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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.

Keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) are known mitogens for normal alveolar Type 2 cells in vitro and in vivo. We wished to determine whether these two growth factors are involved in lung repair after epithelial cell necrosis by determining the levels of each factor in lung lavage fluid collected serially after bleomycin-induced injury , and how these values relate specifically to proliferation of bronchiolar and alveolar epithelial cells. Rats received an intratracheal injection of 1 unit bleomycin in 0.5 ml water and were killed at intervals up to 4 weeks with 1 Ci/g tritiated thymidine injected 1 hour before death. Early necrosis of bronchiolar epithelial (BR) cells and Type 1 alveolar epithelium was followed by an increase in inflammatory cell numbers and high protein levels in bronchoalveolar lavage (BAL) fluids. In addition , the levels of KGF and HGF , measured by enzyme-linked immunosorbent assay in BAL , increased as early as 3 days and peaked at 7-14 days , when KGF was measured at 160 pg/ml (n ‫؍‬ 50) and HGF reached 460 pg/ml (n ‫؍‬ 40). Both values dropped sharply after 2 weeks. Epithelial cell proliferation was quantitated as percentage of labeled cells in autoradiographs of methacrylate sections. Labeling of BR cells predominated in the first week and peaked at 7% at 3 days. Type 2 cell proliferation was delayed somewhat but occurred in 3 to 10 days with a peak of 7% labeled cells at 1 week. The results demonstrate that both HGF and KGF are present in the lung in greatly increased amounts soon after bleomycin-induced epithelial cell necrosis. These high levels are associated with both BR and alveolar epithelial cell proliferation. (Am J Pathol 1999, 155:949 -954)

Alveolar macrophages are thought to arise from both marrow-derived monocytes and pulmonary interstitial cells. Macrophage kinetics are now studied under various conditions of alveolar loading using several doses of carbon (0.03 micrometers diameter), polystyrene latex (0.1 and 1.0 micrometers), and heat-killed bacteria. In serial studies we examined the number of macrophages recovered by lavage, DNA synthesis by lung cells on autoradiographs, and the passage of free particles into lung tissues by electron microscopy. The dual origin of the alveolar macrophage was confirmed for each particulate. The observed peak in macrophagic output at 1 day may be explained by monocytic egress. With greater loads, the peak value did not increase, but the continuing macrophagic production correlated with a period of interstitial cell proliferation. For all particles used, the number of new macrophages was related more closely to number of particles instilled than to the total dose by weight delivered to the lungs. With increasing number, more free particles of carbon and latex crossed the Type 1 epithelium to be phagocytized by interstitial macrophages. The results suggest that the adaptive outpouring of alveolar macrophages occurs by an acceleration of the normal biphasic pathway; when the adaptive response is prolonged, the interstitial compartment appears to be the predominant source of new cells.