at 3 days after infection and had a substantially smaller effect than DEP at later days. Exposure to DEP or CB resulted in enlarged lung-draining lymph nodes and increased the number and percentage of CD4(+) and CD8(+) T cells. These results showed that exposure to DEP decreased the ability of macrophages to produce antimicrobial oxidants in response to Listeria, which may play a role in the increased susceptibility of rats to pulmonary infection. This DEP-induced suppression is caused partially by chemicals adsorbed onto the carbon core of DEP, because impaired macrophage function and decreased Listeria clearance were not observed following exposure to CB.

Exposure to coal mine dust or crystalline silica can result in the initiation and progression of interstitial lung disease. Pathogenesis is the consequence of damage to lung cells and resulting lung scarring associated with activation of fibrotic processes. This review presents the radiologic and histologic characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathological indices of acute and chronic silicosis. This presentation also reviews the results of in vitro, animal, and human investigations that elucidate mechanisms involved in the development of these pneumoconioses. Results support the involvement of four basic mechanisms in the etiology of CWP and silicosis: 1. Direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring. 2. Activation of oxidant production by pulmonary phagocytes, such as alveolar macrophages. When oxidant production exceeds antioxidant defenses, lipid peroxidation and protein nitrosation occur, resulting in tissue injury and consequent scarring. 3. Activation of mediator release from alveolar macrophages and alveolar epithelial cells. Chemokines recruit polymorphonuclear leukocytes and macrophages from the pulmonary capillaries into the air spaces. Once within the air spaces, these leukocytes are activated by proinflammatory cytokines to produce reactive species, which increase oxidant injury and lung scarring. 4. Secretion of growth factors from alveolar macrophages and alveolar epithelial cells. Release of such mediators stimulates fibroblast proliferation and induces fibrosis. In conclusion, results of in vitro and animal studies have provided the basis for proposing mechanisms that may lead to the initiation and progression of CWP and silicosis. Data obtained from exposed workers has lent support to these proposals. The mechanistic understanding obtained for the development of CWP and silicosis should be useful in elucidating the possible pathogenicity of other inhaled particles.

Shrinkage of dog red blood cells (RBC) activates a Na transport pathway that is CI dependent, amiloride sensitive, and capable of conducting Na-proton counterflow. It is possible to establish transmembrane gradients for either Na or protons and to demonstrate that each cation species can drive reciprocal movements of the other. The nature of the coupling between Na and proton movements was investigated using the fluorescent probe diS-C3(5) and also by an indirect method in which K movements through valinomycin channels were used to draw inferences about the membrane potential. No evidence was found to suggest that the Na-proton pathway activated by shrinkage of dog RBC is a conductive one. By exclusion, it is presumed that the coupling between the counterflow of Na and protons is electroneutral . The volume-activated Na-proton fluxes in dog RBC have certain properties that distinguish them from similar transport pathways in other cell types.

n B S T R A C T External ATP causes a prompt increase in the Na and K permeability of dog red blood cells. By manipulating intra-and extracellular ion composition it is possible to observe ATP-induced net fluxes which can be explained in terms of the contribution of Na or K diffusion potentials to the membrane potential. Measurements of membrane voltage by a fluorescent dye technique confirm the existence of such potentials. A rough calculation of chloride permeability gives a value of the order of 10 -s cm/s, which agrees with results in other species. The cells appear to be somewhat more permeable to bromide than to chloride. I N T R O D U C T I O NAn interesting p r o p e r t y of dog red blood cells is that their permeability to Na and K increases on exposure to external A T P in concentrations of 0.1-1.0 mM (Parker and Snow, 1972;Elford, 1975;Romualdez et al., 1976). T h e effect is A T P specific and reversible. It can be p r e v e n t e d by including physiologic concentrations o f divalent cations in the m e d i u m and is t h e r e f o r e of uncertain significance for the cell's function in vivo. This action of exogenous A T P was first described in ascites t u m o r cells ( H e m p l i n g et Stewart et al., 1969) and has also been r e p o r t e d in isolated renal tubules (Rorive and Kleinzeller, 1972) and other tissues ( T r a m s , 1974). T h e mechanism of A T P ' s interaction with the m e m b r a n e surface is obscure.We suspected that in the presence of external A T P dog red cells might b e c o m e as p e r m e a b l e to Na and K as they are to small anions. O u r hypothesis was c o n f i r m e d by m e a s u r e m e n t s o f net ion flux and m e m b r a n e potentials. T h e data have f u r t h e r m o r e allowed us to draw some conclusions about chloride and b r o m i d e m o v e m e n t s in this species o f cell. This a p p r o a c h has p r e c e d e n t in work with cation-specific i o n o p h o r e s such as gramicidin and valinomycin (Scarpa et al., 1968; H u n t e r , 1971;Tosteson et al., 1973).It should be emphasized that the data in the present study concern net anion movements, presumably by electrodiffusion. Dog red blood cells have a tightly coupled, electrically silent anion exchange mechanism similar to that of all other species examined (Wieth et al., 1974). T h e possible relationship between net and exchange pathways will be briefly discussed in connection with o u r observations on the m o v e m e n t s o f different halide ions.

A B S T R A C T Divalent cations and group-specific chemical modifiers were used to modify sodium efflux in order to probe the molecular structure of sodium channels in dog red blood cells. Hg ++, Ni ÷+, Co ++, and PCMBS (parachloromercuribenzene sulfonic acid), a sulfhydryl reactive reagent, induce large increases in Na + permeability and their effects can be described by a curve which assumes 2:1 binding with the sodium channel. The sequence of affinities, as measured by the dissociation constants, reflects the reactivity of these divalent cations with sulfhydryl groups. In addition, the effects of Hg ++ and PCMBS can be reversed by the addition of dithiothreitol, an SH-containing compound, to the medium. Much smaller increases in Na + permeability are produced by Zn +÷ and the amino-specific reagents, TNBS (2,4,6-trinitrobenzene sulfonic acid) and SITS (4-acetamido-4'-isothiocyano-stilbene-2-2'-disulfonic acid). The Zn ++ effect can be described by a curve which assumes bimolecular binding with the channel, and its effect on Na + permeability can be reversed by the addition of glycine to the medium. The effects of Ni ++ and SITS can be completely reversed by washing the cells in 0.16 M NaC1 while TNBS binding is partially irreversible. Measurements of mean cell volumes (MCV) indicate that the modifier-induced increases in Na + permeability are not caused by shrinkage of the cells. It is concluded that the movement of sodium ions through ionic channels in dog red blood cells can be enhanced by modification of amino and sulfhydryl groups. Zn ++, TNBS, and SITS increase Na + permeability by modifying amino groups in the channel while Hg ++ , Ni ++ , Co ++, and PCMBS act on sulfhydryl groups.