The alveolar macrophage is one of the few tissue macrophage populations readily accessible to study both in the human and in animals. Since harvesting of these cells by bronchoalveolar lavage was first described in 1961, alveolar macrophages have been extensively investigated. This population is the predominant cell type within the alveolus, and undoubtedly serves as the first line of host defense against inhaled organisms and soluble and particulate molecules. Early studies focussed on this endocytic role and delineated the cells' phagocytic and microbicidal capacities. More recent investigations demonstrated an extensive synthetic and secretory repertoire including lysozyme, neutral proteases, acid hydrolases and O2 metabolites. In addition, the complex immunoregulatory role of the macrophage has also been appreciated. These cells have been shown to produce a wide variety of pro- and anti-inflammatory agents including arachidonic acid metabolites of the cyclooxygenase and lipoxygenase pathways, cytokines which modulate lymphocyte function and factors which promote fibroblast migration and replication.
Ganciclovir, when combined with high-dose intravenous immune globulin, appears to have significantly altered the outcome of patients with cytomegalovirus pneumonia after allogeneic bone marrow transplantation.
Human alveolar macrophages obtained by bronchoalveolar lavage were labeled overnight with [3H]arachidonic acid. The cells were stimulated with calcium ionophore A23187, and the 20:4 oxygenated metabolites released into the culture medium were identified by reverse-phase HPLC. Leukotriene B4 was the major 20:4 metabolite produced by these cultures. Leukotriene B4 was identified by its reverse-phase HPLC elution time, its UV spectrum, and its chemotactic and chemokinetic activities for neutrophils. In addition, the macrophage. and neutrophil-derived leukotriene B4 free acids and methyl esters were found to have identical HPLC retention times.The leukotrienes are a recently discovered class of biologically active compounds that are formed from arachidonic acid (20:4) via the lipoxygenase pathway. They include leukotriene B4 [LTB4, (5S, 12R) dihydroxy-6, 14-cis-8, 10-trans-icosatetraenoic acid] (1), a compound with multiple proinflammatory actions, including chemotactic activity for neutrophils (2), and the slowreacting substances, leukotrienes C4 [(5S)-hydroxy-(6R)-S-glutathionyl-7,9-trans-11, 14-cis-icosatetraenoic acid] and D4 [(5S)-hydroxy-(6R)-S-cysteinylglycine -7,9-trans-11, 14 -cis-icosatetraenoic acid] (3, 4), which have vasoactive properties in addition to their contractile activity on select smooth muscle.All major classes ofgranulocytes have been shown to produce leukotrienes in vitro. However, recent studies with murine pulmonary and peritoneal macrophages indicated that macrophages may be a particularly rich source of these compounds, with LTC4 being the major lipoxygenase product (5, 6). To date, the macrophage is the only cell type known to synthesize substantial quantities of leukotrienes in response to inflammatory stimuli such as zymosan (5), and IgG (7) and IgE (8) immune complexes.In this paper, we report the capacity of human alveolar macrophages to produce leukotrienes. Pulmonary alveolar macrophages represent a large population of resident leukocytes in the lung and as such are believed to be the first line of defense against inhaled material. These cells therefore are ideally positioned to initiate inflammatory and allergic reactions in the lung. The available evidence suggests that human alveolar macrophages generate a low molecular weight chemotactic factor for neutrophils that may be a lipid (9). Our work identifies one such molecule and demonstrates that LTB4 is the major lipoxygenase product of these cells when they are stimulated with calcium ionophore A23187. MATERIALS AND METHODSIsolation of Human Alveolar Macrophages. Human alveolar macrophages were obtained by fiberoptic bronchoscopy with bronchoalveolar lavage in patients who had given informed consent. Lidocaine (2%) was used to anesthetize the nose and upper airways. The bronchoscope (model FB-19D, Pentex Precision Instrument, Norwood, NJ) was then passed transnasally and wedged into a subsegmental bronchus of the right middle lobe or lingula. Lidocaine (1%) was used as needed to suppress cough. Sterile saline, 100 to 1...
We measured H202 release by human alveolar macrophages (AM) from normals and sarcoid patients in suspension immediately after bronchoalveolar lavage in the presence and absence of the triggering agent, phorbol myristate acetate (PMA). AM from 11 sarcoid patients produced a mean (±SE) of 21.7±23 and 5.9±3.4 umol H202/10' macrophages in the presence and absence of PMA, respectively. By contrast, AM from normals (n = 6) produced 9.8±1.7 and 1.6±0.7 nmol H202/106 macrophages with and without PNMA, respectively. Macrophage activation, as monitored by H202 production, did not correlate with the angiotensin-converting enzyme levels, the result of gallium-67 scans, or the percent of lymphocytes in the bronchoalveolar lavage. To determine whether AM from normals could be stimulated to increase their H202 production to the level seen in patients with sarcoid, we measured H202 released by adherent AM after incubation in each of four potential activating agents: recombinant interferons aA, B, -y (rIFNaA, rIFN,6, and rIFN'y, respectively), and 1,25-dihydroxyvitamin D3. H202 release in the range seen in sarcoid patients could be induced in PMAtriggered AM from normals by rIFN-y in a time (t½ -1 d) and dose-dependent fashion (threefold increase, ECso 5 antiviral U/ ml) and by rIFNaA and rIFN# at higher concentrations, but not by 1,25-dihydroxyvitamin D3.
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