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The potential toxicity of an atmospheric dust sample EHC-93 has been attributed to the soluble fraction and, more specifically, to the zinc component. The concentration of Zn is the highest among the metals present in the soluble EHC-93 fraction. We now determine whether other metal components of this dust could cause similar lung injury if present at the same concentration as Zn (4.8 mg/g dust). Solutions of Zn, Cu, V, Ni, Fe, and Pb salts in 0.1 mL water were instilled to mouse lung and animals were killed at intervals up to 2 weeks later; each mouse received tritiated thymidine 1 hour before death. Solutions containing Zn and to a lesser degree Cu induced lung injury; in addition, increased numbers of alveolar macrophages and polymorphonuclear leukocytes were found in the lavage fluid, which also contained increased protein levels up to 1 week later. The magnitude of response was similar to that seen after administering EHC-93 dust at 1 mg in 0.1 mL water, whereas the response to other metal solutions containing Ni, Fe, Pb, and V was minimal. Morphologic evidence of lung injury and inflammation was also seen after EHC dust and the Zn or Cu solutions only. Reparative cell proliferation was measured after thymidine uptake and autoradiographs showed increased labeling of lung cells, particularly at 3 and 7 days. Labeling was confined to bronchiolar and type 2 alveolar epithelial cells, indicating previous epithelial cell necrosis in response to Zn or Cu. The results indicate that atmospheric contaminant metals Zn and Cu are most likely to cause lung injury and inflammation as compared to metals such as Ni, Fe, Pb, and V at the same concentrations. It appears that similar toxicity occurs when both redox (Cu) and nonredox (Zn) reactions are involved.

Multinucleated giant cells (MGC) are a prominent feature of some chronic inflammatory states in the lung. These cells are formed by macrophage fusion, but how this process relates to the kinetics of alveolar macrophage (AM) production and proliferation is not clear. In this serial study, we compare AM kinetics and MGC formation after instilling carbon, silica, asbestos, bleomycin, and saline into the lungs of mice. Animals were killed up to 16 weeks later with [3H]thymidine injected 1 h before death. Counts of AM and MGC were carried out after bronchoalveolar lavage, and cell labeling was assessed by autoradiography. All test substances induced an inflammatory response with equal AM numbers recovered up to 2 weeks. Subsequently, the number returned to normal after carbon but remained elevated in the other groups. After carbon the lung structure was normal, there was no increase in AM label, and no MGC formed. Bleomycin-injected lungs progressed to fibrosis with only a brief, small increase in AM labeling and no MGC formation. After silica, and particularly asbestos, the lungs showed fibrosis, and many granulomas with large MGC were seen. Lavaged AM from these lungs showed a significant increase in DNA synthesis after 2 weeks, followed by higher numbers of MGC, none of which were labeled. Labeled AM tended to be free of particles, whereas MGC after 4 weeks contained many particles. The results indicate a relationship between AM proliferation and fusion, whereby AM growth appears to be prerequisite for cell infusion and MGC formation as a feature of granulomatous disease.

Altered cytokine production in the lung follows the deposition of urban air particles. The present study was designed to measure changes in tumor necrosis factoralpha (TNFalpha) and endothelin-1 (ET-1) levels in rat lung after instilling various fractions of the dust EHC-93, while in vitro, alveolar macrophages (AMs) and type 2 epithelial cells were studied to determine relative production of these molecules in response to the same particles. Whole dust and its soluble and leached components were instilled into rat lung and the animals were killed at intervals to 2 weeks; they received tritiated thymidine by intraperitoneal injection 1 hour before death. All samples induced some inflammation, with the highest cellular efflux being found by bronchoalveolar lavage 1 day after leached particles. Lung injury, illustrated by protein levels in lavage fluid, was maximal after instilling the soluble fraction and subsequently epithelial regeneration was also maximal in this group. TNFalpha levels were highest after instilling whole dust or its leached fraction at 4 hours and 1 day, and cell culture studies indicated a predominant AM source for this cytokine. ET-1 levels were also increased in BAL from 4 hours to 3 days and were mostly associated with the instillation of leached particles. The results demonstrate that the rapid production/release of TNFalpha and ET-1 after particle deposition is largely due to the insoluble particulate fraction. There appears to be a differential response to whole dust where the soluble components cause some inflammation and epithelial cell necrosis, whereas the leached particles are more likely to react with macrophages to induce the production of proinflammatory cytokines such as TNFalpha.