Chrysotile asbestos exposures can produce an alveolitis with limited fibrosing activity in a subset of high fibre retainer sheep

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1 Eur Respir J 1990, 3, Chrysotile asbestos exposures can produce an alveolitis with limited fibrosing activity in a subset of high fibre retainer sheep R. Begin, A. Cantin, P. Sebastian Chrysotile asbestos exposures can provide an alveolitis with limited fibrosing activity in a subset of high fibre retainer sheep. R. Begin, A. Cant in. P. Sebastien. ABSTRACT: Inhalation of flbrogenlc mineral dust may enhance flbronectin (Fn) production by alveolar macrophages and Increase flbrobla:st growth activity (FGA) In lung lavage fluid. To investigate the relationship of these changes to flbre retention and the development of asbestosis, we exposed 15 sheep to 100 mg Canadian chrysotue flbres In 100 ml saline, and ten sheep to 100 ml saline only, at ten day Intervals. The animals were studied at 3 month Intervals. At month 18, ten sheep bad abnormal chest radiograph (category ~1) (group B) and five bad normal radiograph (category 0) (group A). Pulmonary function data indicated restrictive patterns or abnormalities In both groups, more severe In group B. Sheep In group A bad broncboalveolar lavage (BAL) cellularlty and biochemistry compa rable to controls; sheep In group B bad significant Increases In total BAL cells (x2), macrophages (x2), neutrophlls ( x4) and eoslnophus (x3), Increased BAL lactate dehydrogenase and Fn, but FGA and procollagen 3 comparable to controls. Fibre retention was significantly increased in an exposed sheep and 2.5 x higher in group B vs group A despite similar exposures (70 intratracheal, 100 mg chrysotue Infusions). Enhanced fibre retention in group B preceded the appearance of disease. This study confirms our earlier observation linking Individual susceptlbiuty to development of alveolltls to individual dust burden and provides evidence that the excess or fibre retention can be obsen ed before detectable disease. In addition, we report a chrysotlle-lnduced early alveolltls with Incompletely expressed flbroslng activity at the time of initial radiographic detection. The Intensity or the alveolltls Is related to the degree of fibre retention. Eur Respir J., 1990, 3, Unit~ de Recherche Pulmonaire, Universit~ de Sherbroolce, Sherbroolce, Qu~bec, Canada and Dust Disease Unit, McGill School of Occupational Health, Montreal, Quebec, Canada. Correspondence: R. B~gin, CHUS, Sherbrooke, Quebec, Canada JJH 5N4. Keywords: Asbestos; chrysotile; pulmonary fibrosis. Received: August Accepted after revision September 1, Supported by MRC Canada and lrsst Quebec, Canada. Individual susceptibility of humans to development of disease is well recognized. In humans chronically exposed to asbestos dust inhalation at work, it is well documented that, for a given level of exposure, only a fraction of the workers develop asbestosis [1-6]. To investigate the so-called "individual susceptibility factor", immunological background, lung structure and lung clearance capacity have been considered. Reports on human immunological histocompatibility in asbestos workers, including our own recent work [7, 8], have failed to identify definite markers for susceptible individuals. Anatomical structure characteristics of the major airways have been related to risk factors in adverse pulmonary response to asbestos exposure [2], and these characteristics may influence mucociliary clearance of the asbestos deposited in the lung. Alveolar dust clearance in humans has not been directly studied as a determinant factor for individual susceptibility to asbestosis. However, lung tissue fibre burden has been found to be increased in asbestos workers compared to the general population [9]. Asbestos workers with isolated airway disease have twice the lung fibre content of workers without the airway disease [10] but only 50% of the fibre content of patients with asbestosis [11-14]. Analyses of bronchoalveolar lavage (BAL) fibre content of workers with asbestosis were also found to be significantly higher than values found in exposed workers without asbestosis [15, 16]. Since exposure levels cannot be precisely determined in human studies, it is not possible to compare groups of workers with similar exposure but different disease activity. Furthermore, the currently available techniques for measurement of fibre deposition and clearance using radioactive fibres evaluate primarily the rapid phase of dust clearance and its validity in reflecting the late slower phase of dust clearance, or overall clearance, have not been established. Alternatively, fibre retention in the bronchoalveolar space, as determined by BAL, has been documented in humans [17, 18] and in our sheep model [19] to reflect

2 82 R. BEGIN, A. CANTIN, P. SEBASTIEN lung tissue retention. Thus, with this approach we estimated lung tissue fibre retention and related it to other phenomena in the sheep exposed to chrysotile dusts. Our sheep model of asbestosis, which utilizes multiple intratracheal injections of the chrysotile dust as a means of exposure, has reproduced the heterogeneity of lung tissue response previously observed in humans [1-6] and other animal models [20, 21]. This model made it possible to establish that susceptible sheep were retaining more asbestos fibres [22, 23]. The levels of dust retention in our initial studies were measured only after disease was established. The present experiment was therefore designed to test the above hypothesis of a dust retention related individual susceptibility. Thus, we obtained repeated measurements of BAL fibre content during the course of induction of experimental asbestosis. An additional objective of this study was to characterize the fibrogenic activity of the early chrysotile-induced alveolitis in the susceptible sheep, at time of initial radiograph detection, and to relate the individual response of lung tissue to the de!:,>tee of retention of the chrysotile fibres. Methods Animals. Twenty five sheep weighing kg were used in this study. They were prepared and accustomed to the pulmonary techniques as previously reported [22, 23]. Experimental design. The flock was divided into a group of ten sheep exposed to phosphate buffered saline (PBS) only and a group of 15 sheep exposed to 100 mg UICC Canadian chrysotile asbestos fibres in loo m! PBS every ten days. These fibres were relativity unifonn and well characterized, 92% being less than 0.25 J.!m in diameter and 20 J.!m in length. Exposures were carried out after nasotracheal intubation via repeated slow infusions of the suspension in the trachea at ten day intervals throughout the 24 month study. Sequence of analyses. The animals were studied prior to exposure and at three month intervals thereafter by chest radiographs (CR), pulmonary function tests (PFT) and BAL analyses. Transbronchial lung biopsies were not obtained as we have previously correlated the histopathology of the early radiographic changes in this model [24-27]. Chest radiograph. Each sheep was positioned on a mobile cart with a wooden board and a grid cassette under the thorax. The X-ray source was placed at a 30 caudal angle, 2 feet from the cassette. The intubated animal was held at total lung capacity (TLC) using a giant syringe, and radiographs were taken at exposure factors 80 kv, 20 mas, and 0.02 s. Each radiograph was scored according to the International Labor Organization (flo) classification of radiographic profusion of parenchyma! opacities [28]. This classification recognizes the existence of a continuum of change, from no opacity to the most advanced category. The scores were converted to a linear scale of 0-10 (12 categories) as follows: ILO grade 0/- (clearly nonnal) and grade 0/0 (nonnal after close examination) = 0 on the linear scale; 0/1 = 1; 1/0 = 2; 1/1 = 3; 1/2 = 4; 2/1 = 5; 2/2 = 6; 2{3 = 7; 3/2 = 8; 3/3 = 9; 3/4 = 10. In the ILO classification, four categories are defined on the basis of these same profusion scores: category 0 =profusion scores 0/-, 0/0, and 0/1: category 1= profusion scores 1/0, 1/1, and 1/2; category 2 =profusion scores 2/1, 2/2, and 2/3; category 3 =profusion scores 3/2, 3/3, and 3/4. The radiographs in category 0 are generally considered normal whereas those in category 1 or above are definitely abnonnal. Pulmonary function tests. The methods used in PFT assessment of the sheep have been published previously [23-26]. Briefly, transpulmonary pressure was monitored with a naso-oesophageal 7 ml balloon catheter and an airway catheter connected to a Hewlett-Packard 270 differential pressure transducer (Hewlett-Packard, Waltham, MA). Gas flow at the airway opening was measured by connecting the cuffed endotracheal tube to a Fleisch no. 2 pneumotachograph (Dyna-sciences, Blue Bell, PA) attached to a flow integrator recorder system and a Mink data processing system (Digital Equipment, Montreal, Quebec), for on-line analysis and storing of the data. Each PFT measurement was obtained after three inspiratory capacity measurements at a constant volume; TLC was defined as the lung volume at a transpulmonary pressure of +35±5 cmhp, and residual volume RV was defined as the lung volume at a transpulmonary pressure of -35±5 cmhp. The static expiratory lung compliance (Ctst) was determined by multiple-step syringe deflation between TLC and functional residual capacity (FRC). Diffusion capacity (DLCo) was obtained by a passive rebreathing method using a gas mixture of 10% helium, 0.30% carbon monoxide, and 21% oxygen in nitrogen, a Collins catherometer (Warren E. Collins, Braintree, MA) and a Beckman infra-red carbon monoxide analyser (Beckman Instruments, Fullerton, CA). For the DLco test, the animals were passively ventilated with a 2.5 I syringe at a rate of 30 breaths min 1 with a 1 1 tidal volume. Bronchoalveolar lavage and cell analysis. The techniques in BAL procedures and analyses have been described previously [22, 23]. The BAL effluent was passed through four layers of cheesecloth to remove mucus, and the cells were pelletized by centrifugation. Cells were counted in a haemocytometer, and cell viability was determined by the trypan blue exclusion technique. Cytocentrifuge smears served to identify the cellular populations recovered with the Wright-Giemsa stain. BAL proteins and enzymes. In the supematant, albumin was determined by the immunochemical method of Kn.LJNGSWORTH and SAVORY [29), with a laser nephelometer (Behring LN modular system, Hoechst Behring, Frankfurt, DDR) using specific antiserum raised in

3 ALVEOLITIS IN CHRYSOTILE ASBESTOS EXPOSURE 83 rabbits (Cappel Lab. Inc., Downington, PA). The activity of lactate dehydrogenase (LDH), an indicator of cytoplasmic toxicity, was measured by spectrophotometric methods [30]. BAL mljtrix constituents. To assess interstitial lung matrix changes we looked at the fibronectin accumulations in BAL fluid. We also measured the production of fibronectin by BAL cells in culture [31, 32]. To determined cellular production of fibronectin, BAL cells were incubated without adherence step in 24 well culture plates (Linbro Chemical Co., New Haven, Conn.) in Dulbecco's modified Eagles medium (DMEM, Gibco Diagnostic Laboratories, Grand Island, NY) containing 100 Umi 1 penicillin and 100 Jlg ml 1 streptomycin, at a density of 2x1()6-ml 1, for 1 h at 37 C, 10% C0 2 At the end of the incubation period, the supernatants were centrifuged (500xg, 10 min) and stored at -20 C before fibronectin measurement. Fibronectin was determined by direct enzyme-linked immunoadsorbent assay (ELISA) technique adapted from RENNARD et al. [31]. Briefly, 96 well polystyrene plates (Costar, Cambridge, Mass.) were coated with gelatin (500 Jlg per well) at 20 C for 12 h, rinsed three times with PBS, and samples of BAL supernatant were placed in each well at 20 C for 2 h. The plates were then washed and the concentration of fibronectin was determined by using antisheep fibronectin antibodies raised in rabbits and peroxidase conjugated goat antirabbit immunoglobulin G (IgG) (Boehringer Mannheim Biochemicals, Mannheim, DDR). Using the ELISA technique, the alveolar macrophages are the only BAL cells producing significant amounts of fibronectin [32]. Fibroblast proliferation assay. Since activated alveolar macrophages can release increased amounts of molecules that are mitogenic for fibroblasts [33, 34]. we tested the release of fibroblast growth factors from lung inflammatory cells. Lung inflammatory cells were suspended in Dulbecco's modified Eagles medium (DMEM) containing 100 U.ml 1 penicillin and 100 Jlg ml 1 streptomycin at a density of 1()6 cells mp and incubated at 37 C, 10% C0 2, for 18 h. The adherence step was omilted here as macrophages have been documented to be the sole BAL cell source of growth factor for fibroblasts [35). The cells were then centrifuged (500xg, 10 min) and the supematants were passed through a 0.22 J.!M Millex filter (Millipore, Bedford, MA) before use in the fibroblast proliferation assay. Diploid human fetal lung fibroblasts (HFL-1 CCL 153, American Type Culture Collection, Rockville, MD) (Bradley et al.) were grown to confluence in DMEM, 10% calf serum (Bocknek, Rexdale, Ontario), treated with 0.5 mg ml 1 trypsin and 0.2 mg ml 1 edetic acid (EDTA), and seeded in 24 mm culture wells (Linbro Chemical Co., New Haven, Conn.) at a density of 5xl0' 1 cells per well in DMEM 0.4% calf serum, 10% C0 2, 37 C for four days. The cells were then washed three times with PBS and incubated with supematants from alveolar macrophage cultures diluted 1:2 in DMEM 0.4% calf serum at 37 C, 10% C0 2 for three days. At the end of the incubation, the cells were treated with trypsin/edt A for 15 min and counted in an electronic particle counter (Model ZM, Coulter Electronics Inc., Hialeah, FLA). Each experiment included a negative control consisting of fibroblasts incubated with DMEM alone and a positive control consisting of DMEM + 10% calf serum. The results were expressed as the percentage increase in fibroblast number over control values. Electron microscopy. The analytical transmission electron microscope was used to detect chrysotile fibres in lung lavages. All samples were prepared in a "clean room", using filtered chemicals and carefully cleaned glassware. Thirteen ml were isolated from the third effluent of lavage and allowed to react at room temperature with sodium hypochlorite, in order to digest the biological material. An aliquot of the suspension, corresponding to 5 ml of BAL, was filtered on a polycarbonate membrane filter 25 mm in diameter with a pore size of 0.2 j..lm (Nucleopore Corp., Pleasanton, CA). Particles collected at the upper surface of the membrane were embedded in a carbon film and subsequently transferred onto 200 mesh grids [15]. Several grid openings were observed in the transmission mode at a screen magnification xlo,ooo. Chrysotile fibres were identified by their morphological features and their elemental composition as determined by energy-dispersive X-ray spectrometry (PGT system IVR; Princeton Gamma Tech, Princeton, NJ). The length of each individual fibre encountered was measured directly on the screen to the nearest 0.2 Jlm; diameter was measured using an eyepiece graticule. Fibre count analyses were performed at months 3, 15 and 24 of the study. Statistical analysis. In the presentation of the results, values of the data for each group of sheep are followed by the standard error as an index of dispersion. The data were evaluated by analysis of variance for experiments having repeated measurements on the same subjects. When a significant effect was detected, a Kruskal-Wallis test was used to determine which group means were significantly different (p<0.05) [36). Analyses of correlation of fibres in BAL to other parameters of disease activity were performed with the Spearman correlation rank test [36]. Results Subsets of sheep. At month 12, the group of 15 sheep exposed to chrysotile had significant changes in radiographic score, static lung compliance, vital capacity and arterial oxygen tension (Pao 2 ) compared to saline exposed sheep and these changes were accentuated thereafter. Analyses of individual results of the 15 asbestos exposed sheep showed that these changes were the effect of disease limited to ten of the 15 sheep. The chest radiograph was abnormal in ten. Analysis of lung functions and BAL cellularity of individual sheep with reference to the 95% confidence interval of control sheep also clearly separated the diseased subset.

4 84 R. B~GIN, A. CANTIN, P. S~BASTIEN We therefore divided the group of chrysotile exposed sheep into two subsets: a subset of five sheep with nonnal chest radiograph (0/0 or 0/1 score) (subset A) and a subset of ten sheep with abnonnal chest radiograph (1/0 or above score) (subset B). In this model of asbestosis, histopathological changes associated with early changes in chest radiograph have been reported in detail [25-27] and briefly consist of a diffuse peribronchiolar macrophagic alveolitis extending into the adjacent interstitium and alveolar spaces. Bronchoalveo/ar exposure index. This index is a time integral of fibre estimated to be retained in the bronchoalveolar space. It is expressed as number of fibres J.1). 1 per month. Results are presented in table 1. For the two groups of sheep, which received the same exposures, the bronchoalveolar exposure indices were not significantly different. two chrysotile exposed sheep. The fibre length also significantly changed in the two groups over time. In the chrysotile exposed sheep with nonnal chest radiograph, the mean fibre length J.1). 1 of BAL was 4.3±1.5, 4.6±1.7 and 15.1±1.2 at months 3, 15 and 24, respectively. In the chrysotile exposed sheep with abnonnal chest radiograph, the mean fibre length was 3.2±1.4, 5.2±1.3 and 10.1±1.9 ~ J.tl 1 at months 3, 15 and 24, respectively. In both groups, the average fibre length was significantly longer at month 24 only (p<0.05). Lung functions. In figure 1, we present the time course of changes in chest radiograph scores in each of the three groups of sheep in parallel with selected lung functions. It can be appreciated that, whereas lung functions of diseased sheep are clearly distinct from control sheep, the functions of chrysotile exposed sheep with nonnal radiograph remained between the normal and the Table 1. - Fibre exposure and retention Control sheep Sheep with normal radiograph Sheep with abnormal radiograph Exposure Bronchoalveolar exposure index fibres ~-tl" 1 per month ± ±360 Retention Fibre number fibres ~-ti <0.2 <0.2 < ±3 34.6± ±2.9 84±2* 91.6±2* 25.5±2.5* Fibre length <1 <1 <1 4.3± ± ± ± ± ±1.9 Bronchoalveolar exposure index is a time integral of fibre estimated to be retained in the bronchoalveolar space (fibres ~-tl" 1 per month). Results are geometric mearis±l SI!. *: p<0.05 for sheep with abnormal radiograph vs sheep with normal radiograph. At month 24, mean fibre length was longer in exposed sheep but the difference between the two groups of exposed sheep was not significant. Fibre retention. BAL fibre analyses were obtained at months 3, 15 and 24 of the study (table 1). In the saline exposed sheep, fibre counts were always <0.2 fibres ~! and all were shorter than 1 J.L in length. In the chrysotile exposed sheep with nonnal chest radiograph, fibre counts were 51.6±3, 34.6±19 and 10.5±2.9 fibres J.Ll" 1 at months 3, 15 and 24, respectively. In the chrysotile exposed sheep with abnonnal chest radiograph, fibre counts were 84.1±2, 91.6±2 and 25.5±2.5 fibres J.Ll" 1 at months, 3, 15 and 24, respectively. The ratio of fibre counts for normal/abnonnal ~as 0.61, 0.37 and 0.41 at months 3, 15 and 24, respectively. Differences between the two groups were significant at p<0.05 at all times. A few asbestos bodies were observed in the radiographically abnonnal groups. Lung resistance (RL) at last point of study, month 24, was 0.24±0.08 kpa / 1 s in controls, 0.33±0.07 in subset A and 0.52±0.09 in subset B (p<0.05 for B vs controls). These changes in RL were accompanied by significant reduction of effective lung compliance at 54 and 45% controls in groups A and B, respectively. These values in both exposed groups suggested a peribronchiolar process as previously described in the sheep model [22-24]. The alveolitis. In figure 2, we present results of cellularicy of lung lavage and in figure 3, the biochemistry and cell culture results. In the saline exposed sheep, there was no significant change over time in all parameters

5 ALVEOLITIS IN CHRYSOTILE ASBESTOS EXPOSURE Profusion of parenchyma! 500 Static lung 6 VC I opacities score compliance ml cmh 2 0' * ! Pao 2 torr 40 DLCO ml mln 1 torr 1 Control sheep Asbe.tos exposed sheep with normal radiograph eo 20.A. Asbestos exposed sheep wllh abnormal radiograph * pco.os v control pco.os v sheep with normal radiograph Fig. I. - Results of chest radiograph scoring and lung f~mction tests in the three groups of sheep. VC: vital capacity; Pao 2 : arterial oxygen tension; DLco: carbon monoxide diffusion capacity. 60 Total cell 1 x10' 1 mf 1 * Eoslnophll1 x10' 1 ml H Neutrophil 1 x mf ! * ! ! Fig Time course of bronchoalveolar lavage cellularity in the three groups of sheep identified as in figure I.

6 86 R. BEGlN, A. CANTIN, P. SEBASTffiN 2oo Albumin aoo Flbronactln o.o6o Procollagen 3/albumln ng 11g 1 * LDH miu ml 1 20 Flbronectln production* 1oo Flbroblast growth activity ng 10-4 calls per 24 h ~ ~50, Fig Tune course of selected biochemical marlcers of disease process in lbe three groups of sheep identified as in figure 1. The upper lbree panels and the bottom left panel are from bronchoalveolar lavage (BAL) fluid analyses. The bouom middle and right panels are derived from BAL cell cultures as detailed in the Methods section. LDH: lactate dehydrogenase. except for the increase in lymphocytes which has not been observed in our prior studies of the sheep model and remains otherwise totally unexplained. This was not observed in another conl.rol group of sheep evaluated during the same two year period (our silicosis study). The increase in lymphocytes in this study also caused total BAL cells to be slightly raised over time in conlrols. In the chrysotile exposed sheep with normal chest radiograph, group A, values of cellularity were comparable to saline exposed sheep without significant changes in lymphocytes over time which remained at 10±2% of total BAL cells. In the chrysotile exposed sheep with abnormal chest radiograph, group B, there were significant increases in total BAL cells, macrophages, eosinophils and neutrophils at month 12 and thereafter, compared to controls and group A. Furthermore, BAL albumin was slightly but significantly increased 50-70% above conl.rols with parallel increases in IgG and IgM (data not shown) and more accentuated (300% of controls, month 18) increases in BAL lactate dehydrogenase. Fibroncctin (Fn) production by macrophages in culture remained below detection level (<2 ng l0 6 cells per 24 h) in controls throughout the study. In group A, Fn did not differ from controls. Fn in group B was increased above controls after month 12 and accumulated to values 300% of controls in the BAL supernatant of the sheep in group B. These changes occurred in the absence of significant increase in BAL procollagen 3/albumin ratio or fibroblast growth activity. Fibre retention correlates. Analysis of correlation of fibre retention to other parameters of disease activity documented a significant relationship between individual fibre retention and radiographic disease (p<o.ol), cytotoxicity (LDH in BAL) (p<o.ol), fibronectin production by alveolar macrophages (p<o.ol), increased cellularity of BAL (p<0.02) and loss of vital capacity (p<0.05). These associations strengthen the concept that, for a given chrysotile exposure, the intensity of disease process directly relates to the individual fibre retention. Discussion The present study reproduced the heterogeneity of lung tissue response previously observed in sheep chronically exposed to chrysotile [22, 23], in asbestos workers [1--6] and in other animal models of asbestosis [20, 21]. The sequential analyses of BAL fibre content, an index of alveolar dust retention [15, 17, 23, 37] documented the following observations which have not previously been reported. Firstly, given that exposure was continued throughout the 24 months of the study at the same exposure level (one injected dose per ten day interval), both groups of chrysotile exposed animals had a gradual decrease in alveolar dust retention which implies eicher

7 ALYEOLlTIS IN CHRYSOTILE ASBESTOS EXPOSURE 87 an enhancement of the alveolar clearance up the tracheobronchial tree or a larger transfer to the interstitial space. Secondly, fibre length significantly increased after month 15 in both groups of exposed sheep. The observation of a gradual decrease may be particular to the model and/or mode of exposure, but it also concurs with observations by W AGNER et al. [20] on rat asbestosis, and RoWLAND et al. [38] and S~BASTIEN et al. [39] in human asbestosis. The enrichment in long fibres has also been documented [39]. This enhanced alveolar clearance was observed in both groups of sheep with or without disease. Thirdly, the animals with asbestosis not only retained significantly more fibres but a significant excess of fibre accumulation could be detected before any abnormality of pulmonary radiograph, function or bronchoalveolar lavage. This observation therefore documented that this high retention state preceded the development of the disease. A link to individual susceptibility for disease development can, therefore, be firmly considered. Our study is also of interest as it further characterized the early stage of asbestosis at the time of initial radiographic recognition of the disease process. Previous studies in humans (4, 40-42] and in several animal models, including sheep [22-27, 43-52] have clearly documented that lungs chronically exposed to asbestos or other mineral dusts have an excessive early accumulation of macrophages in the lower respiratory tract. This initial macrophage alveolitis may not necessarily lead to interstitial lung fibrosis. Indeed, it has been documented in long-term asbestos and silica workers [53] that the macrophage population of the lower respiratory tract may be expanded in the absence of interstitial lung fibrosing disease; in the animal model, it is a wellrecognized early lung tissue reaction to inert dust particles which usually disappears without residual scar in the months after exposure cessation [54, 55]. This type of "transient macrophagic alveolitis" has been observed following latex bead, carbon, graphite, and particulate carborundum exposures (54-56]. Pathological characteristics of this lesion are its absence of distortion of the normal histological lung structure and the clearance of the phagocyte accumulation after cessation of exposure [54-56). In terms of cell biology of the macrophage, we should ask what differentiates the macrophages of the transient dust alveolitis from that of the normal lung or that of a fibrosing alveolitis? Firstly, the macrophage of the normal lung is a permanent component of the lung defence mechanisms which, under normal healthy conditions, is in a quiescent state, producing minimal amounts of secretions [57, 58]. The deposition of the particles in the lower respiratory tract initiates in situ chemotactic activity for the macrophage which accumulates at the site of particle deposition [51]. Basal metabolic activity is increased, it displays pronounced ruffling of surfaces, phagocytosis and cell size increases, function is enhanced and, usually within hours, most particles deposited are phagocytosed [48-50]. If the particle or fibre phagocytosed is "inert", limited secretory activity of the alveolar macrophages occurs, the macrophage alveolitis is transient with little or no lung tissue scarring [55-57). Under the circumstances of exposure to inert dusts, alveolar macrophages rapidly phagocytose the vast majority of particles but they do not increase secretion of molecules known to contribute to the pathogenesis of chronic lung disease [54-56). Exposure of the lower respiratory tract to fibres or particles known to cause lung injury, bioactive, can lead to the following lung tissue responses: 1. The no-retention reaction: most fibres appear to be cleared away from the lung tissue rapidly without significant lung tissue scarring. This is the case in several experimental conditions of low exposures to chrysotile [59). It is also the case in some long-term asbestos workers which may be estimated in our clinical work to be up to 50% of all workers [4-6]. This has been observed in the animal model [59] and in long-term chrysotile miners [10]. 2. The low-retention reaction: fibre retention is low because of the so-called "individual susceptibility factor", lung tissue reaction is limited to the site of deposition where macrophages accumulate and eventually are replaced by fibrotic scars limited to the distal airways [10, 23). In this study it appears to be the case in our sheep in group A. 3. The high-retention reaction: fibre retention is significantly higher, lung tissue reaction is more intense, a diffuse macrophagic alveolitis can be recognized. The secretory activity of macrophages is enhanced. Oxidant production is increased [42], fibronectin production [22, 41, 42, 54], neutrophil chemotactic activity [60, 61] and fibroblast growth activity [42, 62] are increased, plasminogen activator [63] and interleukin 1 [64] are secreted at higher levels. If these secretions are sustained, diffuse lung damage occurs with the development of chronic interstitial lung disease. The latter observation has been particularly well documented in animal models. This high-retention reaction is probably the case of individuals with interstitial lung disease associated with chronic inhalation of inorganic dust, asbestos in particular [41, 42]. The men with asbestosis have a high fibre content of their lung tissue [10-15] and a well-described fibrosing alveolitis where macrophages are clearly activated [5, 41, 42, 61). This type of reaction has also been well characterized in animal models. In the sheep model [22, 27], this high retention reaction has all of the secretory characteristics reported in humans and becomes a progressive interstitial lung fibrosing disease even in the absence of further dust exposure. The animal models have demonstrated that these macrophage secretions needed to be sustained to initiate and maintain the development of a fibrosing lung process. In this paper, we report on sheep which developed a relatively less intense alveolitis than in our previous experiments but, nonetheless, a diffuse reaction of the lung to chrysotile exposure. The sheep in group B had diffuse lung infiltrates; their BAL analyses documented an expanded cell population of the lower respiratory tract (fig. 2). Furthermore, there was evidence of enhanced secretory function of the cells: oxidant production was

8 88 R. BEGIN, A. CANTIN, P. SEBASTlEN increased, fibronectin production and accumulation was increased; LDH release was increased and albumin was accumulating slightly in the alveolar space. This alveo Iitis has been shown previously in the sheep model to enhance Gallium-67 lung uptake [4]. However, this reaction of modest intensity did not significantly alter fibroblast growth activity or increase procollagen 3 of lung lavage as previously documented in the presence of fibrosing lung disease [41, 42] and, thus, could at least "in theory", regress, leaving minimal lung damage. This observation is of interest as we have previously documented enhanced prostaglandin E 2 activity in the sheep model at the stage of early asbestosis [65), a prostaglandin which is capable of inhibiting fibroblast growth [66). The prostaglandin E 2 secretion by fibroblasts could be induced by alveolar macrophages and inhibit the fibrotic lung response [67). This observation of an intermediate lung reaction between the "low- and the high-retention reactions" occurring after exposures to dusts with known fibrogenic potentials is important as it describes a potentially reversible/non-scarring reaction if exposure is stopped. In addition, the present study documents that the chrysotile induced alveolitis at the time of initial radiographic detection has an incompletely expressed fibrosing activity. It could provide an explanation for the clinical observation of non-progression/regression of several cases of minimal asbestosis in humans. References 1. Becklake MR. - Asbestos-related diseases of the hmg and other organs: their epidemiology and implications for clinical practice. Am Rev Respir Dis, 1976, 114, Becklake MR. - Lung structure as a risk factor in adverse pulmonary responses to asbestos exposure. Am Rev Respir Dis, 1983, 128, Becklake MR, Fournier-Massey G, McDonald JC, Siemiatycky J, Rossiter CE. - Lung function in relation to chest roentgenographic changes in Quebec asbestos workers. Bull Eur PhysiopaJhol Respir, 1970, 6, 637~ Begin R. Cantin A, Drapeau G. Lamoureux G. Boctor M, Masse S, Rola-Pleszczynski M. - Pulmonary uptake of Gallium-67 in asbestos exposed human and sheep. Am Rev Respir Dis, 1983, 127, 623~ Begin R, Cantin A, Berthiaume Y, Boileau R, Bisson G, Lamoureux G, Rola-Pleszczynski M, Drapeau G, Masse S, Boctor M, Breault J. Peloquin S, Dalle D. - Clinical features to stage alveolitis in asbestos workers. Am J lnd Med, , Begin R, Boileau R, Peloquin S. - Asbestos exposure, cigarette smoking and airflow limitation in long-term Canadian chrysotile miners and millers. Am J Ind Med, 1987, Gregor A, Singh S, Tumer-Warwick M, Lawler S, Raymond Parkes W. - The role of histocompatibility (HLA) antigens in asbestosis. Br J Dis Chest, 1979, 73, B6gin R. Menard H. Decarie F, St-Sauveur A. - Immunogenetic [actors as determinants of asbestosis. L ung Churg A, Wamock ML. - Asbestos fibers in the general population. Am Rev Respir Dis, 1980, 122, Churg A.- Asbestos fiber content of the lungs in patients with and without asbestos airways disease. Am Rev Respir Dis, 1983, Ashcroft T, Heppleston AG. - The optical and electron microscopic determination of pulmonary asbestos fibre concentration and its relation to the human pathological reaction. J Clin Patho/, 1973, 26, Whitwell F. Scott J, Grimshaw M. - Relationship between occupations and asbestos-fibre content of the lungs in patients with pleural mesothelioma, lung cancer, and other diseases. Thorax, 1977, 32, Roggli VL, Greenberg SD, Seitzman LH, McGavran MH, Hurst GA, Spivey CG, Nelson KG, Hieger LR. - Pulmonary fibrosis, carcinoma, and ferruginous body counts in amosite asbestos workers. Am J Clin Pathol, 1980, 73, Wamock ML, Kuwahara TJ, Wolery G. - The relation of asbestos burden to asbestosis and lung cancer. Pathol Annu, 1983, 18, Sebastien P, Billon MA, Janson X, Bonnaud G, Bignon J. - Utilisation du microscope electronique a transmission (MET) pour la mesure des contaminations par l'amiante. Arch Mal Prof. 1978, 39, Bignon J, Sebastien P, Gaudichet A. - Measurement of asbestos retention in the human respiratory system related to health effects. In: Proceedings of the Workshop on Asbestos, Gaitherburg, MD, 1977, pp Sebastien P, Armstrong B, Monchaux G, Bignon J. - Asbestos bodies in bronchoalveolar lavage fluid and in lung parenchyma. Am Rev Respir Dis, 1988, 137, Dodson RF. Williams MG Jr, O'Sullivan MF, Corn CJ, Greenberg SD, Hurst GA. - A comparison of the ferruginous body and uncoated fiber content in the lungs of former asbestos workers. Am Rev Respir Dis, 1985, 132, Begin R, Sebastien P. - Alveolar dust clearance capacity as determinant of individual susceptibility to asbestosis: experimental observations. Ann Occup Hyg, 1989 (in press). 20. Wagner JC, Berry G, Skidmore JW, Timbrell V.- The effects of the inhalation of asbestos in rats. Br J Cancer, 1974, 29, Davies JMG, Becketl ST, Bolton RE, Collings P, Middleton AP. - Mass and number of fibres in the pathogenesis of asbestos-related lung disease in rats. Br J Cancer, 1978, 37, Begin R, Bisson G, Lambert R, Cote Y, Fabi D, Martel M. Lamoureux G, Rola-Pleszczynski M. Boctor M, Dalle D, Masse S. - Gallium-67 uptake in the lung of asbestos exposed sheep: early association with enhanced macrophage-derived fibronectin accumulation. J Nuc/ Med, 1986, 27, B6gin R, MasseS, Sebastien P, Bosse J, Rola-Pleszczynski M, Boctor M, Cote Y, Fabi D, Dalle D. - Asbestos exposure and retention as determinants of airway disease and asbestos alveolitis. Am Rev Respir Dis, 1986, 134, Begin R, Masse S, Bureau MA. - Morphologic features and function of the airways in early asbestosis in the sheep model. Am Rev Respir Dis, 1982, 126, Begin R, Rola-Pleszczynski M, MasseS, Lemaire I, Sirois P, Boctor M, Nadeau D, Drapeau G, Bureau MA. - Asbestos induced lung injury in the sheep model: the initial alveolitis. Environ Res, 1983, 30, Begin R. Rola-Pleszczynski M, Masse S, Nadeau D, Drapeau G. - Assessment of progression of asbestosis in the sheep model by bronchoalveolar lavage and pulmonary function tests. Thorax, 1983, 38, Masse S, Boctor M. Begin R. - In: Pathological, radiological and functional correlations in early asbestosis of the sheep. ILO Vlth International Pneumoconiosis Conference Monograph, vol. 2, 1984,

9 ALVEOLITIS IN CHRYSOTILE ASBESTOS EXPOSURE ILO/UC International Classification of radiographs of pneumoconiosis 1980 No. 22 revised. - Occupational Safety and Health Series. International Labour Office, Geneva, Killingsworth LM, Savory J. - Manual nephelometric methods for immunochemical determination of immunoglobulins lgg, IgA and IgM in human serum. Clin Chem, 1973, 18, Wacker W, Uimer DD, Vallee BL. - Metalloenzymes and myocardial infarction.. Malic and lactic dehydrogenase activities and zinc concentrations in serum. N Engl J Med, 1956, 225, Rennard SI, Berg R, Martin GR, Froidart JN, Gehron Robey P. - Enzyme-linked immune assay (ELISA) for connective tissue components. Anal Biochem, 1980, 104, Rennard SI, Hunninghake GW, Bitterman PB, Crystal RG. -Production of fibronectin by the human alveolar macrophage: mechanisms for the recruitment of fibroblasts to sites of tissue injury in interstitial lung disease. Proc Natl Acad Sci, 1981, 78, Bitterman PB, Adelberg S, Crystal RG. -Mechanisms of pulmonary fibrosis: spontaneous release of the alveolar macrophage derived growth factor in the interstitial lung disorders. J Clin Invest, 1983, 72, Martinet Y, Rom WN, Grotendorst GR, Martin GR, Crystal RG. - Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med, 1987, 317, Bitterman PB, Rennard SI, Hwminghake GW, Crystal RG. - Human alveolar macrophage growth factor for fibroblasts. Regulation and partial characterization. J Clin Invest, 1982, 70, Snedecor GW, Cochran CW.- Statistical methods. Ames. Iowa State University Press, Sebastien P, Begin R. - In: Alveolar clearance of chrysotile in the sheep model: preliminary observations. ILO Vlth International Pneumoconiosis Conference Monograph, 1984, 2, Row lands N. Gibbs GW, McDonald AD. -Asbestos fibres in the lungs of chrysotile miners and millers. Arch Occup Hyg, 1982, 26, Sebastien P, Begin R, Case BW, McDonald JC.- Inhalation of chrysotile dust. In: Accomplishments in Oncology - The Biological Effects of Chrysotile, vol J.C. Wagner ed., Lippincott, Philadelphia, 1986, pp Begin R, Masse S, Rola-Pleszczynski M, Drapeau G. - Bronchoalvcolar and lung tissue analyses in asbestos-exposed humans and sheep. In: In Vitro Effects of Mineral Dusts. E.G. Beck and J. Bignon eds, Springer-Verlag, Berlin, Heidelberg, 1985, pp Begin R, Martel M, Desmarais Y, Drapeau G, Boileau R, Rola-Pleszczynski M, MasseS.- Fibronectin and procollagen 3 levels in bronchoalveolar lavage of asbestos-exposed human subjects and sheep. Chest, 1986, 89, Rom WN, Bitterman PB, Rennard SI, Cantin A, Crystal RG. - Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts. Am Rev Respir Dis, 1987, 136, Holt PF, Mills J, Young DK. - The early effects of chrysotile asbestos dust on the rat lung. J Pathol, 1964, 87, Goldstein B, Webster I, Rendall REG, Skikne MI.- The effect of asbestos-cement dust inhalation on baboons. Environ Res, 1978, 16, Brody AR, Hill LH, Adkins B. O'Connor RW. - Chrysotile asbestos inhalation in rats: deposition pattern and reaction of alveolar epithelium and pulmonary macrophages. Am Rev Respir Dis, 1981, 123, Barry BE, Wong KC, Brody AR, Crapo ID.-Reaction of rat lungs to inhaled chrysotile asbestos following acute and subchronic exposures. Exp Lung Res, 1983, 5, Pinkerton KE, Pratt PC, Brody AR, Crapo ID. - Fiber localization and its relationship to lung reaction in rats after chronic inhalation of chrysotile asbestos. Am J Pathol, 1984, 117, Brody AR, Hill LH, Warheit DB. - Induction of early alveolar injury by inhaled asbestos and silica. Fed Proc, 1985, 44, Pinkerton KE, Plopper CG, Mercer RR, Roggli VL, Patra AL, Brody AR, Crapo JD. - Airway branching patterns influence asbestos fibcr location and the extent of tissue injury in the pulmonary parenchyma. Lab Invest, 1986, 55, Kagan E, Oghiso Y, Hartmann DP. - Enhanced release of a chemoattractant for alveolar macrophages after asbestos inhalation. Am Rev Respir Dis, 1983, 128, W arheit DB, Hill LH, George G, Brody AR. -Time course of chemotactic factor generation and the corresponding macrophage response to asbestos inhalation. Am Rev Respir Dis, 1986, 134, Spurzem JM, Saltini C, Rom W, Winchester RJ, Crystal RG. - Mechanisms of macrophage accumulation in the lungs of asbestos-exposed subjects. Am Rev Respir Dis, 1987, 136, Begin R, Bisson G, Boileau R, Masse S. - Assessment of disease activity by Gallium-67 scan and lung lavage in the pneumoconioses. Semin Respir Med, 1986, 7, Bowden DH, Adarnson IYR. - Adaptive responses of the pulmonary macrophagic system to carbon. 1. Kinetic studies. Lab Invest, 1978, 38, Begin R. MasseS, Rola-Pleszczynski M. Drapeau G, Dalle D. - Selective exposure and analysis of the sheep tracheal lobe as a model for toxicological studies of respirable particles. Environ Res, 1985, 36, Begin R, Dufresne A, Cantin A, Masse S, Sebastien P, Durand P, Perrault G.- Carborundum pneumoconiosis: fibers in the mineral activate macrophages to produce fibroblast growth factors and sustain the chronic inflammatory disease. Chest, 1989, 95, North RJ. - The concept of the activated macrophage. J lmmunol, 1978, 121, Cohn ZA. - The activation of mononuclear phagocytes: fact, fancy, and future. J lmmuml, 1978, Begin R, Masse S, Rola-Pleszczynski M. Boctor M. Drapeau G. - Asbestos exposure dose. Bronchoalveolar milieu response in asbestos workers and the sheep model: evidences of a threshold for chrysotile-induced fibrosis. Drug and Chem Toxicol, 1987, 10, Rola-Pleszczynski M, Gouin S, Begin R. - Asbestosinduced lung inflammation. Role of local macrophage-derived chemotactic factors in accumulation of neutrophils in the lungs. Inflammation, 1984, 8, Hayes AA, Rose AH, Musk AW, Robinson BWS. - Neutrophil chemotactic factor release and neutrophil alveolitis in asbestos-exposed individuals. Chest, 1989 (in press). 62. Lemaire I, Rola-Pleszczynski M, Begin R. - Asbestos exposure enhances the release of fibroblast growth factor by sheep alveolar macrophages. J Reticuloendothelial Soc. 1983, 33, Cantin A, Allard C, Begin R. - Increased alveolar

10 90 R. BEGIN, A. CANTIN, P. SEBASTlEN plasminogen activator in early asbestosis. Am Rev Respir Dis. 1989, 139, Schmidt JA, Oliver CN, Lepe-Zuniga JL, Green I, Gery I. - Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin 1. J Clin Invest, 1984, 73, Sirois P, Drapeau G, Begin R. - Biochemical components of bronchoalveolar lavage in early experimental asbestosis of the sheep: phospholipase A 2 activity, prostaglandin E 2 and proteins. Environ Health Persp, 1983, 51, Elias JA, Zurier RB, Rossman MD, Berube ML, Daniele RP. - Inhibition of lung fibroblast growth by human lung mononuclear cells. Am Rev Respir Dis, 1984, 130, 811) Elias JA, Rossman MD, Zurier RB, Daniele RP. - Human alveolar macrophage inhibition of lung fibroblast growth. Am Rev Respir Dis, 1985, 131, Les exposition a l'asbeste chrysotile peuvent provoquer une alveolite avec activite fibrosante Iimitee dans un sous-groupe de moutons avec tendance elevee a retention des fibres. R. Besin, A. Cantin, P. Sebastien. RESUME: Des observation anterieures de notre laboratoire et d'autres institutions ont mis en evidence que!'inhalation de poussiere minerale fibrogene peut stimuler la production de fibronectine par les macrophages alveolaires (Fn) et augmenter l'activite de croissance des fibroblastes dans le liquide de lavage pulmonaire (FGA). Pour investiguer les relations entre ces modifications et la retention de fibres, et le developpement d'asbestose, nous avons expose 15 moutons a 100 mg de fibres de chrysotile canadien dans 100 ml de solution saline a 10 jours d'intervalle, et 10 moutons a 100 ml de solution saline aux memes intervalles. Les anirnaux ont ete etudies a des intervalles de 3 mois par cliche thoracique, examen fonctionnel pulmonaire (PFf) et lavage pulmonaire (BAL). Au 18e mois, 10 moutons avaient des anomalies au clincm thoracque (categoric ~ 1) (groupe B), et 5 moutons avaient des radiographies normales (categoric 0) (groupe A). Les epreuves fonctionnelles ont mis en evidence des types restrictifs d'anomalies dans les deux groupes, plus severcs toutefois dans le groupe B. Les analyses du BAL ont mis en evidence que les moutons du groupe A avaient une cellularite et un examen biochimique comparables a ceux des controles; par contre, les moutons du groupe B avaient des augmentations significatives du nombre total de cellules dans le BAL (x 2) des macrophages (X 2), des neutrophiles (x 4), et des eosinophiles (x 3). On notait en outre une augmentation de la lactate dehydrogenase du BAL, une augmentation de Fn, alors que FGA et le procollagene 3 etaient comparables aux controles. La retention des fibres est significativement augmentee chez tous les animaux exposes, et 2.5 fois plus elevee dans le groupe B que dans le groupe A malgre des expositions sirnilaires (70 infusions intra-trachcales de 100 mg de chrysotile). La stimulation de la rentetion des fibres dans le groupe B a precede!'apparition de la maladie. En conclusion, cette etude confrrme nos observations anterieures, qui reliaient la susceptibilite individuelle a developper une alveollite a la charge individuelle en poussiere, et qui documentaient que l'exces de retention de fibres peut etre observe avant que la maladie ne soit detectable. En outre, nous avons mis en evidence une alveolite precoce induite par le chrysotile avec une activitc fibrosante incompletement exprirnee au moment de la detection radiographique initiale. L'intensite de l'alveoltie est en relation avec le degre de retention de fibres. Eur Respir J., 1990, 3,

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