- Email: [email protected]
Pulmonary Macrophages
necessary to regain completely normal levels of TIC. Thus, it is possible that side effects and cost of Dannazol can be limited to the amount necessary to achieve these lower levels. · CoNCLUSIONs This study indicates that there is not a significant difference between PiMZ and PiM when evaluated by time. Thus, from this study, PiMZ does not appear to be a significant independent risk factor for the development of CAL.
1 Mittman C: The PiMZ phenotype: is it a significant risk factor for the development of chronic obstructive lung
disease? (editorial) Am Rev Respir Dis 118:649-52, 1978 2 Patterson CD, Mackenthum A, Anderson PS, et al: Phenotypes Pi MS, MZ alpha1 antitrypsin and lung disease. Bull Int Union Tuberc 51 (I Pt 2) :675-79, 1976 3 Morse JO, Lebowitz MD, Knudson RJ, et al: Relation of protease inhibitor phenotypes to obstructive lung diseases in a community. N Engl J Med 296:1190-94, 1977 4 Fagerhol MK, Laurell CB: The polymorphism of "prealbumins" and 2-1-antitrypsin in human sera. Clin Chim Acta 16:199-203, 1967 5 Kory RC, Callahan R, Boren NG, et al. The Veterans Administration-Army cooperative study of pulmonary function. I. Clinical spirometry in normal men. Am J Med 30:243, 1961 6 Gadek J, Fulmer MF, Petty T, et al : Danazol-induoed elevation of serum alpha 1 antibypsin in individuals with severe deficiency of this antiprotease. Chest 77:279, 1980
Pulmonary Macrophages When Do They Prevent and When Do They Cause COPD? Joseph D. Brain, S.D.(Hyg)
ulmonary macrophages are important since their Pmigratory patterns and phagocytic behavior are
often pivotal events in the outcome between damaging particles or pathogens and a responding host. Resident macrophages in the respiratory tract are recognized as largely responsible for keeping lung surfaces clean and sterile, and for protecting against a wide variety of foreign materials. Their phagocytic and lytic potentials provide most of the known bactericidal properties of the lungs. During acute infection or injury they are also supplemented by other leukocytes. Increased inert or infectious particles stimulate the recruitment of additional macrophages. Most free cells containing particles eventually reach the airways and are quickly carried to the pharynx and swallowed. Additional dimensions of the phagocytic responsibilities of macrophages are becoming apparent. In addition to destroying microbial pathogens, they may also prevent excessive antigen stimulation by ingesting and catabolizing inhaled foreign proteins and antigens derived from bacteria, viruses, fungi, and other microbes. Alternatively, they may preserve and present antigens to lymphocytes and act cooperatively with components of the immune system. Pulmonary macrophages may also ingest effete type 1 and type 2 epithelial cells, occasional red blood cells, and perhaps even "worn out" surfactant. Macrophages also influence the length of time inhaled insoluble particles are retained in the respiratory tract. Because of their ameboid and phagocytic properties, pulmonary macrophages decrease the probability of par-
• Harvard University School of Public Health. Department of Physiology, Boston. Reprint req~: Dr. Brain, Department of Physiology Haroard School of Publlc Heolth, Boston 02115
264 22nd ASPEN LUNG CONFERENCE
tide penetration through epithelial barriers. Particles deposited on airway and alveolar surfaces, if they remain unphagocytized, are more likely to pass through or between epithelial cells. Having gained access to connective tissue and lymph nodes beneath the epithelia, they are retained for longer periods of time and have a greater opportunity to cause disease. The number and activity of macrophages and the speed of phagocytosis are thus related to the probability of particle penetration and retention. Evidence is rapidly accumulating to indicate that macrophages have roles besides phagocytosis. We now recognize macrophages as secretory and regulatory cells which interact with cells as diverse as lymphocytes and fibroblasts. They are involved in the induction and expression of several forms of cell-mediated and humoral immunity. They are capable of recognizing and destroying neoplastic cells, thus preventing the development of cancer. They can secrete such diverse substances as lysosomal enzymes, interferon, certain components of complement, angiogenesis factor, plasminogen activator, cyclic nucleotides, prostaglandins, granulopoietins, and a number of agents iniluencing the proliferation of fibroblasts and tumor cells. Still other macrophage products may interact with humoral enzyme systems such as those controlling clotting, fibrinogenesis, fibrinolysis, and kiningeneration. In so doing, they are involved with the regulation of multi-enzyme cascades and of the replication, differentiation, and activity of such cells as lymphocytes, fibroblasts, and even other macrophages. .But, in addition to a variety of protective postures which help prevent COPD, macrophages may also be participants in the pathogenesis of COPD. First, their defensive role can he compromised. A number ofjnves-
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
tigators using both in vivo and in vitro bactericidal or phagocytic assays have shown that such diverse agents as silica, immunosuppressives, ethanol intoxication, cigarette smoke, air pollution, and oxygen toxicity, can dramatically depress the ability of pulmonary macrophages to protect their host. Sometimes the agent or factor acts directly on the macrophage producing a damaged or even a dead cell. In other cases ( eg high concentrations of inhaled particles) the mechanism can be competitive inhibition in which the phagocytic machinery becomes saturated even in the absence of cytotoxicity. In other instances, particularly those situations involving pulmonary edema or altered acid-base balance, the macrophages may be undamaged, but their activity may be depressed because of an indirect effect on their milieu, the airway or alveolar microenvironment. Non~theless, it is important to realize that macrophage failure or damage is not always a cause of the disease in question; in many instances, alterations in macrophage function may simply reflect the onset and progression of the disease. For example, changes in macrophage activity during pulmonary edema as~ociated with oxygen toxicity fall in this class. It is not the macrophage's failure to ingest particJes or bacteria which causes the edema; rather the reverse. Many investigators have similarly misinterpreted associations between other altered respiratory defense mechanisms and COPD. For example, the presence of altered mucociliary transport in COPD does not necessarily imply that depressed mucociliary transport has caused COPD or in any way contributed to its pathogenesis. Defective mucus movement may be a result of the disease rather than a cause. Carefully designed experiments are needed to make these distinctions. Finally, there are situations in which pulmonary macrophages not only fail, but are directly implicated in the pathogenesis of pulmonary diseases. For example, the ingestion of some particJes by macrophages causes the release of lysosomal enzymes into the macrophage cytoplasm. These enzymes may kill the macrophage and dead or dying macrophages release substances which can attract fibroblasts and elicit fibrogenic responses. Other toxic particJes, particularly cigarette smoke, may lead to a release of proteases and other toxic enzymes and agents. When smokes and other pollutant particJes act to recruit more cells, to activate them, and to release proteolytic enzymes, macrophages may then be centrally involved in many stages of the development of COPD. The same agents may also elicit similar responses from other white blood cells such as polymorphonuclear leukocytes. In addition, connective tissue macrophages may contribute to COPD by concentrating and storing potent toxic particJes for long periods. Thus, even though macrophages serve as a first line of defense for the alveolar surface, they may also be capable of injuring the host while exercising their defensive role. ACKNOWLEDGMENT: These investigations were supported by Grant R805091010 from the Environmental Protection Agency and by Grant HL19170 from the National Heart, Lung and Blood Institute.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
Impaired Mucociliary Transport as a Pathogenetic Factor in Obstructive Pulmonary Diseases* B;om Mossberg, M.D., and Per Canmer, M.D. of the mucociliary transport system of the A failure airways has been considered as a possible patho-
genetic factor in obstructive pulmonary disease. The importance of mucociliary cJearance has usually been motivated by theoretical considerations. A direct evaluation of the importance of this system has now become possible through the recognition of a human syndrome caused by congenital ciliary immotility. We have studied mucociliary clearance in various obstructive pulmonary diseases, and have compared the findings on cJearance, ventilatory function and clinical picture in these diseases with findings in the "immotile-cilia syndrome.,. METIIOD
Mucociliary transport is studied as the tracheobronchial clearance of an inhaled test aerosol of 6 ~ Teflon particles tagged with 98 •Tc. The aerosol is inhaled in a standardized way with an inhalation air flow of about 1.2 L/sec. The radioactivity retained in the lungs is usually followed for two hours by profile scanning over the thorax of the supine subject. The test particles are deposited mainly in larger airways, and after two hours, most of them are usually cleared from the lungs of healthy persons. 1 REsULTS
In ten patients with chronic bronchitis and severe obstructive pulmonary disease, who could avoid coughing during the measurements, clearance was in most cases slow, indicating a severely impaired mucociliary transport. Mean retention of test particJes after two br was 65 ± 34 ( SD) percent of the initial value. In five bronchitic subjects who could not avoid coughing during the measurements, mean two hr retention was 30 ± 8 percent, a value not significantly different from that of a control group of healthy persons. 1 In another ten patients with chronic bronchitis, with airway obstruction ranging from none to severe, cJearance was equally slow as in the first ten patients (mean 2 hr retention was 72 ± 20 percent), but was in about half the cases markedly stimulated by subcutaneous administration of 0.25 mg of the beta-adrenergic agent terbutaline sulphate. 2 In 12 asthmatic subjects in partial clinical remission, cJearance did not differ significantly from that of healthy persons (mean 2 hr retention was 45 ± 36 percent) .3 In five patients with emphysema without bronchitis, with homozygous deficiency of alpha 1-antitrypsin, clearance did not differ from that of healthy persons (2 hr reten•From the Department of Thoracic Medicine, Karolinska Hospital, and Department of Environmental Hygiene, Karolinska Institute, Stockholm, Sweden. Reprint requests: Dr. Mossberg, Department of Thorocfc Medicine, Karolinsko Hospital, 10401 Stockholm, Sweden
CHRONIC OBSTRUCTIVE LUNG DISEASE 285
1 Mittman C: The PiMZ phenotype: is it a significant risk factor for the development of chronic obstructive lung
disease? (editorial) Am Rev Respir Dis 118:649-52, 1978 2 Patterson CD, Mackenthum A, Anderson PS, et al: Phenotypes Pi MS, MZ alpha1 antitrypsin and lung disease. Bull Int Union Tuberc 51 (I Pt 2) :675-79, 1976 3 Morse JO, Lebowitz MD, Knudson RJ, et al: Relation of protease inhibitor phenotypes to obstructive lung diseases in a community. N Engl J Med 296:1190-94, 1977 4 Fagerhol MK, Laurell CB: The polymorphism of "prealbumins" and 2-1-antitrypsin in human sera. Clin Chim Acta 16:199-203, 1967 5 Kory RC, Callahan R, Boren NG, et al. The Veterans Administration-Army cooperative study of pulmonary function. I. Clinical spirometry in normal men. Am J Med 30:243, 1961 6 Gadek J, Fulmer MF, Petty T, et al : Danazol-induoed elevation of serum alpha 1 antibypsin in individuals with severe deficiency of this antiprotease. Chest 77:279, 1980
Pulmonary Macrophages When Do They Prevent and When Do They Cause COPD? Joseph D. Brain, S.D.(Hyg)
ulmonary macrophages are important since their Pmigratory patterns and phagocytic behavior are
often pivotal events in the outcome between damaging particles or pathogens and a responding host. Resident macrophages in the respiratory tract are recognized as largely responsible for keeping lung surfaces clean and sterile, and for protecting against a wide variety of foreign materials. Their phagocytic and lytic potentials provide most of the known bactericidal properties of the lungs. During acute infection or injury they are also supplemented by other leukocytes. Increased inert or infectious particles stimulate the recruitment of additional macrophages. Most free cells containing particles eventually reach the airways and are quickly carried to the pharynx and swallowed. Additional dimensions of the phagocytic responsibilities of macrophages are becoming apparent. In addition to destroying microbial pathogens, they may also prevent excessive antigen stimulation by ingesting and catabolizing inhaled foreign proteins and antigens derived from bacteria, viruses, fungi, and other microbes. Alternatively, they may preserve and present antigens to lymphocytes and act cooperatively with components of the immune system. Pulmonary macrophages may also ingest effete type 1 and type 2 epithelial cells, occasional red blood cells, and perhaps even "worn out" surfactant. Macrophages also influence the length of time inhaled insoluble particles are retained in the respiratory tract. Because of their ameboid and phagocytic properties, pulmonary macrophages decrease the probability of par-
• Harvard University School of Public Health. Department of Physiology, Boston. Reprint req~: Dr. Brain, Department of Physiology Haroard School of Publlc Heolth, Boston 02115
264 22nd ASPEN LUNG CONFERENCE
tide penetration through epithelial barriers. Particles deposited on airway and alveolar surfaces, if they remain unphagocytized, are more likely to pass through or between epithelial cells. Having gained access to connective tissue and lymph nodes beneath the epithelia, they are retained for longer periods of time and have a greater opportunity to cause disease. The number and activity of macrophages and the speed of phagocytosis are thus related to the probability of particle penetration and retention. Evidence is rapidly accumulating to indicate that macrophages have roles besides phagocytosis. We now recognize macrophages as secretory and regulatory cells which interact with cells as diverse as lymphocytes and fibroblasts. They are involved in the induction and expression of several forms of cell-mediated and humoral immunity. They are capable of recognizing and destroying neoplastic cells, thus preventing the development of cancer. They can secrete such diverse substances as lysosomal enzymes, interferon, certain components of complement, angiogenesis factor, plasminogen activator, cyclic nucleotides, prostaglandins, granulopoietins, and a number of agents iniluencing the proliferation of fibroblasts and tumor cells. Still other macrophage products may interact with humoral enzyme systems such as those controlling clotting, fibrinogenesis, fibrinolysis, and kiningeneration. In so doing, they are involved with the regulation of multi-enzyme cascades and of the replication, differentiation, and activity of such cells as lymphocytes, fibroblasts, and even other macrophages. .But, in addition to a variety of protective postures which help prevent COPD, macrophages may also be participants in the pathogenesis of COPD. First, their defensive role can he compromised. A number ofjnves-
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
tigators using both in vivo and in vitro bactericidal or phagocytic assays have shown that such diverse agents as silica, immunosuppressives, ethanol intoxication, cigarette smoke, air pollution, and oxygen toxicity, can dramatically depress the ability of pulmonary macrophages to protect their host. Sometimes the agent or factor acts directly on the macrophage producing a damaged or even a dead cell. In other cases ( eg high concentrations of inhaled particles) the mechanism can be competitive inhibition in which the phagocytic machinery becomes saturated even in the absence of cytotoxicity. In other instances, particularly those situations involving pulmonary edema or altered acid-base balance, the macrophages may be undamaged, but their activity may be depressed because of an indirect effect on their milieu, the airway or alveolar microenvironment. Non~theless, it is important to realize that macrophage failure or damage is not always a cause of the disease in question; in many instances, alterations in macrophage function may simply reflect the onset and progression of the disease. For example, changes in macrophage activity during pulmonary edema as~ociated with oxygen toxicity fall in this class. It is not the macrophage's failure to ingest particJes or bacteria which causes the edema; rather the reverse. Many investigators have similarly misinterpreted associations between other altered respiratory defense mechanisms and COPD. For example, the presence of altered mucociliary transport in COPD does not necessarily imply that depressed mucociliary transport has caused COPD or in any way contributed to its pathogenesis. Defective mucus movement may be a result of the disease rather than a cause. Carefully designed experiments are needed to make these distinctions. Finally, there are situations in which pulmonary macrophages not only fail, but are directly implicated in the pathogenesis of pulmonary diseases. For example, the ingestion of some particJes by macrophages causes the release of lysosomal enzymes into the macrophage cytoplasm. These enzymes may kill the macrophage and dead or dying macrophages release substances which can attract fibroblasts and elicit fibrogenic responses. Other toxic particJes, particularly cigarette smoke, may lead to a release of proteases and other toxic enzymes and agents. When smokes and other pollutant particJes act to recruit more cells, to activate them, and to release proteolytic enzymes, macrophages may then be centrally involved in many stages of the development of COPD. The same agents may also elicit similar responses from other white blood cells such as polymorphonuclear leukocytes. In addition, connective tissue macrophages may contribute to COPD by concentrating and storing potent toxic particJes for long periods. Thus, even though macrophages serve as a first line of defense for the alveolar surface, they may also be capable of injuring the host while exercising their defensive role. ACKNOWLEDGMENT: These investigations were supported by Grant R805091010 from the Environmental Protection Agency and by Grant HL19170 from the National Heart, Lung and Blood Institute.
CHEST, 77: 2, FEBRUARY, 1980 SUPPLEMENT
Impaired Mucociliary Transport as a Pathogenetic Factor in Obstructive Pulmonary Diseases* B;om Mossberg, M.D., and Per Canmer, M.D. of the mucociliary transport system of the A failure airways has been considered as a possible patho-
genetic factor in obstructive pulmonary disease. The importance of mucociliary cJearance has usually been motivated by theoretical considerations. A direct evaluation of the importance of this system has now become possible through the recognition of a human syndrome caused by congenital ciliary immotility. We have studied mucociliary clearance in various obstructive pulmonary diseases, and have compared the findings on cJearance, ventilatory function and clinical picture in these diseases with findings in the "immotile-cilia syndrome.,. METIIOD
Mucociliary transport is studied as the tracheobronchial clearance of an inhaled test aerosol of 6 ~ Teflon particles tagged with 98 •Tc. The aerosol is inhaled in a standardized way with an inhalation air flow of about 1.2 L/sec. The radioactivity retained in the lungs is usually followed for two hours by profile scanning over the thorax of the supine subject. The test particles are deposited mainly in larger airways, and after two hours, most of them are usually cleared from the lungs of healthy persons. 1 REsULTS
In ten patients with chronic bronchitis and severe obstructive pulmonary disease, who could avoid coughing during the measurements, clearance was in most cases slow, indicating a severely impaired mucociliary transport. Mean retention of test particJes after two br was 65 ± 34 ( SD) percent of the initial value. In five bronchitic subjects who could not avoid coughing during the measurements, mean two hr retention was 30 ± 8 percent, a value not significantly different from that of a control group of healthy persons. 1 In another ten patients with chronic bronchitis, with airway obstruction ranging from none to severe, cJearance was equally slow as in the first ten patients (mean 2 hr retention was 72 ± 20 percent), but was in about half the cases markedly stimulated by subcutaneous administration of 0.25 mg of the beta-adrenergic agent terbutaline sulphate. 2 In 12 asthmatic subjects in partial clinical remission, cJearance did not differ significantly from that of healthy persons (mean 2 hr retention was 45 ± 36 percent) .3 In five patients with emphysema without bronchitis, with homozygous deficiency of alpha 1-antitrypsin, clearance did not differ from that of healthy persons (2 hr reten•From the Department of Thoracic Medicine, Karolinska Hospital, and Department of Environmental Hygiene, Karolinska Institute, Stockholm, Sweden. Reprint requests: Dr. Mossberg, Department of Thorocfc Medicine, Karolinsko Hospital, 10401 Stockholm, Sweden
CHRONIC OBSTRUCTIVE LUNG DISEASE 285