The contribution of alveolar macrophages to hyperreactive airway disease

The contribution of alveolar macrophages to hyperreactive airway disease

stgraduate course ontribution of alveolar rnacrophage erreactive airway disease Rankin, MD West Haven, Conn. The macrophage is part of a family of ...

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ontribution of alveolar rnacrophage erreactive airway disease Rankin, MD West Haven, Conn.

The macrophage is part of a family of mononuclear pbagocytic cells found in virtually all organs. Traditionally, the classification of lung macrophages divides them into two categories based on their anatomic distribution: alveolar or interstitial. AMs reside predominately in the alveoli on top of epithelial cells. ecause of this strategic location and because of their pronounced phagocytic capabilities, AMs are an important component of the first line of the defences of the body.” It is precisely this anatomic location that makes these cells one of the first phagocytic cells to encounter inhaled particles and solubilized constituents of particles that may be allergens. As will be discussed below, macrophages also reside in human airways where they are poised to meet any inhaled matter that settles in this more proximal location. Interstitial macrophages reside in the interstitium of the lung and may have both similar and different charfrom their AM counterparts. Studies are ut the available data support the notion that these cells have characteristics of both their precursors, PBMs, and their descendants, AMs. The pathologic findings in the lungs of subjects with atopic asthma who die of an exacerbation of their disease include smooth muscle hypertrophy, basement membrane thickening, disruption of airway epithehum, and airway inflammation associated with mucous plugging. I-Iistologic examination of the airways reveals diffuse infiltration with neutrophils, eosinophils, lymphocytes, and mononuclear phagocytes.2 Frequently, mast cells and basophils are not conspicious because they have degranulated in vivo. The precise mechanisms by which all these cells work individually and in concert in the induction and main-

From the Research Service, West Haven Veterans Hospital, Yale University School of Medicine, Pulmonary Disease Section, New Haven, Corm. Accepted for publication Oct. 15, 1988. Reprint requests: John A. Rankin, MD, Associate Professor of Medicine, Pulmonary Section 689/ 11 lA, West Haven Veterans Hospital, West Haven, CT 06516.

Abbreviations used BAL: FcR: PAF: AM: PBM: LTD,, LTB,, LTC,: PGD,, PGE,, PGF,: K,:

Bronchoalveolar Fc receptor


Platelet-activating factor Alveolar macrophage Peripheral

blood monocyte

Leukotrienes D,, B,, and C, ProstaglandinsD,, E,, and FZ Equilibrium


tenance of this inflammatory reaction are poorly defined at this time. It is also not clear which, if any, of these cell types are more important in the pathophysiologic events present in the airways. A single cell, the lung macrophage, will be reviewed in this article and details of evidence suggesting that macrophages may figure promine~tIy in the inflammatory airway responses observed in subjects with atopic asthma. The emphasis on this cell in no way is meant to deemphasize the important role other cells play in these processes. For the purposes of this discussion I will confine my remarks to one type of hyperreactive airway disease, namely, atopic asthma. This article is divided into four parts. Each part will address a statement concerning the potential relevance of macrophages to atopic asthma.

MACROPHAGES ARE THE AIR-SURFAC HUMAN AIRWAY For the greater part of two decades, researchers have retrieved lung macrophages for study wit technique known as BAL.’ In this procedure ahquots of a physiologic solution are instilled and aspirated through a bronchoscope wedged in a p way. The macrophages retrieved with lieved to arise mostly from the alveoli because examination of these terminal gas exchange units with electron microscopy confirms their presence there and because the area of alevoli distal to the tip of the fiberoptic bronchoscope is much greater than the area


of airways. For years investigators have believed that macrophages traverse the airways as they pass up the mucociliary escalator and eventually are either expectorated or are swallowed. Indirect support for this is provided by the observation that macrophages are present in the first aliquot of BAL fluid, which is believed to sample airways preferentially. Proof that macrophages are airway cells in animals has been provided by Brain et a1.4who have directly visualized macrophages in airways of hampsters. Their identification depended on the ability of these cells to phagocytose iron particles. Therefore, their studies established that macrophages are present on the air-surface interface of the airways and that these cells are viable. To determine conclusively if macrophages reside on airway epithelial surfaces of human airways, my laboratory and other investigators have developed techniques to isolate and lavage a segment of airway (the left main stem bronchus) in vivo. The various techniques involve the use of a single or double balloon-tipped catheter. The catheter tip is positioned at the distal end of the left main stem bronchus. The distal and proximal balloons then are inflated to occlude the airway. Lavage of that airway between the two balloons is performed. Results by Eschenbacher and Gravelyn’ reveal that macrophages are the predominant white blood cell recovered in airway lavage from both normal subjects (Table I) and from subjects with mild asthma, whereas lymphoctyes and neutrophils are present in far fewer numbers. Studies in my laboratory with a slightly different technique demonstrate that macrophages are present in airway lining fluid of normal nonsmoking volunteers, but that neutrophils are present in approximately equal numbers, whereas lymphocytes represent only a small portion of the total cells retrieved (Table I).6 The identity of the cells as macrophages has been confirmed by Wright-Giemsa staining, nonspecific esterase staining, and by transmission electron microscopy. Furthermore, the cells are viable (assessedby their ability to exclude trypan blue) and therefore are not simply refuse from the alveoli. It is considerably more difficult to isolate and lavage airways smaller than the left main stem bronchus, but it is a safe assumption that macrophages are present in these smaller airways as well. How many macrophages exist there and whether or not there are functional differences between AMs and airway macrophages are unknown, but it is being studied currently. Clearly, macrophages should be considered airway cells. OPHAGES POSSESS IgE RECEPTORS In the early 197Os, Capron et al.’ were first to discover evidence for IgE FcR on macrophages by im-


and reactivity



plicating IgE antibodies in macropha~e-depe~dcnt cytotoxic damage to parasites. They were able to demonstrate that incubation of parasitic antigen (Schistosoma mansoni larvae) with the serum from rats immune to S. mansoni resulted in the activation and adherence of peritoneal macrophages from normal rats and subsequent cytotoxic damage to the schistosomules. Follow-up experiments revealed that serum-immune complexes composed of specific antischistosomal IgE and parasite antigen induced these effects.* An important finding was that the activation of rat macrophage antischistosomal cytotoxicity occurred through the interaction of IgE immune complexes with an IgE FcR on the macrophage sur; face.*, 9 It is now known that the IgE FcR expressed on the surface of macrophages is similar, if it is not identical, to that on T- and B-lymphocytes, platelets, and eosinophils. This receptor is referred to as IgE FcR2 and differs both structurally and functionally from the IgE FcR on mast cells and basophils, which is referred to as IgE FcRl. The most important functional difference is that the IgE FcR2 on macrophages is a low-affinity receptor. The estimated K, for IgE monomer binding to rat macrophages” and to U937 cells” approximates 10’ mol/L-‘. This contrasts with the tighter binding of IgE to the high-affinity receptor found on mast cells K, approximating 109 to 10” mol/L-‘.” Evidence for structural differences between these two receptors is suggested by the fact that IgE FcR2 is sensitive to trypsin digestion, whereas IgE FcRl is not. In addition, goat polyclo~al antisera to IgE FcRl inhibit the binding of IgE to this receptor but do not block the binding of IgE to IgE FcR2.” Studies to determine the structural proteins of the lowaffinity receptor on macrophage-like U937 cells demonstrate two main peptide bands with molecular weights approximating 20,000 to 25,000 and 45,000 to 50,000.‘2 In addition, Finbloom and Metzger’3 analyzed structural components of the IgE FcR on rat macrophages. They found two peptides, one with a molecular weight of 40,000 to 70,000 and one with a molecular weight of 33,000. Taken together, these data suggest that this receptor has a smaller alpha chain and a larger beta chain similar to those in the IgE FcRl . The cDNA for the alpha chain of the IgE FcRl has been cloned.14 The sequence of amino acids is not homologous to the IgE FcR2.15.I6 Two separate laboratories have estimated that there are about 4 to 5 X lo4 low-affinity receptors on rat macrophages” and about 5 to 9 X lo4 receptors on U937 cells, l1 whereas basophils are reported to possess between IO” and lo6 receptors per cell. “, I8 Thus, both similarities and dissimilarities exist between the two types of IgE receptors. Collectively, these studies suggest that the



LE 1. Cellular


of BAL and ALF from normal



5 6

CLIN. I~M~~O~. APRIL 1989







95.4 I 1.9 73.4 +- 17.9

4.6 + 1.9 24.1 +- 18.2

0 1.8 f 1.7


0.1 t 0.1

ND 0.2 + 0.3

k 41.1 r 26.6 i

25.1 9.9

5.3 4 2.1 7.7 + 3.2

LF, AhaY-1aVage fluid; M, macrophages;L, lymphocytes; N, neutrophils; E, eosinophils; f3, basophils;ND, not d&mined, *Data are mean _’ SD.


of IgE receptor-positive Normal

Be~erence 12, 20, 21 19

PBMs and AMs*


Mild atopic






15.3 2 4.8 ND

8.0 ‘- 2.6 6 t 4t

18.6 k 3.5

ND 17 +- 5


Severe atopic


PB 56.0 + 39.3



ND, not determined. “Data are mean Ifr SD. ?Actaal numbers estimated from reference 19.

ononuclear phagocyte products ive role in asthma syndromes LTB.,, LTC,, LTD,, 5-hydroxyeicosatetraenoic PAF Eosinophil-activating factor(s) Macropbage-derived mucous secretagogue Histamine-releasing factor(s) Superoxide anion /3-Glucuronidase Neutral proteases PGE2, PGF,,, Thromboxane, ? PGD,


l~w-~~~~ty receptor on the macrophage may be activated preferentially by IgE immune complexes that offer multiple binding sites and therefore higher binding affinity. This contrasts with basophil activation that occurs via antigen bridging of IgE coupled to IgE dditional investigators have determined the percentage of macrophages and monocytes from man that bear IgE receptors.“‘, ‘9-21Indeed, approximately 5% to 10% of PEMs and AMs from normal nonatopic humans bear PgE FcRs (Table II). Interestingly, the number of IgE FcR-positive AMs and PBMs increases in atopic subjects compared to normal subjects. For ) Melewicz et al.” found that as many as 80% s from patients with severe atopic dermatitis are IgE FcR positive when the ability of these cells to form rosettes with IgE-coated red blood cells is assessed. Interestingly, patients with severe asthma

and atopic dermatitis treated with corticosteroids had the lowest percentage of IgE FcR-positive P Spiegelberg” also noted that monocytes from severely atopic subjects induced significantly more 5’Cr release from IgE-coated red blood cells than mQnocytes from nonatopic or mildly atopic subjects. Thus, monocytes phagocytose and lyse IgE-coated target cells, and IgE is an effective opsonin for monocytes. Ad~~~i~nal studies by other investigators with AMs from subjects with mild atopic asthma reveal that approximately 20% of these cells are IgE FcR positive.” It is difficult to retrieve, ethically, AMs from individuals with severe atopic asthma because of the risks inherent in the bronchoscopic procedure. Nevertheless, it is reasonable to propose that the number of IgE FcR-positive AMs in such patients exceeds that in subjects with mild asthma and approximates the high percentages observed on PBMs from patients with severe atopic dermatitis mentioned above.

MACROPHAGES RELEAS WITH A POSSIBLE ROLE Macrophages and monocytes release a vast array of molecules in response to various stimliu. For a detailed discussion of mononuclear pbagocytes and their secretory products, the reader is referred to two recent and excellent articles. ‘, 22 any of the molecules produced and released by mononuclear phagocytes have no known role in asthma syndromes at this time. Evidence supporting a putative role for some of these products (Table III), however, does exist. The



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3.9 r 5.8 32.0 It 21.0

0 0.2 + 0.4

ND 0

discussion in this article will be limited to those substances that have more than a theoretical role in asthma. Several pieces of evidence support the concept that inflammation is directly related to the development and/or maintenance of airway hyperreactivity.23 Airway inflammation frequently is associated with bronchial edema, mucosal permeability, sensory nerve exposure, and release of proinflammatory mediators. All these conditions are proposed components of the airway reaction observed in patients with atopic asthma. Indeed, there is direct evidence for a defect in the permeability of the lungs of patients with mild asthma to serum proteins .24 One potential link between mononuclear phagocytes and atopic asthma revolves around the possibility that these cells orchestrate or participate in the inllammatory response ongoing in the airways of subjects with atopic asthma. With macrophages appropriately positioned to encounter inhaled allergen when it settles on the epithelial surface of airways, it is plausible to hypothesize that macrophages might release chemotaxins that are responsible for directing the migration of neutrophils and eosinophils into the airways. In this respect it is important to note that macrophages are capable of releasing at least six neutrophil chemotaxins. These are LTB4,“-‘* PAF,29tumor necrosis factor,30 C5a,22 platelet-derived growth factor,31 and a 10,000 molecular-weight molecule that has yet to be characterized fully.32 Interestingly, PGI&, a putative macrophage product,27 potentiates LTB,-induced chemotaxis, but it is not by itself a significant neutrophil chemotaxin.33 Eosinophils are conspicuous participants in the airway inflammatory events of subjects with atopic asthma to inhaled allergen.“, 34-38These cells release an impressive array of mediators and other products that have a putative role in allergic forms of asthma.39 Included in these mediators are LTC4, PAF, and major basic protein. Macrophages are potential modifiers of eosinophil participation in asthma and of the secretion of mediators by these cells. In this respect macrophages release at least three substances that directly effect the eosinophil. LTB, is a reasonably potent eosinophil chemoattractant.40. 41 Since human AMs are


and reactivity



capable of releasing large quantities of I,TBq925,26,28 it is reasonable to hypothesize that macrophages and LTB, possess at least some potential role directing the migration of eosinophils into human airways in vivo. Another macrophage product, PAF, is an even more potent chemotaxin for eosinophils.“’ Last, Elsas et a1.43reported that human PBlvIs release factor(s) that enhance at least two biologically important eosinophil functions, helminthotoxicity and generation of 5-lipoxygenation products. Dessein et [email protected] also have observed that monocyte products (monocles) exert a regulatory effect on endogenous arachidonic acid metabolism by eosinophils and have extended these observations to neutrophils. This factor(s) may be similar to the eosinophil-activating factor described by Veith and Butterworth. Fitzharris et aL4” also have demonstrated that monocyte-derived eosinophilactivating factor(s) enhance IgG-dependent LTC, release by normal density eosinophils. When these observations are considered together, they outline a direct link between macrophage and eosinophil functions and raise the possibility that such interactions between these two cell types may occur in asthma and may contribute to the inflammatory responses in the airways of these patients. Plugging of airways with mucous is a hallmark of the lungs of patients with atopic asthma and is responsible, in large part for the symptoms and physiologic abnormalities observed in these patients. In part, this plugging is due to mucous hypersecretion. The regulatory mechnisms of mucous secretion in human airways are complex. An in vitro model for the assessment of airway mucous glycoprotein secretion has been developed by Marom et al.47 They have found that many mediators enhance mucous secretion. Of particular note is that at least two of these mediators are the macrophage products 5-hydroxyeicosatetraenoic acid and 4 (Marom z. Personal communications.). Both t mediators at concentrations ranging from 4 to 100 nmol i L augment mucous glycoprotein release from human airway tissue in vitro. These investigators also have established that human AMs, when they are stimulated by complement-activated zymosan or ~~u~~y~~c~~c~~aureu~ organisms, synthesize and release a substance with a molecular weight of 1200 to 1400 that elicits mucous glycoprotein release.48Interestingly, s release an identical substance.d9 Further iden ion of this molecule(s) has not been reported, but these data firmly demonstrate that macrophages can in mucous glycoprotein release and implicate these cells as one potential regulator of mucous secretiou. Work performed several years ago by Schulman et a1.5oestablished that human AMs, when they are




cultured in vitro, spontaneously synthesized and released a product that caused calcium-dependent histamine release from basophils. Mast cells responded similarly if they were exposed to higher concentrations of this factor(s). Additional studies by Liu et al.‘l found that the macrophage factor(s) effected histamine release by interaction with IgE on the surface of the cell. Histamine-releasing factors are now known to be a family of substances that are capable of eliciting histamine release from basophils through interaction with a subset of IgE molecules. For an up-to-date and in-depth discussion of these factors, recent articles exist.52*53These observations are strong evidence supporting the provocative concept that macrophages may directly influence some basophil and mast cell functions. One of the main functions of mononuclear phagocytes is the initiation of immune responses. Macrophages accomplish this complex task by presenting antigen to lymphocytes and by elaborating monokines, such as interleukin-1 , that, in turn, stimulate lymphocytes for diverse effector functions. Recently, Tonne1 et al.54 challenged AMs by IgE-dependent mechanisms and observed that these cells released a factor(s) that inhibited thymocyte proliferation. If macrophages from subjects with atopic asthma release more of this inhibitory factor than macrophages from nonatopic subjects, it would be reasonable to hypothesize that this results in an alteration of the normal immune response to inhaled allergen that in turn might contribute to the chronic inflammatory reaction present in the airways of subjects with asthma. ES CAN BE ACTIVATED BY ICALLY RELEVANT STIMULI MEDIATORS THAT HAVE A ROLE IN ASTHMA SYNDROMES The IgE-antigen complexes used in the rat experiments by Dessaint et a1.55activated rat peritoneal macrophages to release lysosomal enzymes and superoxide anion, Macrophage products of oxygen metabolism have proinflammatory effects56A*56B and thereby may contribute to the inflammatory airway reaction observed in subjects with asthma. Importantly, at about the same time that Dessaint et a1.55 made their observations, Bach et a1.57observed that rat peritoneal macrophages were capable of releasing LTC,. Collectively, these observations led us to investigate whether IgE activation of rat AMs would induce the release of LTC,, a potent smooth muscle spasmogen. Our studies established that normal rat AMs could be activated by a monoclonal IgE and its specific antigen to release LTBd’ and LTC4” in a timeand dose-dependent manner. Further studies revealed that immune complexes comprised of IgE and its an-


tigen were responsible for eliciting the synthesis and release of these products.60 Several laboratories have demonstrated that mononuclear phagocytes could have an important role in IgE-mediated diseases through experiments examining the activation of human PBMs or AMs from nonatopic subjects by IgE-dependent mechanisms. Ferreri et a1.61challenged in vitro PBMs from normal subjects with chemically aggregated IgE and found that these cells released small quantities of LT PGE,. Fuller et a1.62challenged AMs from patients with various nonatopic lung diseases with Ig anti-IgE and observed that these cells released PGF2, thromboxane B,, and B-glucuronidase. Fur: thermore, when AMs from normal individuals are incubated with IgE and then anti-IgE or with the sera from atopic persons and with specific allergen, or with anti-IgE alone, release of lysosomal enzymes, such as neutral proteases and B-glucuronidase, is observed.63 Additional data have been generated with mononuclear phagocytes from atopic subjects. A preliminary study reveals that AMs from atopic subjects release PAF after in vitro stimulation with antigen.6” In addition, AMs from patients with atopic asthma also release lysosomal enzymes in response to challenge with specific allergen or anti-IgE.63 Interestingly, these data suggest that macrophages from subjects with and without asthma do not differ in this respect.63 However, other results do reveal differences in lung macrophages from these two patient groups. First, Goddard et a1.65noted that AMs from subjects with atopic asthma were less viable and phagocytosed a yeast cellwall extract (zymosan) less well than cells from nonatopic control subjects. They also noted a positive correlation between these deficits and the percentage of eosinophils in the BAL fluid from their patients, suggesting eosinophils or their products may adversely effect macrophage functional capabilities. Second, lung macrophages from subjects witk atopic asthma function less well as suppressor cells, determined by their decreased ability to modulate lymphoproliferative responses to polyclonal T cell mitogens) compared to control subjects.34Third, the respiratory burst of in vitro-cultured macrophages from subjects with asthma at rest and after stimulation is increased compared to that observed in macrophages from normal [email protected] Last, Carroll et a1.67observed that the number of PBMs forming rosettes with complementcoated red blood cells increased in patients after allergen bronchoprovocation but not after histamineinduced bronchoconstriction. Although neutrophils are prominent cellular constituents of the BAL fluid from subjects with atopic asthma after allergen bronchoprovocation,‘j* it is of


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interest that lung macrophages from subjects with atopic asthma release in vitro a low-molecular-weight neutrophil chemotactic factor when macrophages are challenged with allergen or anti-IgE.69 Further studies TV characterize this factor have not yet been performed. More recently, in vivo studies with humans have been completed that also point toward a role for macrophages in asthma. Investigators have measured the amount of B-glucuronidase in BAL fluid and in macrophages retrieved from a group of patients with asthma and sensitivity to house dust mite, and in whom a segment of lung was challenged with mite antigen instilled directly through a fiberoptic bronchoscope positioned in a peripheral airway. The levels of B-giucuronidase in BAL fluid were elevated, and macrophage intracellular levels were decreased compared to levels found in BAL fluid from nonatopic control subjects, suggesting that macrophage secretory processes were activated by allergen70 Additional studies with similar methodologies have examined BAL fluid from subjects with atopic asthma for several arachidonic acid metabolites.71 PGD2, a potent bronchoconstrictor, was found in BAL fluid at levels averaging 150 times the level present before instillation of antigen. PGD, is a mast cell product7’ and may be released from AMs.27 It is possible, but it has yet to be proved, that this mediator originated, at least in part, from macrophages present in the lungs and airways of these patients. Several investigators are assessing immunologic events occurring in the airways of subjects with atopic asthma by performing BAL after direct instillation of allergen into a local segment of lung or after allergen bronchoprovocation. Metzger et a1.68have used this technique and found that the total numbers of mononuclear phagocytes present in BAL fluid are increased at 48 and 96 hours after allergen challenge. Importantly, the number of peroxidase-staining macrophages in BAL of their subjects with asthma increased significantly at 48 hours, suggesting that a population of monocytes had entered the alveolar space from blood or interstitial spaces. These observations also support the concept that macrophages may have an important role in the events that shape the late-phase response. We have discussed tbe concept that macrophages may participate in airway inflammation in patients with atopic asthma through the release of proinflammatory products and release of factors that modulate the function of other cells. It is also clear that other cells and their secretory products regulate macrophage functions. There are many mediators that fall under this category. Experiments performed recently in my laboratory have focused on the ability of one mediator,



and reactivity


interferon-gamma, to influence the generation and release of mediators from human lung macrophages. Interferon-gamma is a glycoprotein produced by lymphocytes in response to a variety of stimuli.73 We observed that this lymphokine primed human macrophages, retrieved by BAL, for the release of LT in response to an IgG stimu1us.74 This lympl~~kine was very potent in this effect because as little as 10 U/ml successfully primed the cells for augmented release of LTB,. Higher concentrations of interferongamma produced even further dose-dependent increases in LTB, generation. Inte~eron-gamma appeared to effect this response at least in part by increasing the number, but not the affinity, of receptors for IgG on the surface of the rnacr~~~age. The response was specific for interferon-gamma since it was not observed with either interferon-a~pl~a or interferon-beta. Thus, it appears the macrophage capacity for LTB, synthesis can regulated by at least one lymphocyte product. Because interferongamma increases not only the number of IgG receptors but also the number of IgE receptors on tbe surface of macrophage-like U937 cells,75 some of our current investigations are directed at assessing whether this lymphokine will increase IgE-receptor expression on macrophages and whether or not i~te~ero~-mamma will effectively prime human AMs for the release of LTB, in response of an IgE stimulus. SUMMARY Thus, there is substantial evidence that favors a role for macrophages in subjects with atopic asthma. The precise manner in which these cells participate and the relative degree to which these cells contribute to, or orchestrate, events remains to be Research on the potential role of macrophages in asthma syndromes remains in its infancy. In time we will discover new roles for mononuclear phagocytederived mediators and many more new mediators that will play a role in the complex immunologic events ongoing in the airways of patients with asthma. Also, future research will continue to explore what promises to be a productive area of research namely, cell-cell interactions and the manner in which many cells participate together in the pathophysiology of asthma, If macrophages can be demonstrated to influence airway inflammation associated with atopic disease, they may be appropriate targets for therapeutic intervention. REFERENCES 1. Fels AOS, Cohn ZA. The alveolar macrophage. J Appl Physiol 1986;60:353-69. 2. Dunnill MS. The pathology of asthma. In: Middleton E, Jr, Reed CE, Ellis EF, eds. Allergy: principles and practice, vol 2. St. Louis: CV Mosby, 1978:678.



3. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis 1987;135:2§0-63. 4. Brain JD, Gehr P, Kavet RI. Airway macrophages: the importance of the fixation method. Am Rev Respir Dis 1984; !29:823-6. 5. Eschenbacber WL, Gravelyn TR. A technique for isolated airway segment lavage. Chest 1987;92:105-9. 6. Ratin JA, Marcy TW, Smith S, Olchowski J, Sussman J, Merrill WW. Human airway lining fluid: cellular and protein constituents. Am Rev Respir Dis 1988;137:5A. 7. Capron A, Dessaint JP, Capron M, Bazin H. Specific IgE antibodies in immune adherence of normal macrophages to Schistosoma mansoni schistosomules. Nature 1975;253: 474-5, 8. Capron A, Dessaint JP, Rousseau R, Capron M, Bazin H. Interaction between IgE immune complexes and macrophages in the rat: a new mechanism of macrophage activation. Eur J Immunol 1977;1:315-22. 9. Dessaint JP, Torpier G, Capron M, Bazin H, Capron A. Cytophilic binding of IgE to the macrophage. I. Binding characteristics of IgE on the surface of macrophages in the rat. Cell Immunol 1979;46: 12-23. 10. Findbloom DS, Metzger H. Binding of immunoglobulin E to the receptor on rat peritoneal macrophages. .I Immunol 1981;129:2004-8. 11. Anderson CL, Spiegelberg HL. Macrophage receptors for IgE: binding of IgE to specific IgE receptors on a human macrophage cell line, U937. .I Immunol 1981;2470-3. 12. Spiegeiberg HL. Structure and function of Fc receptors for IgE on lymphocytes, monocytes, and macrophages. Adv Immunoi 1984;35:61-88. 13. Finbloom DS, Metzger H. Isolation of cross-linked IgEreceptor complexes from rat macrophages. J Immunol 1983; 30;1489-91. 14. Shin&u A, Tepler I, Benfy PN, Berenstein EN, Siraganian RP, Leder P. Human and rat mast cell high-affinity immunoglobulin E receptors: characterization of putative alpha-chain gene products. Proc Nat1 Acad Sci USA 1988;85: 1907-l 1. 15. Ravetch JV, Luster AD, Weinshank R, Kochan .I, Pavlovec A, Portnoy DA, Hulmes J, Pan Y-C E, Unkeiess JC. Strucmraf heterogeneity and fttnctional domains of murine immunoglobulin G Fc receptors. Science 1987;234:718-25. t6. Dreskin S, Metzger H. The high-affinity receptor for immunoglobulin E. JAMA 1988;260:1265-8. 17. Malveaux FJ, Conroy MC, Adkinson NF Jr, Lichtenstein LM. IgE receptors on human basophils: relationship to serum IgE concentration. J Clin Invest 1978;62: 176-8 1. 18. Ishizaka T, Soto CS, Ishizaka K. Mechanisms of passive sensitization. III. Number of IgE molecules and their receptor sites on human basophil granulocytes. J Immunol 1973; 111:5OO-11. 19. Joseph M, Tonne1 AB, Torpier G, Capron A, Amoux B, Benveniste J. Involvement of immunoglobulin E in the secretory processes of alveolar macrophages from asthmatic patients. J Clin Invest 1983;11:221-30. 20. Melewicz FM, Kline LE, Cohen AB, Spiegelberg HL. Characterization of IgE receptors for IgE on human alveolar macrophages. Clin Exp Immunol 1982;49:364-70. 21. Melewicz FM, Zeiger RS, Mellon MH, O’Connor D, Spiegelberg H. Increased peripheral blood monocytes with Fc receptors for IgE in patients with severe allergic disorders. J Immunol 1981;126:1592-5. 22. Nathan CF. Secretory products of macrophages. J Clin Invest 1987;7$:319-26. 23. Chung KF. Role of inflammation in the hyperreactivity of airways in as&ma. Thorax 1986;41:657-62.



24. Fick RB Jr, Metzger WJ, Richerson MB, Zavala DC, Moseley PL, Schoderbek WE, Hunninghake GW. Increased bronchovascular permeability after allergen exposure in sensitive asthmatics. J Appl Physiol 1987;63:1147-55. 25. Rls AOS, Pawlowski NA, Cramer EB, Cohn ZA, Scott WA. Human alveolar macrophages produce leukotriene B1. Proc Nat1 Acad Sci USA 1982;79:7866-70. 26. Martin TR, Raugi G, Merritt T, Henderson WR Jr. Relative contribution of leukotriene 8, to the neutrophil chenotactic activity produced by the resident human alveolar macro&age. J Clin Invest 1987;80;1114-24. 27. MacDermot J, Kelsey CR, Waddell KA, Richmond R, Knight RK, Cole PJ, Dollery CT. Landon DN, Blair IA. Synthesis of leukotriene B, and prostanoids by human alveolar macrophages: analysis by gas chromatography/mass spectromeq. Prostaglandins 1984;27:163-77. 28. Laviolette M, Coulombe R, Picard S, Braquet P, Borgeat P. Decreased leukotriene B, synthesis in smokers’ alveolar macrophages in vitro. J Clin Invest 1986;77:54-60. 29. Amoux B, Duval D, Benveniste J. Release of plateletactivating factor (PAF-acether) from alveolar macrophages by the calcium ionophore A23187 and phagocytosis. Em J Clin Invest


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