Pathophysiologic correlations in asbestos-induced airway disease in the guinea pig

To determine whether asbestos-induced changes in the structure of the walls of small airways might be associated with abnormalities of pulmonary function, guinea pigs were given 10 mg of amosite asbestos (test group) or saline (control group) by intratracheal instillation. Pulmonary function tests performed 6 months later revealed significant increases in FRC, RV, and TLC in the test group. Measurement of airway wall thickness showed that both membranous and respiratory bronchioles were significantly thickened in the test group; this group also had airways of smaller internal diameter than the controls. Analysis for lung collagen content as hydroxyproline showed a 50% increase in the asbestos exposed animals. There was, however, only minimal and very focal interstitial fibrosis (asbestosis) in the lung parenchyma. Analysis of fiber size indicated that the fibers obtained by digestion of the tissue or from the lavage fluid were significantly longer and wider than those in the original asbestos sample; however, the tissue contained considerably larger fibers than the lavage fluid. We conclude that: Asbestos can produce airway fibrosis and narrowing causing air trapping on pulmonary function examination; this process occurs in the absence of significant interstitial fibrosis of the parenchyma (asbestosis), implying that abnormalities of pulmonary function which are consistent with airflow obstruction in asbestos exposed animals can be caused by pathologic changes in the small airways alone; long asbestos fibers are preferentially retained in the lung, and the longest fibers appear to be in a compartment inaccessible to lavage, presumably, in this model, in airway walls. Enhanced penetration of long fibers into tissue may be one reason why long fibers are more pathogenic than short ones.     

Neutrophil chemotactic factor release and neutrophil alveolitis in asbestos-exposed individuals

Alveolar neutrophil accumulation occurs in asbestosis. To evaluate a possible role for release of neutrophil chemotactic factor (NCF) in the pathogenesis of asbestosis, spontaneous NCF release from alveolar macrophages obtained by bronchoalveolar lavage (BAL) in eight individuals with asbestosis, 13 asbestos-exposed individuals without asbestosis, and five control subjects has been studied. Alveolar macrophages were incubated in medium (four hours; 37 degrees C), and neutrophil responses to the supernatants were assayed in a microchemotaxis chamber. Alveolar macrophages from subjects with asbestosis released more NCF (97 +/- 19 neutrophils per high-power field [N/HPF]) than controls (3 +/- 1 N/HPF; p less than 0.01). Alveolar macrophages from individuals with asbestos exposure and increased BAL neutrophil proportions (n = 7) released more NCF (93 +/- 24 N/HPF) than individuals with asbestos exposure and normal BAL neutrophil proportions (n = 6; 11 +/- 6 N/HPF; p less than 0.02). The results show that spontaneous NCF release occurs in asbestosis and that NCF release is associated with neutrophil alveolitis in asbestos-exposed individuals without asbestosis, suggesting a pathogenic role for NCF in mediating this neutrophil alveolitis. The results of the study also suggest that the presence of crackles is a better predictor of the presence of neutrophil alveolitis than is an abnormal chest x-ray film.     

Usual interstitial pneumonia: idiopathic pulmonary fibrosis versus collagen vascular diseases

BACKGROUND: Bronchoalveolar lavage fluid (BALF) lymphocytosis was found in patients with usual interstitial pneumonia (UIP) associated with collagen vascular diseases (CVD) other than diffuse systemic sclerosis (SSc), but it was not found in patients with idiopathic pulmonary fibrosis (IPF), a disease histologically diagnosed as UIP. This difference could be partly due to variations of UIP spectrums between IPF and interstitial pneumonia associated with CVD. METHODS: We scored histopathological findings of lung specimens obtained from 31 cases (16 IPF, 9 CVD other than SSc and 6 SSc) using a semiquantitative scoring method. All cases were diagnosed as UIP by surgical lung biopsy. None of the patients were current smokers. RESULTS: Compared with IPF and SSc cases, CVD patients without SSc presented decreased scores of fibrosis (p < 0.01) and alveolar space cellularity (severity, p < 0.05). Lymphocytes were mainly localized in the alveolar walls and the majority of cells in the alveolar spaces were macrophages. On the other hand, other scores such as cellularity and alveolar wall cell infiltrate did not vary among these three groups. CONCLUSION: Fewer macrophages in the alveolar spaces and a decrease in the degree of fibrosis may contribute to BALF lymphocytosis more in patients with UIP/CVD non-SSc than in patients with IPF/UIP and UIP-SSc.     

Cigarette smoke, asbestos, and small irregular opacities

The long-term inhalation of cigarette smoke is associated with the appearance of diffuse small irregular opacities of mild profusion on chest roentogenograms of some subjects in a limited number of reports. Human histologic and experimental animal studies have shown the presence of pulmonary interstitial fibrosis. The radiographic abnormalities may be explained by interstitial fibrosis, although bronchiolar wall thickening may also be involved. Because asbestos causes diffuse pulmonary fibrosis, the literature was reviewed for evidence concerning an interaction between cigarette smoke and asbestos in the frequency of pulmonary asbestosis. A majority of 14 prevalence studies and 7 cohort studies of asbestos workers with information on smoking habits have shown a positive interaction between the 2 agents. The interaction appears to be additive rather than synergistic. Smoking may exert an effect on the frequency of pulmonary asbestosis by increasing the effective fiber dose retained in the lungs through interference with clearance.     

Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology and ultrastructural evidence for a type II pneumocyte defect

STUDY OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a poorly understood chronic respiratory disease of humans, which has no correlate in other animals. Understanding the role that inflammation, alveolar epithelial cells, and myofibroblasts play in the progression of the disease is controversial, and hampered by the lack of an animal model. We have identified spontaneous IPF in domestic cats and hypothesized that this newly identified disease shares the pathology of human IPF; further, this work provides data suggesting that the disease is related to a defect in type II pneumocyte biology. SETTING AND SUBJECTS: Chronic respiratory disease with pathology consistent with usual interstitial pneumonia (UIP) spontaneously developed in 16 domestic cats. RESULTS: The histopathology of feline IPF consisted of the following: (1) interstitial fibrosis with fibroblast/myofibroblast foci, (2) honeycombing with alveolar epithelial metaplasia and type II pneumocyte hyperplasia, and (3) alveolar interstitial smooth-muscle metaplasia. Interstitial inflammation was not a prominent feature of the disease. alpha-Smooth muscle actin-positive myofibroblasts were prominent in myofibroblast foci, beneath honeycomb and hyperplastic epithelium, and in alveolar septa away from the remodeling. Feline IPF type II pneumocyte ultrastructure is similar to a heritable form of human IPF, with abnormal cytoplasmic lamellar body-like inclusions. CONCLUSIONS: We conclude the following: (1) chronic respiratory disease with clinical and pathology features of UIP/IPF occurs in the domestic cat; (2) as in human IPF, the type II pneumocyte and myofibroblasts are important cellular constituents of feline IPF; and (3) type II cell ultrastructure suggests feline IPF is a defect in the type II pneumocyte.     

Inorganic particles induce secretion of a macrophage homologue of platelet-derived growth factor in a density-and time-dependent manner in vitro.

The inhalation of inorganic dust can lead to the development of interstitial pulmonary fibrosis, characterized by the accumulation of fibroblasts and connective tissue matrix in the lung interstitium. The fibrosis causes alterations in the architecture of the lung parenchyma, resulting in abnormal gas exchange and hypoxemia. In a rat model of asbestos exposure, inhaled fibers are deposited on alveolar duct bifurcations, followed by an accumulation of alveolar macrophages at the sites of dust deposition. The alveolar macrophage is thought to be a major mediator of the pulmonary inflammatory response to inhaled dust. Platelet-derived growth factor (PDGF) is a cytokine that has potent chemotactic and mitogenic effects on mesenchymal cells, such as fibroblasts and smooth muscle cells. We studied the secretion of an alveolar macrophage-derived homologue of PDGF in response to carbonyl iron spheres or chrysotile asbestos fibers in vitro. We demonstrate here that rat alveolar macrophages attached to a plastic substrate produce 69 +/- 79 picograms (pg) of PDGF per 10 million macrophages. This is similar to amounts recovered from human platelets. In contrast, macrophages exposed to iron spheres secrete 429 +/- 177 pg of PDGF/10(6) macrophages after 24 h in culture. Exposure to asbestos fibers increased the PDGF production to 628 +/- 213 pg/10(6) cells. PDGF secretion was influenced by the particles in a density- and time-dependent manner. We hypothesize that PDGF and other cytokines secreted by macrophages mediate the development of dust-induced lung disease.     

Increased alveolar plasminogen activator in early asbestosis

Alveolar macrophage-derived plasminogen activator (PA) activity is decreased in some chronic interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis but increased in experimental models of acute alveolitis. Although asbestos fibers can stimulate alveolar macrophages (AM) to release PA in vitro, the effect of chronic asbestos exposure of the lower respiratory tract on lung PA activity remains unknown. The present study was designed to evaluate PA activity of alveolar macrophages and bronchoalveolar lavage (BAL) fluid in asbestos-exposed sheep and asbestos workers. Forty-three sheep were exposed to either 100 mg UICC chrysotile B asbestos in 100 ml phosphate-buffered saline (PBS) or to 100 ml PBS by tracheal infusion every 2 wk for 18 months. At Month 18, chest roentgenograms were analyzed and alveolar macrophage and extracellular fluid PA activity were measured in samples obtained by BAL. Alveolar macrophage PA activity was increased in the asbestos-exposed sheep compared to control sheep (87.2 +/- 17.3 versus 41.1 +/- 7.2 U/10(5) AM-24 h, p less than 0.05) as was the BAL fluid PA activity (674.9 +/- 168.4 versus 81.3 +/- 19.7 U/mg alb-24 h, p less than 0.01). Among the asbestos-exposed sheep, 10 had normal chest roentgenograms (Group SA) and 15 had irregular interstitial opacities (Group SB). Strikingly, whereas Group SA did not differ from the control group in BAL cellularity or PA activity, Group SB had marked increases in alveolar macrophages (p less than 0.005), AM PA activity (p less than 0.02), and BAL PA activity (p less than 0.001) compared to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asbestos-induced release of a human alveolar macrophage-derived neutrophil chemotactic factor

Neutrophils accumulate in the alveoli of asbestos-exposed individuals. In determining whether asbestos fibers induce the release of neutrophil chemotactic factor (NCF) from human alveolar macrophages, alveolar macrophages (10(6) cell/mL) obtained by bronchoalveolar lavage from six non-asbestos-exposed control subjects were exposed to crocidolite (0.1 and 1 mg/mL), chrysotile (1 mg/mL), or medium alone for 4 h, and NCF activity was measured in the supernatants in a 48-well microchemotaxis chamber with polycarbonate membrane filters (pore size, 3 microns) and purified human neutrophils. Alveolar macrophages in medium alone released negligible amounts of NCF (4 +/- 1 neutrophils per high-power field [N/HPF]). When macrophages were exposed to crocidolite (0.1 and 1 mg/mL), significant NCF release occurred (43 +/- 9 and 105 +/- 32 N/HPF, respectively; p less than 0.01 for each amount compare to alveolar macrophages cultured in medium alone). Chrysotile (1 mg/mL) induced similar NCF release (96 +/- 14 N/HPF; p less than 0.01 compared to unstimulated alveolar macrophages). Partial characterization of the NCF by Sephadex G-25 fine gel filtration demonstrated a molecular size of less than 1,000 daltons. These results show that human alveolar macrophages release NCF after exposure to asbestos. Release of NCF by alveolar macrophages in asbestos-exposed individuals may play a central role in the pathogenesis of asbestosis.     

Intratracheal bleomycin causes airway remodeling and airflow obstruction in mice

In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling) assay, and immunohistochemistry for transforming growth factor β1 (TGFβ1), TGFβ2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high-dose bleomycin. Increased TUNEL(+) bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFβ1 and TGFβ2 and accumulation of S100A4(+) fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling.     

Asbestos exposure results in increased lung procoagulant activity in vivo and in vitro

Enhanced fibrin deposition is a common histologic finding in fibrotic lung disorders including asbestosis and may be an important mechanism by which fibroblast proliferation is modulated. Asbestos-induced activation of lung interstitial cells may result in enhanced expression of procoagulant activity which contributes to the inflammatory response resulting in subsequent fibrin deposition. The current study examines procoagulant activity in bronchoalveolar lavage fluid from patients with clinically diagnosed asbestosis, patients with asbestos exposure without asbestosis, and normal, control subjects. Results indicated that asbestos exposure resulted in increased lung procoagulant expression in vivo, and furthermore, suggested that both endothelial cells and alveolar macrophages represented lung parenchymal cells which may contribute to this activity. This imbalance in coagulation homeostasis may be important in the regulation of fibrotic responses observed in asbestosis.     

Phosphoramidon, an endothelin-converting enzyme inhibitor, attenuates lipopolysaccharide-induced acute lung injury

Phosphoramidon blocks the formation of endothelin-1 (ET-1), a proinflammatory mediator implicated in the pathogenesis of a variety of lung diseases. To determine whether phosphoramidon can ameliorate pulmonary inflammation, our laboratory undertook a series of experiments involving treatment of hamsters with either intraperitoneal (i.p.) or aerosolized phosphoramidon prior to induction of acute lung injury by intratracheal administration of lipopolysaccharide (LPS). The results indicate that phosphoramidon significantly reduces LPS-induced pulmonary inflammation as measured by lung histology, neutrophil content of bronchoalveolar lavage (BAL) fluid, percent tumor necrosis factor receptor 1 (TNFR1)-labeled BAL macrophages, and alveolar septal cell apoptosis. In additional experiments, i.p. administration of a novel endothelin A receptor anatgonist (HJP272) similarly decreased BAL neutrophils, whereas i.p. administration of either ET-1, or its precursor peptide, "big" ET-1, had the opposite effect. These findings support further evaluation of phosphoramidon and other ET-1 suppressors as potential treatments for human inflammatory lung disease.     

Neutrophil chemotactic factors in the respiratory tract of patients with chronic airway diseases or idiopathic pulmonary fibrosis.

This study was designed to clarify the contributions of specific neutrophil chemotactic factors (NCF) in neutrophil accumulation in the human respiratory tract associated with various diseases. The activity and characteristics of the NCF in the bronchoalveolar lavage (BAL) fluid and culture media of alveolar macrophages obtained from normal volunteers, control patients, patients with chronic airway diseases (CAD) and patients with idiopathic pulmonary fibrosis (IPF) were examined. The BAL fluid from normal volunteers contained NCF comparable with the chemotactic factors interleukin-8 (IL-8) and leukotriene B4 (LTB4). Analysis of the biochemical characteristics of NCF released from alveolar macrophages suggests that they are derived from alveolar macrophages. The NCF activities in BAL fluids from patients with CAD and IPF were higher than those in BAL fluids from normal volunteers and control patients. Biochemical analysis demonstrated that several kinds of NCF, including those derived from the complement component C5 and alveolar macrophages, were present in the BAL fluid from patients with CAD and respiratory infections. The especially marked increase of C5-derived NCF indicate their importance in neutrophil accumulation in the respiratory tract of patients with CAD. Alveolar macrophages released different types of NCF after different lengths of culture periods (4 h and 24 h). Alveolar macrophages from patients with IPF released larger amounts of NCF than alveolar macrophages from normal volunteers, indicating the importance of alveolar-macrophage-derived NCF as well as C5-derived NCF in neutrophil accumulation in the respiratory tract of patients with IPF. These results suggest that various types of NCF increase in response to different disease states of the respiratory tract and serve to regulate the accumulation of neutrophils.     

Oxygen radical production by alveolar inflammatory cells in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by the accumulation of alveolar macrophages (AMs) and neutrophils in the lower respiratory tract, parenchymal cell injury, and fibrosis of the alveolar structure. Reactive oxygen intermediates (ROI) are claimed to be a major cause of tissue damage in IPF; however, the source of ROI has not been unequivocally identified. AMs, as well as neutrophils, are capable of releasing these agents. The contributions of these possible sources are not known. To address this question, we evaluated the spontaneous and stimulated (PMA or zymosan) ROI release of total bronchoalveolar cells and isolated AMs in 14 patients with IPF by means of luminol-enhanced chemiluminescence. Bronchoalveolar lavage (BAL) cells from 17 individuals without any signs of inflammation served as controls. In comparison with the controls, the spontaneous as well as the stimulated ROI release of total BAL cells in IPF are markedly increased (20,763.9 +/- 5,079.3 versus 2,509.5 +/- 300.6 counts/10 s/2.10(5) cells, spontaneously, IPF versus control; 106,819.3 +/- 33,802.8 versus 8,919 +/- 1,357.9 PMA induced; 41,597.1 +/- 8,442.6 versus 6,223.8 +/- 1,025.1 zymosan induced, p less than 0.001). Measurement of the ROI release of purified AMs revealed that these cells produce the bulk part of ROI released by BAL cells (84%). In spite of the fact that, on a per cell basis, the ROI release of neutrophils is 1.7-fold of that of AMs, there is no correlation between the ROI production of total BAL cells and the percentage of neutrophils in BAL, demonstrating a minor role of these cells in the generation of the total ROI burden in IPF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alveolitis of pulmonary asbestosis. Bronchoalveolar lavage studies in crocidolite- and chrysotile-exposed individuals

Bronchoalveolar lavage (BAL) findings in 27 individuals with crocidolite- or chrysotile-induced asbestosis were compared to BAL findings in 29 unexposed control subjects. Alveolitis, defined as an increase in the proportions and/or absolute numbers of inflammatory cells present in BAL fluid compared to values in control subjects, was present in 26 (96 percent) subjects with asbestosis. Most exhibited a neutrophil-eosinophil alveolitis, with neutrophil proportions increased to 7.4 +/- 0.7 percent and eosinophil proportions increased to 2.2 +/- 0.4 percent, compared to 2 +/- 0.5 percent and 0.4 +/- 0.01 percent, respectively, in control subjects (p less than 0.01 for both neutrophils and eosinophils). An increase in the total number of neutrophils and eosinophils per ml of lavage fluid was also seen (neutrophils 23 +/- 5 and eosinophils 13 +/- 4 per ml; p less than 0.05 compared to control subjects). Severity of the alveolitis, defined by the neutrophil or eosinophil proportions, was independent of a history of exposure to cigarette smoke. The pattern and severity of alveolitis in crocidolite- and chrysotile-induced asbestosis were similar. There was a significant correlation between duration of exposure to asbestos and neutrophil proportions (p less than 0.01). No significant difference in the severity of the alveolitis was observed between individuals with radiologic and physiologic evidence of asbestosis compared to those with asbestos exposure and crackles alone, suggesting that, in asbestosis as in other chronic interstitial lung diseases, radiologic and physiologic parameters do not reflect the severity of the alveolitis. This study demonstrates that a neutrophil-eosinophil alveolitis is present in individuals with crocidolite- and chrysotile-induced asbestosis, that this alveolitis is independent of cigarette smoking, and that the severity of the BAL changes is not reflected in radiologic and physiologic changes.     

Cells,collagen and idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a usually fatal disorder of lung with clearly defined clinical, roentgenographic, physiologic, morphologic, scintigraphic and bronchoalveolar lavage features. Current concepts of the pathogenesis of this disorder suggest a central role for a chronic alveolitis in causing changes in parenchymal cell populations and derangements in interstitial collagen. Of the many inflammatory and immune effector cells comprising the alveolitis of IPF, it is likely that the neutrophil is the most important mediator of parenchymal damage. To follow the status of lung neutrophils in patients with this disease, two methods have been utilized. Both gallium-67 scanning and bronchoalveolar lavage quantitate the extent of the alveolitis and can be used to stage and follow these patients. The treatment of IPF remains controversial, but it is likely that corticosteroids reduce the alveolitis and prolong the lifespan of these patients.     

特发性肺纤维化的治疗进展

特发性肺纤维化是一种慢性、弥散性肺间质病变,以普通型间质性肺炎为特征性组织学表现。特发性肺纤维化以进行性肺损伤、炎症、肺组织纤维化为特征。糖皮质激素和免疫抑制剂/细胞毒性药物临床效果欠佳,提示炎症并未在肺纤维化中起重要的病理生理作用,研究发现肺泡上皮损伤可以直接导致肺纤维化。目前尚无有效的治疗方案能取得肯定的疗效。因此,新的治疗措施引发了研究者浓厚的兴趣。然而特发性肺纤维化的研究进展缓慢,预后很差,诊断后中期生存率小于3年。本文主要介绍特发性肺纤维化在治疗方面的进展。     

Current issues regarding the pathobiology of asbestosis: a chronologic perspective

Asbestosis is a pneumoconiosis that results from the inhalation of asbestos fibers. There is a body of evidence that implicates the alveolar macrophage in the pathogenesis of asbestosis because of its prominence in asbestos-related histologic lesions. Injury to the alveolar epithelium also may contribute to the pathogenesis of asbestosis. Evidence is presented to suggest that pulmonary fibrosis may result from the persistent release of inflammatory mediators (chemoattractants, lysosomal enzymes, toxic oxygen radicals, arachidonic acid metabolites, interleukins, and fibroblast growth factors) at sites of asbestos deposition. Histologic features of asbestosis can be detected within months after the initial contact with asbestos. In contrast, the stigmata of asbestos-related disease usually are not radiologically detectable, even by the most sensitive imaging techniques, until after a latency period of at least a decade, and often considerably longer. There is, therefore, a long diagnostic delay between the time when asbestosis is histologically detectable and when it is radiographically detectable.     

Phenotype of blood monocytes and alveolar macrophages in interstitial lung disease

The immunologic phenotype of the monocyte-macrophage cell populations in bronchoalveolar lavage (BAL) fluid and monocytes in peripheral blood (PB) were studied in 20 patients with sarcoidosis, 18 with idiopathic pulmonary fibrosis (IPF), seven with extrinsic allergic alveolitis (EAA), and 12 healthy volunteers. There were no significant differences in expression of the immunologic markers CD13(My7), CD14(My4), and Monocyte-2 on blood monocytes between the patient groups and healthy volunteers, but there were marked differences between groups in the expression of the three markers on BAL macrophages. The percentage of Monocyte-2+ macrophages was increased in BAL in subjects with sarcoidosis, EAA, and IPF compared with healthy volunteers, greatest in EAA. This increase is probably due to increased recruitment of blood monocytes into alveoli, since the cells had a monocytic morphology on phase contrast microscopy (in normal subjects the majority of blood monocytes, but few alveolar macrophages, express the Monocyte-2 antigen). Patients with IPF had a significantly lower percentage of CD13(My7)+ macrophages in BAL than the other three groups. Compared with IPF patients and healthy volunteers, patients with EAA had a significantly higher percentage of CD14(My4)+ macrophages, whereas in sarcoidosis patients the numbers were reduced. These observations suggest an increased influx of blood monocytes into the alveoli in interstitial lung disorders. Phenotypic differences were found between the BAL macrophage populations of the various interstitial diseases. These differences in alveolar macrophage phenotype may be due to local factors, depending on the type of inflammation.     

Asbestos stimulation triggers differential cytokine release from human monocytes and alveolar macrophages

Inhalation of asbestos fibers results in a variety of lung diseases, including pulmonary fibrosis. Various animal models have demonstrated the importance of cytokines in the pathogenesis of pulmonary fibrosis. Alveolar macrophages from patients exposed to asbestos spontaneously release increased amounts of cytokines. The purpose of these studies was to determine whether asbestos directly stimulates cytokine release from human alveolar macrophages after in vitro exposure. We demonstrate that, although asbestos triggers cytokine release from blood monocytes, normal alveolar macrophages do not respond to asbestos stimulation with cytokine release. However, normal alveolar macrophages are activated by asbestos particles, in vitro, as determined by the upregulation of mRNAs for cytokines, and activation of the p38 kinase, which has been shown to be important in the translation of cytokine message into protein. These studies demonstrate that asbestos stimulates both normal blood monocytes and normal alveolar macrophages, but that there is a block in translation of cytokine mRNAs in the macrophages.     

Bronchoalveolar macrophages from patients with idiopathic pulmonary fibrosis are unable to kill facultative intracellular bacteria

The accumulation of inflammatory and immune effector cells in the lungs of patients at early stages of interstitial lung disease has been well documented, but little is known about the functional activity of these cells, particularly alveolar macrophages. The purpose of the experiments described here was to determine whether alveolar macrophages from patients with idiopathic pulmonary fibrosis (IPF) differed from alveolar macrophages of normal subjects using a model system that assesses a component of cell-mediated immunity. Alveolar macrophages were tested for their ability to phagocytose and kill the facultative intracellular bacterium Listeria monocytogenes. Because this system requires the stimulation of macrophages by antigen-specific T-cells, it allows the assessment of effector functions of macrophages found in the lower respiratory tract of patients with IPF. Data showed that alveolar macrophages from normal subjects both phagocytosed and killed those bacteria. However, alveolar macrophages from patients with IPF phagocytosed bacteria normally but expressed little bactericidal or bacteriostatic activity. Further, we found no difference in HLA-DR expression by normal and IPF alveolar macrophages. Therefore, it does not appear that this defect in bactericidal activity in IPF macrophages results from a defect in the antigen-presenting function of these cells. These data suggest that alveolar macrophages from patients with IPF express a functional deficiency in their ability to kill facultative intracellular bacteria.