Category Archives: Asbestos

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 4)

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 4)In contrast to other asbestos-mediated responses on endothelium such as increased prostaglandin synthesis and cell cytotoxicity, the asbestos-stimulated tissue factor expression did not appear to be dependent on the production of reactive oxygen species. These results indicate that two important lung parenchymal cells, AM and vascular endothelial cells, may be activated by interaction with interstitial asbestos resulting in enhancement of procoagulant expression. These studies further suggest that expression of procoagulant activities may be yet another important lung response following asbestos inhalation which contributes to lung inflammation and fibrogenesis. buy flovent inhaler
Besides tissue factor/factor VII mediated PCA in lung fluids, other factors may act to increase lung fibrin deposition in response to asbestos. For example, release of inflammatory cell proteases such as cathep-sin G and elastase amplify fibrinogen cleaving activities. Patients with asbestosis demonstrated significant increases in BAL neutrophils, eosinophils and AM, which are rich sources of these active proteases. Thus, enhanced fibrinogen cleavage, and hence, fibrin deposition may result from these components as well as activation of the extrinsic coagulation pathway by asbestos. Ultimately, fibrin deposition represents a balance between procoagulant and fibrinolytic activities. Although a significant increase in BAL procoagulant activity was detected in our asbestos-exposed and asbestotic patients, fibrinolytic capacities were not assessed and examination of fibrinolytic pathways will be required to fully interpret these findings.

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 3)

Current evidence suggests that a number of major cell types can contribute to both clotting and fibrinolytic activities in the lung, including the AM, endothelial cells, and alveolar epithelial lining cells. The normal AM expresses low basal levels of PCA which can be greatly enhanced by interaction with inflammatory mediators and cytokines. Because AMs are postulated as a key target cells in the pathogenesis of asbestosis, we assessed procoagulant activity in macrophages from patients with asbestosis or asbestos exposure in comparison to AM from normal control subjects. Macrophages from asbestotic patients demonstrated significantly greater basal PCA than that found in AM from either asbestos-exposed or control subjects. The increased procoagulant activity in the asbestotic patients’ AM cannot be directly attributed to the deposited asbestos fibers and may represent a nonspecific inflammatory response in these subjects. However, the inhaled asbestos is presumably a major contributor to this inflammatory process and may act either directly, or indirectly, to increase the coagulant state of the resident lung macrophages. There was no significant difference in the isolated AM procoagulant activity between the asbestos-exposed patients without asbestosis and nonexposed control subjects although only a limited number of samples were available for this study. buy asthma inhalers

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 2)

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 2)The hypothesis that an enhancement of lung procoagulant activities exists in patients with asbestos exposure was tested in the present study, and potential cell types within the lung which may contribute to this disturbance of coagulation were investigated. Our results demonstrated that patients with asbestos exposure had significantly increased PCA in cell-free BAL fluid when compared to control subjects and considerably less BAL PCA. in comparison to asbestotic patients. Furthermore, patients with asbestosis had the greatest increase in procoagulant activity in both BAL fluid and AM when compared to their asbestos-exposed counterparts as well as to the normal control subjects. buy asthma inhaler

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Discussion (Part 1)

There is now convincing evidence that a balance between procoagulant and antithrombotic mechanisms exists within epithelial lining fluids of the lung and that the alveolar surface appears to be functionally saturated with complexes of tissue factor and factor VII. When an imbalance in these mechanisms occurs to favor procoagulant activities, fibrin formation and deposition may result. Intra-alveolar deposition of fibrin has been observed in animal models of acute lung injury, and in humans with the adult respiratory distress syndrome. Recent studies of alveolar procoagulant activity in BAL fluids during acute lung injury in animals and in human ARDS indicate that procoagulant activity is increased, which correlates temporally with fibrin deposition in the lung. These studies suggest that this enhancement results from an influx of vital coagulation factors across a leaking alveolar capillary surface.

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 6)

Effect of Oxidant Inhibitors on PCA in Asbestos-Exposed HUVEC
In previous investigations of asbestos-induced activation of endothelial cell functions, we reported that HUVEC synthesized PGI2 in response to asbestos exposure and that the synthesis was blocked by inclusion of oxidant inhibitors. Consequently, experiments were performed to test the hypothesis that asbestos induction of PCA was due to oxidant generation. Co-incubation of amosite asbestos (250 jig/ml) with catalase (3000 U/ml), a scavenger of hydrogen peroxide, had marginal inhibitory effect (inhibition of 6.2 percent ±0.2 percent) on the enhanced PCA resulting from asbestos alone.

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 5)

To further support these data, other experiments were conducted examining asbestos-mediated effects on the functional activity of the intact endothelial cell surface by monitoring the rate of factor Xa formation from purified factor X. As illustrated in Figure 4 (upper), intact HUVEC monolayers demonstrated a similar dose-dependent response to asbestos exposure as found with the disrupted cell pellets (Fig 3). The time-course of the asbestos-induced increase in HUVEC tissue factor expression indicated that maximal activity occurs at five to seven hours following asbestos exposure (Fig 4 [lower]).

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 4)

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 4)Alveolar Macrophage Procoagulant Activity
In vitro clotting activity was assessed in BAL AM obtained from a limited number of patients in the three study groups. The PCA values expressed as tissue factor units are shown in Figure 2. The BAL AM from control subjects (n = 5) exhibited the longest clotting times (89.9 ±4.0 s) and lowest TFU (383.6 ±40). The AM from asbestos-exposed patients without asbestosis (n = 9) demonstrated clotting times (85.5 ±2.7 s) and TFU (462 ±38) which were not statistically different from that of control subjects’ AM. In contrast, AM from asbestotic patients (n = 5) demonstrated significantly reduced clotting times (71.4 ±8.3 s) and significantly higher TFU (864.5±257). Although only this limited number of samples was available for investigation, AM basal PCA from asbestotic patients was clearly different from PCA measured in macrophages obtained from the other two groups. These data indicate that asbestosis is associated with increased PCA by these patients’ AM; however, the specific role of asbestos cannot be ascertained from these results.

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 3)

As control subjects were all nonsmokers, it was possible that observed differences among the three groups were related to smoking habits. Consequently, the PCA data from BAL were evaluated in relation to smoking history as shown in Table 2. The asbestotic group 1 patients had marked and significant reductions in clotting times in comparison to the asbestos-exposed group 2 patients regardless of the smoking history. In addition, the asbestotic group 1 nonsmokers demonstrated significantly shortened clotting times in comparison to normal, nonsmoking group 3 control subjects. There were also significant differences in PCA from both the former and current smokers in asbestos-exposed group 2 patients when compared to group 3 control subjects.

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 2)

The clinical asbestosis group 1 patients had both a higher percentage of BAL neutrophils as well as total BAL neutrophils (total PMNs = 1.4 ± 0.6 x 106) when compared with the asbestos-exposed group 2 patients (total PMNs = 0.5 ± 0.2 X 106, p<0.01), or normal control group 3 subjects (total PMNs = 0.07 ± 0.02 x 106, p<0.001). In addition, group 1 subjects exhibited significant increases in both percentage of BAL eosinophils and total BAL eosinophils (total EOS = 1.2 ± 0.8 X 106) compared to the two other groups (p<0.05 for group 1 vs group 2 or group 3). Group 2 demonstrated significantly greater BAL neutrophils (percent PMNs or total PMNs) compared to group 3 (p = 0.04).

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 1)

Asbestos Exposure Results in Increased Lung Procoagulant Activity in Vivo and in Vitro: Results (Part 1)Clinical and Functional Data
The clinical data and results of pulmonary function tests for the three study groups are shown in Table 1. Group 1 was comprised of nine patients with clinically diagnosed asbestosis, group 2 consisted of 80 patients with a history of asbestos exposure but without asbestosis, whereas group 3 was composed of 13 normal nonsmoking, nonasbestos-exposed volunteers. There were differences in ages among the groups as group 3 subjects were considerably younger than the patient cohorts. Both groups 1 and 2 had comparable years of asbestos exposure and comparable smoking exposure (pack-years). Group 1 patients with asbestosis had reduced FVC, TLC and Deo values compared to group 2 asbestos-exposed patients.

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