Serge Massé

Airway disease in a subset of nonsmoking rheumatoid patients: Characterization of the disease and evidence for an autoimmune pathogenesis

Previous investigations of airway disease in rheumatoid patients have been oriented toward establishing the prevalence of the disease, but the pathogenesis and the time course of the airflow obstruction in rheumatoid disease are still unclear. In this study, we analysed the clinical, serial pulmonary function and histopathologic data of six rheumatoid patients who had never smoked but who had airflow limitations documented repeatedly up to 10 years previously. We have attempted to characterize the site, nature and evolution of the chronic airway disease in this group of patients. Bronchiectasis was excluded in all patients by bilateral bronchography. Clinical and histopathologic evidence of the Sjörgen autoimmune exocrinopathy was documented in five of the patients, and the sixth patient had lymphoplasmocytic infiltrates of the labial glands without obstruction of the lumen or destruction. By pulmonary function tests and histopathologic examination of four open lung biopsies, the airway disease was found to be located predominantly in the peripheral airways of the lung. On each biopsy, the lesions were in different stages of activity, but on all specimens there was a definite predilection for selective bronchiolar injury. Early stage lesions were characterized by mononuclear cell infiltrates of the peribronchiolar tissue which led to deformation of airway lumen, focal mucosal extension and ulceration. Subsequently, the inflammatory reaction was replaced by fibroblastic proliferation, and in the end stage of the disease, there was complete obliteration of many bronchioles by collagenized fibroblastic tissue. From regression analyses of serial pulmonary function tests of these patients, it was concluded that (1) the airway disease in our patients who did not smoke progressed inevitably but not uniformly and (2) deterioration of pulmonary functions was more rapid in our patients than it was in the cigarette smokers who had chronic obstructive lung disease. This study also documents major dysfunctions of the chest wall mechanics which appear to contribute to the restriction of lung volumes in some rheumatoid patients.

Asbestos-induced lung injury in the sheep model: The initial alveolitis

In order to study the cellular and biochemical changes in early asbestosis, three groups of sheep were repeatedly exposed to intratracheal instillations of either saline (controls), low doses of UICC chrysotile asbestos (LD), or high doses of the fibers (HD) until an alveolitis was observed in all HD sheep during the twelfth month of exposure. All sheep were studied bimonthly by transbronchial lung biopsy (LB), bronchoalveolar lavage (BAL), pulmonary function tests (PFT), and chest roentgenograms (CXR). While LBs of the HD sheep demonstrated large accumulations of monocyte-macrophages in the alveolar and interstitial spaces, those of controls and LD sheep did not. In BAL, there was no difference in total and differential cell counts between groups, but the BAL lymphocyte proliferative capacity was clearly depressed in all asbestos-exposed sheep. In the BAL supernatant, total proteins (mainly albumin, beta + gamma globulins) and lactate dehydrogenase were significantly elevated in the HD group only. This alveolitis was associated with a fall in vital capacity, lung compliance, diffusing capacity, and arterial PO2. Abnormalities on CXR appeared 3 months later. Thus, the cellular and biochemical features of early asbestosis are clearly distinct from those reported in idiopathic pulmonary fibrosis.

Airway function in lifetime-nonsmoking older asbestos workers

Previous studies of lung function in asbestos workers have documented airflow limitation in many of the workers, but the specific influence of asbestos exposure could not be clearly differentiated from the effects of the cigarette smoking habit. In this study, airway function was evaluated in lifetime-nonsmoking, long-term workers of the mines and mills of Québec. The 17 asbestos workers in this study had worked for an average of 28 years in the mines and mills of the local asbestos industry and did not have any other respiratory industrial dust exposure. They did not have a history of previous pulmonary disease and did not meet the usual diagnostic criteria for chronic bronchitis, emphysema, or asthma. Seven of the workers met the diagnostic criteria for asbestosis and 10 workers did not. The latter group of workers did not differ from a matched control group except in terms of a higher isoflow volume (p less than 0.05). The workers with asbestosis, however, had a restrictive pattern of lung function, increased isoflow volume, and increased upstream resistance at low lung volumes (p less than 0.01). Lung biopsy in three of the patients with the disease demonstrated peribronchiolar alveolitis and fibrosis with obliteration and narrowing of the small airways. These data on lifetime-nonsmoking, long-term asbestos workers provide further evidence of small airway obstruction associated with asbestos exposure and independent of the smoking habit. This airflow limitation was observed predominantly in workers with a restrictive pattern of lung function associated with peribronchiolar alveolitis. The lifetime-nonsmoking asbestos workers without restrictive patterns of lung function had minimal dysfunction of the peripheral airways.

Soybean trypsin inhibitor and cerulein accelerate recovery of cerulein-induced pancreatitis in rats

The role of exogenous and endogenous cholecystokinin has been studied in the process of pancreatic regeneration after acute pancreatitis. A mild form of pancreatitis was induced in rats by subcutaneous cerulein at 12 micrograms.kg-1, three times a day for 2 days. After 3 days of rest, the cerulein-treated rats were divided into four groups: rats with acute pancreatitis fed 20% casein, who received no treatment; rats fed 50% casein; rats fed 20% casein supplemented with 1% soybean trypsin inhibitor (SBTI); and rats fed 20% casein who received 1 microgram.kg-1 of subcutaneous cerulein, three times a day. Controls were fed 20% casein plus saline subcutaneously. Rats were killed after 5, 10, or 20 days of treatment. Pancreatitis resulted in significant decreases in pancreatic weight and contents of protein, amylase, chymotrypsin, RNA and DNA. During the regenerative process, 1 microgram.kg-1 of cerulein increased all parameters to control values within 5 days and induced pancreatic growth thereafter. SBTI restored the pancreas to normal after 10 days with cellular hypertrophy; the 50% casein diet gave a response similar to SBTI without hypertrophy. It can be concluded that cerulein and SBTI can accelerate pancreatic regeneration after an attack of acute pancreatitis.

Ischemic Fecal Incontinence and Rectal Angina

In 36 patients who consulted for fecal incontinence or rectal pain, or both, there was grossly visible scarring of the rectum and biopsy revealed mucosal atrophy and fibrosis. A steal from the hemorrhoidal arteries to the iliac vessels was demonstrated in 3 subjects. Maximum tolerable volumes within a rectal balloon were smaller than in control subjects, both in men (192 vs. 273 ml) and in women (142 vs. 217 ml) (p less than 0.01). The rectoanal inhibitory reflex was abnormal in all but 1 patient. Specific abnormalities were a decreased amplitude or a prolonged duration of the reflex. It was totally absent in 2 patients. This study is compatible with the hypothesis that chronic ischemia of the rectum may cause fecal incontinence or rectal pain.

Colonic hamartomas in tuberous sclerosis

Twelve patients, 5 from the same family, diagnosed consecutively to suffer from tuberous sclerosis were investigated for gastrointestinal polyps. Six patients had no clinical neurologic involvement. Nine had colonic polyps: in 5 patients, these were hamartomas, in 3 patients adenomatous polyps, and the ninth patient had hamartomas and adenomatous and villoglandular polyps. Hamartomatous polyps were identical to those found in the Peutz-Jeghers syndrome. However, in 1 patient they included neural structures and in another there were angiomatous and adipous structures in addition to colitis cystica profunda. Two patients with hamartomatous polyps had normal intelligence and no clinical neurologic symptoms. The evaluation of one kindred revealed the association of hamartomatous polyps of the colon with forme fruste of tuberous sclerosis in different members, but none had the typical disease. Tuberous sclerosis should thus be considered in the differential diagnosis of hamartomatous colonic polyps. Conversely, colonic endoscopy may be a useful adjunctive test in the diagnosis of tuberous sclerosis, particularly in the incomplete varieties of disease.

An assessment of the fibrogenic potential of very short 4T30 chrysotile by intratracheal instillation in rats.

Three groups of five rats each received, respectively, a single intratracheal instillation of saline (control), 5 mg of UICC chrysotile B asbestos, and 5 mg of a preparation of very short chrysotile fibers (4T30, 100% less than 8 micron) isolated by a sedimentation procedure. At various intervals after the treatment (1 to 60 days), assessment of lung morphology was performed on each animal. Although the two types of chrysotile fibers have similar chemical composition, structure, and surface charge, the lung tissue reaction differed considerably. Lungs of animals exposed to UICC chrysotile B showed significant pathological alterations as early as 7 days following treatment. The lesions were localized in and around terminal bronchioles and consisted of inflammatory cells, fibroblasts and collagen deposition which distorted and obstructed small airways. Reaction to very short 4T30 chrysotile fibers was quite distinct. Seven days after treatment, lungs of these animals showed alveolar and interstitial accumulation of inflammatory cells. The alveolitis persisted 60 days after treatment and no fibrosis was apparent. It appears that very short 4T30 chrysotile fibers are much less fibrogenic than UICC chrysotile B and that intratracheal instillations in rats may represent a useful mean of rapidly assessing the fibrogenic potential of various dusts. These observations support the concept that fiber length is an important factor for fibrogenicity of asbestos.

Early lung events following low-dose asbestos exposure

Abstract A conscious sheep model recently developed to study sequentially the bronchoalveolar milieu was applied to the investigation of the early lung events following very low dose asbestos exposure. UICC Canadian chrysotile fibers were administered in three monthly intratracheal injections of a suspension of 0 (controls), 1, 2, 4, 8, and 16 mg of asbestos in 50 ml saline. Three sheep per dose were repeatedly exposed to the same monthly doses and all were studied by serial pulmonary function (PF) tests, transbronchial lung biopsies (LB), and bronchoalveolar lavages (BAL). These low-dose exposures did not change the PF tests; routine lung histopathology was not altered except for the observation of occasional fibers in the alveoli, but there was a significantly higher yield in the total BAL cellular due to a marked increase in the macrophage and a small rise in the lymphocyte populations. These changes in the BAL cells occurred without significant changes in the biochemical analyses of the BAL supernatant. These data establish that very low dose asbestos exposure induces migration of macrophages and lymphocytes into the bronchoalveolar milieu. These cells have a major role in the lung defense and have been implicated in the development of asbestos-related diseases.

Sustained Efficacy of Aluminum to Reduce Quartz Toxicity in the Lung

In a recent study of the sheep tracheal lobe model, we have demonstrated that surface chemistry modification of quartz by aluminum lactate significantly alters the biological activity of quartz for at least 2 months after exposure. In the present study, we have extended our observations of the biological reaction of the lung tissue to aluminum treated quartz and to untreated quartz, added lung lavage analyses of surfactant and glycosaminoglycans as additional indicators of activity of the quartz-induced lung injury and analyzed lung lavage and tissue retention of the minerals. The tracheal lobe of 8 sheep was exposed to either 11 mg of aluminum lactate in 100 ml saline (Al group), 100 mg of quartz (Minusil-5) in 100 ml saline (Si group) or 100 mg of quartz treated with 11 mg of Al lactate in 100 ml saline (Si-Al group). The 24 sheep were studied by lung lavage at month 9, 0.13, 1, 2, 3, 5, 7, 9, and 10 and by autopsy at month 10. In the Al group, we found no significant change over time, the pathologic score was 0.38 +/- 0.15 and Si undetectable. In the Si group, we found significant sustained increases in total lavage cells, macrophages, lymphocytes, neutrophils, glycosaminoglycans, lactate dehydrogenase, phosphatidylcholine and phosphatidylglycerol. Histologically we found a macrophagic lymphocytic alveolitis with early nodular silicotic lesions; the pathological score was 3.0 +/- 0.8 at month 10 with an average quartz tissue level of 1.4 +/- 0.4 micrograms/mg. In the Si-Al group, all these changes were significantly reduced early and remained so up to 10 months after exposure; the pathological score was 1.1 +/- 0.4 and lung levels of quartz were undetectable. The data thus demonstrated that Al treatment of quartz significantly reduces the biological activity of quartz and increases its clearance with essentially no detectable particle retention in the lung 10 months after exposure.

Pulmonary bombesin in experimentally induced asbestosis in rats.

The pulmonary levels of immunoreactive bombesin in normal rat lungs and rat lungs exposed to asbestos were determined. Experimental asbestosis was induced in rats by a single intratracheal injection of 5 mg or 10 mg UICC standard Canadian Chrysotile B while sham-operated control rats received only the saline carrier. At 1, 3, 6, and 9 months following instillation, 5 animals of each group were sacrificed and the lungs removed. A section was kept for morphologic analysis, while the remaining portion was submitted to acid extraction and later measured for bombesin content by radioimmunoassay (RIA). The Chrysotile B-exposed tissues displayed the characteristic features typical of the fibrotic state associated with asbestosis one month following exposure and thereafter. The pulmonary bombesinlike immunoreactivity ranged from 4.5-7.5 pmoles/g tissue in normal rat lung, and these levels remained unchanged at 1 and 3 months after asbestos exposure. However at 6 and 9 months, significant increases ranging between 2 and 2.5 fold were observed. The initial increases in bombesin levels occurred at a later time (6 months) than those already observed for vasoactive intestinal peptide (VIP) (3 months). However, VIP levels plateaued at 9 months, while those of bombesin were still increasing. High-pressure liquid chromatography (HPLC) coupled with RIA demonstrates the presence of two bombesin-immunoreactive peaks in normal rat lung, the major one coeluting with the mammalian bombesinlike peptide gastrin-releasing peptide (GRP) and the other one being presumably a C-terminal portion of GRP. These data indicate that immunoreactive bombesin and VIP are selectively increased at different times following asbestos instillation and that these changes occur after the onset of fibrosis and the appearance of well-defined fibrotic lesions.