Elliott Kagan

Asbestos-associated neoplasms of B cell lineage

Three different neoplasms of B cell lineage, chronic lymphocytic leukemia, immunoglobulin A (IgA) myeloma and immunoglobulin G (IgG) myeloma were detected in three patients who had heavy occupational exposure to asbestos dust. Two of the patients had coexistent pulmonary asbestosis, whereas the third patient had a pleural mesothelioma subsequent to his initial presentation with myeloma. Defective cell-mediated immunity and hyperactivity of B cell function have previously been noted in patients with asbestosis. We suggest the possibility that these asbestos-related immunologic derangements may predispose to the development of immunoproliferative and lymphoproliferative neoplasms, since such tumors have been observed in a variety of other settings, characterized by protracted hyperactivity of the immune system.

Early inhibition of myointimal proliferation by angiopeptin after balloon catheter injury in the rabbit

PURPOSE Coronary artery restenosis after percutaneous transluminal angioplasty occurs in more than 40% of patients. Angiopeptin, a stable synthetic octapeptide analogue of somatostatin, attenuates accelerated coronary artery myointimal thickening in rabbit cardiac allografts and myointimal thickening after arterial injury. In this study the temporal relationship between the angiopeptin treatment schedule and efficacy was explored. The relationship between inhibition of myointimal thickening by angiopeptin and inhibition of vascular cell proliferation was also examined. METHODS The aorta and the common and external iliac arteries of the rabbit underwent balloon injury. Angiopeptin (2 to 200 micrograms/kg/day) was administered for 1 day before injury and for 1, 5, and 21 days after injury. Morphometric studies were performed to determine measurement of intimal thickening. Inhibition of vascular cell proliferation by angiopeptin was evaluated by tritiated thymidine incorporation into the balloon-injured rabbit aorta. Thymidine was either administered intraperitoneally or added ex vivo to aorta segments of rabbits treated with angiopeptin (2, 20, or 200 micrograms/kg/day) from 1 day before injury until sacrifice 72 hours later. RESULTS Administration of angiopeptin (2 to 200 micrograms/kg/day) significantly reduced intimal thickening by approximately 50% in all three vessels when evaluated 3 weeks after injury. This inhibitory effect was unrelated to duration of treatment and dose. Treatment initiated at the time of injury was found to be effective, but delaying treatment for 8, 18, or 27 hours abrogated the inhibitory effect of angiopeptin on myointimal thickening. Angiopeptin treatment significantly decreased thymidine-labeled nuclei of smooth muscle cells in vitro. Angiopeptin treatment similarly inhibited thymidine uptake in vitro by balloon-injured aorta segments. CONCLUSION Angiopeptin significantly inhibits myointimal thickening by inhibiting vascular cell proliferation. Administration of angiopeptin for 2 days is as efficacious as 3 weeks treatment in inhibiting myointimal thickening. Delaying treatment for as little as 8 hours after injury abrogates the inhibitory effects of angiopeptin. This speaks to the importance of early events immediately after vascular tissue injury, suggesting that angiopeptin inhibits the expression of early genes causally related to the vascular injury response and thereby triggering vascular cell proliferation.

[32] Elimination of macrophages with silica and asbestos

Publisher Summary This chapter discusses the practical use of some of these agents as selective toxins for mononuclear phagocytes. It explores that silica and asbestos are naturally occurring, silicon-containing compounds which are widely distributed within geologic deposits in the earths crust. Asbestos differs from silica in that, unlike silica, asbestos particulates have a fibrous character. The chapter discusses that certain types of asbestos and silica are toxic to macrophages, both in vitro and in vivo . When macrophages are exposed in vitro to these toxic agents, they exhibit extreme cytoplasmic vacuolation, karyopyknosis, disappearance of pseudopodia, and effacement of plasma membranes. Similar morphologic abnormalities have been observed in alveolar macrophages after experimental silica or asbestos inhalation in animals. It reviews that the cytoplasmic enzyme and lactate dehydrogenase have proved to be a useful marker for assessing macrophage cytotoxicity induced by these mineral dusts. Thus, the release of this enzyme into macrophage culture supernatants provides confirmatory evidence of macrophage lysis. The lethal action of silica is believed to result from a hydrogen bonding interaction of silicic acid with membrane protein and phospholipid moieties. Chrysotile asbestos, on the other hand, appears to exert its cytotoxic effect through an electrostatic interaction of its surface magnesium groups with ionized carboxyl groups of membrane glycoprotein sialic acid residues.

The effects of chrysotile and crocidolite asbestos on the lower respiratory tract: analysis of bronchoalveolar lavage constituents

This study was designed to evaluate the effects of amphibole and serpentine asbestos inhalation on the constituents of the lower respiratory tract. Bronchoalveolar lavage (BAL) analyses were performed on three groups of rats: one group was exposed to chrysotile (serpentine) asbestos, another group was exposed to crocidolite amphibole asbestos, while a third group was sham-exposed. Intermittent inhalational exposures lasted three months. The total BAL cell yields and the macrophage content of BAL cells were significantly lower after asbestos exposure, especially in the chrysotile-exposed group. These effects persisted for as long as 1 year after the cessation of exposure. Multinucleated macrophages were seen in BAL cells from both asbestos-exposed groups. Striking ultrastructural alterations of macrophage morphology were noted in BAL cells from both groups of asbestos-exposed rats. Chrysotile fibers were not seen in any BAL cells from chrysotile-exposed animals. However, 15 months after terminating the exposure regimen, a sizeable proportion of BAL macrophages from crocidolite-exposed rats contained phagocytosed asbestos fibers. Significantly higher beta-glucuronidase and lactate dehydrogenase activity was found in BAL fluids from both asbestos-exposed groups and was detected 17-18 months after exposure had ceased. These observations have served as useful correlates of asbestos-mediated injury to the lower respiratory tract. They have also provided evidence of continual pathological sequelae occurring long after withdrawal from asbestos exposure.

Evidence of a quartz-induced chemotactic factor for guinea pig alveolar macrophages.

Abstract Bronchopulmonary cell populations enriched in alveolar macrophages were obtained by pulmonary lavage from guinea pigs exposed by inhalation to quartz dust. Extracts derived from disrupted bronchopulmonary cell populations in these animals were chemotactic for normal resident guinea pig alveolar macrophages. Similar chemoattractant activity was not, however, demonstrated in extracts of bronchopulmonary cell populations harvested from control (nondusted) guinea pigs. These quartz-induced, cell-associated chemotactic stimuli may account for the recruitment of mononuclear phagocytes into the lung during the evolution of silicotic lesions.

Manifestations of cellular immunity in the rat after prolonged asbestos inhalation: II. Alveolar macrophage-induced splenic lymphocyte proliferation

Abstract The present study has shown that alveolar macrophages from asbestos-exposed rats (dusted macrophages) can induce the proliferation of autologous splenic lymphocytes (dusted lymphocytes) as well as the proliferation of syngeneic lymphocytes from control nonexposed rats (control lymphocytes). Significant lymphoproliferation did not occur when alveolar macrophages from control rats (control macrophages) were cocultured with control or dusted splenic lymphocytes for similar periods of time (72 or 96 hr). The activation of control lymphocytes by dusted macrophages was similar, in some respects, to the lymphoproliferative response evoked by sodium periodate-treated control macrophages, since both these reactions peaked at 72 hr and were abolished by treatment of the macrophages with the reducing agent, l -cysteine. This periodate-like response produced by dusted macrophages appears to result from aldehyde-like modifications on the macrophage cell membrane. l -Cysteine treatment did not, however, affect the blastogenic response induced by dusted macrophages on dusted lymphocytes, which peaked at 96 hr. Since the in vitro addition of crocidolite to cell cultures did not trigger lymphoproliferation, these collective findings suggest the expression of asbestos-related antigen-like determinants on the surface of dusted macrophages. We conclude that the proliferative reactions induced in splenic lymphocytes by dusted macrophages were a consequence of two different phenomena: a periodate-like effect (noted in control lymphocytes) and an effect produced by a putative asbestos-related, macrophage-associated antigen (observed in dusted lymphocytes).

Enhanced Interleukin Production and Alveolar Macrophage Ia Expression After Asbestos Inhalation

Exposure to asbestos is associated with striking alterations of immunological function (Kagan 1981). Clinical studies of asbestos workers have demonstrated a variety of immunological abnormalities in such individuals. These aberrations have included elevations of serum and secretory immunoglobulins (Kagan 1977; Lange 1974), a high frequency of non organ-specific and lymphocytotoxic autoantibodies (Kagan 1977; Lange 1974; Turner-Warwick 1973), an increased incidence of detectable circulating immune complexes (Lange 1983), elevations of the normal helper:suppressor T cell ratios among blood (Miller 1983) and bronchoalveolar lavage (BAL) lymphocytes, loss of suppressor T cell immuno-regulation (Gaumer 1981) and an increased frequency of non-Hodgkin’s lymphomas (Kagan 1983).

Role of Nitric Oxide Radicals in Asbestos-Induced Injury

It is well recognized that inhalation of asbestos fibers is linked to the causation of a variety of clinical disorders including interstitial pulmonary fibrosis, parietal pleural plaques, bronchogenic carcinoma and diffuse malignant mesothelioma of the pleura and peritoneum (Kagan, 1985; Mossman and Gee, 1989). Although the pathogenesis of these diseases has not been elucidated fully, there is evidence that alveolar macrophages (AM) play a pivotal role in mediating asbestos-related injury. Thus, studies in asbestosexposed rodents and in asbestos workers have shown that AM are recruited to the sites of deposition of inhaled asbestos fibers (Kagan, 1988; Rom et al., 1991). It has also been demonstrated that asbestos fibres can activate AM to secrete a diverse group of inflammatory mediators including cytokine growth factors, chemoattractants and arachidonic acid metabolites (Kagan, 1988; Rom, et al., 1991). Several studies also have demonstrated that the in vitro phagocytic uptake of asbestos fibers can generate a variety of reactive oxygen species (ROS) such as the superoxide anion \((O_2^{* - })\), the hydroxyl radical (OH*) and hydrogen peroxide (Shull, et al., 1992; Mossman, et al., 1986). It also has been reported that scavengers of oxygen free radicals, such as superoxide dismutase (SOD) and catalase, may ameliorate the injurious effects of asbestos exposure (Mossman, et al,. 1986; Mossman, et al,. 1990). These studies are predicated on \((O_2^{* - })\)-driven, iron-catalyzed, Fenton-Haber-Weiss reactions which generate the OH* radical (Grisham, 1992), and suggest that ROS may have an important role in the pathobiology of asbestos-related disease.

Altered Functional Expression of Alveolar Macrophage Subpopulations after Serpentine and Amphibole Asbestos Exposure

There is considerable evidence that alveolar macrophages play a pivotal role in the pathogenesis of asbestosis (Kagan 1985, Kagan 1988), since these phagocytic cells are a notable feature of histologic lesions at sites of asbestos deposition in the lungs (Davis 1963, Brody et al. 1981, Oghiso et al. 1984). Multinucleated giant cells also are a prominent component of the macrophage response to inhaled asbestos (Kagan et al. 1983a, Kagan 1988). Conceivably, the accumulation of alveolar macrophages in evolving asbestotic lesions may reflect a localized tissue response to the release of asbestos-induced pulmonary chemoattractants. Support for this concept is provided by experimental studies which have demonstrated that inhalation of, asbestos fibers can evoke the release of chemotactic stimuli for alveolar macrophages (Kagan et al. 1983b, Warheit et al. 1985). Asbestos inhalation also is associated with enhanced expression of immune- associated (la) surface antigens on alveolar macrophages and with augmented production of the immunostimulatory monokine, interleukin-1 (Hartmann et al. 1984a, Hartmann et al. 1984b). Since the surface expression of la antigens on macrophages is a useful morphologic correlate of macrophage activation (Garrett et al. 1984, Kunkel et al. 1984), these findings collectively suggest that contact with asbestos fibers may induce alveolar macrophages to become functionally activated.