Biomedical subjects
Publications and source records attributed to K M Nugent.
One patient with alcoholic cirrhosis and a massive hydrothorax resistant to medical management and thoracocentesis was treated with a Denver peritoneovenous shunt. This patient's progress has been followed for 14 months and the pleural effusion has not recurred.
The occurrence of hemoptysis, dyspnea, and bilateral pulmonary opacities progressed to respiratory failure in a 34-yr-old man. Recovery occurred with corticosteroid therapy. In the absence of evidence for an infectious etiology, the possibility of immunologic trimellitic anhydride (TMA) hemorrhagic pneumonitis was considered when the lung biopsy excluded Goodpasture's and other diseases and because the patient was a spray painter. Serologic evaluation for antibodies against TMA was requested. Because the immunologic studies for TMA were negative, and because the patient was a spray painter, immunoassays for three isocyanates conjugated to human serum albumin (HSA) were carried out although there was no specific history of isocyanate exposure at that time. High levels of IgG and IgE antibodies were detected against hexamethylene diisocyanate (HDI)-HSA and toluene diisocyanate (TDI)-HSA. Further investigation documented exposure to spray paint that contained HDI and another isocyanate. The paint was sprayed on warm metal, and subsequently the worker developed an acute illness. Further plant studies were not possible. We propose that the pathogenesis of this case of hemorrhagic pneumonitis is immunologic because of uncontrolled exposure to HDI and TDI, is analogous to the immunologic hemorrhagic pneumonia caused by TMA, and should be considered as a possible cause of a similar acute lung disease after isocyanate exposure.
We used analytical electron microscopic techniques, including energy-dispersive X-ray analysis, to evaluate a patient with diffuse infiltrates and a history of silica exposure. We identified silica particles in digested bronchoalveolar lavage fluid, sectioned alveolar macrophages recovered by lavage, and parenchymal specimens obtained by transbronchial biopsy. This analysis confirmed our clinical suspicion (a sporadic case of accelerated silicosis) and eliminated the need for additional, more complicated, diagnostic procedures.
We used the ILO classification for occupational lung disease to determine whether there was any correlation between the type and/or severity of pulmonary infiltration on chest roentgenograms and either pulmonary function tests or the types of inflammatory cells present in BAL fluid in patients with interstitial lung disease. Of the 62 patients evaluated (27 with sarcoidosis, 18 with IPF, and 17 with a CV disease and lung involvement), 49 had irregular linear opacities and 13 had normal chest x-rays. There were no significant correlations between the types of cells present in BAL fluid and the various categories of infiltrate or profusion of the infiltrates within each disease group. In patients with sarcoidosis, more extensive infiltration (profusion) was associated with lower FEV, (p less than 0.01). In patients with IPE, linear opacity type, profusion, and the presence or absence of honeycombing were not related to the severity of pulmonary function abnormalities. We conclude that the ILO classification for analysis of chest roentgenograms can be applied to patients with interstitial lung disease not associated with an occupational exposure and that this approach is useful, especially for communication. However, these data provide no information regarding the inflammatory process in the lung and limited information regarding abnormalities in pulmonary function.
Sarcoidosis is a granulomatous disease of unknown cause characterized by a lymphocytic alveolitis. Previous studies have shown that the inflammatory cell population of the distal lung units of patients with this disorder can be accurately assessed using bronchoalveolar lavage (BAL). The present study evaluated the uniformity of BAL between different sites of the lung in patients with sarcoidosis. In general, there was a good correlation between sites for percentages of lymphocytes (LYM) (r = 0.750, p less than 0.0001), LYM number (r = 0.356, p = 0.0007), percentages of neutrophils (NEUT) (r = 0.917, p less than 0.0001), NEUT number (r = 0.999, p less than 0.0001), and macrophage (MAC) number (r = 0.858, p less than 0.001). Despite the good overall correlation, we found that 43% of the patients with high percent LYM (greater than 30%) had this finding on one side only. These patients did not differ from the group as a whole based on radiographic stage of their disease but did differ in the number of radiographs demonstrating focal infiltrates (2 of 28 patients with both sides less than 30% LYM, 2 of 14 with both sides greater than 30% LYM, and 4 of 9 with only one side greater than 30% LYM p less than 0.05 by chi-square); and in each situation the highest percent LYM was seen on the side with focal changes on the chest radiograph.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkylating agents have several effects on cellular host defense responses which could increase either the frequency or the severity of pulmonary infections. In addition, some of these agents directly injure lung parenchyma and could have effects on intrapulmonary killing processes independent of any effect on phagocyte number and function. We have used a murine model for staphylococcal clearance to evaluate the effect of cyclophosphamide and mechlorethamine on intrinsic lung defenses. Single doses of mechlorethamine (40 micrograms IV) or of cyclophosphamide (150 mg/kg IP) reduce peripheral blood neutrophil counts and spleen weights on day 3 after injection; with the exception of neutrophil counts in mechlorethamine-treated mice, these parameters returned to normal by days 10-12. Both drugs reduced the number of alveolar macrophages recoverable by bronchoalveolar lavage on days 10-12 but not day 3. Mechlorethamine delayed the clearance of Staphylococcus aureus 502A from the lung on both days 3 and 12, but cyclophosphamide did not alter clearance on either day 3 or 10. The defect in clearance in mechlorenthamine-treated mice resolved by 3 wk after drug administration. These results demonstrate that alkylating agents do not have uniform effects on antibacterial processes in the murine lung. Since the mechlorethamine effect on staphylococcal elimination appears independent of its effect on macrophage numbers, these results suggest that staphylococcal clearance also depends on nonphagocytic host defense factors.
Antifungal agents alter the function and morphology of Candida cell membranes and cell walls. We observed that brief (30 minute) exposure to either amphotericin B or clotrimazole inhibited the agglutination of Candida blastoconidia by murine bronchoalveolar lavage fluid. This inhibition required continuous drug presence. Neither amphotericin nor clotrimazole inhibited Candida agglutination by concanavalin A or pooled human serum. These results demonstrate that antifungal drugs can produce rapid changes in the surface characteristics of some fungi.
A patient with spinobulbar poliomyelitis had residual dysfunction of the ninth and tenth cranial nerves, which produced bilateral vocal cord paresis and recurrent aspiration. Critical glottic stenosis developed 28 years after the initial episode of poliomyelitis; this course appeared to be explained by fibrosis of the intrinsic laryngeal muscles and ankylosis of the right cricoarytenoid joint. Thus it appears that significant upper airway obstruction may develop as a late complication in patients with stable neurologic deficits and chronic immobility of the vocal cords.
We showed that brief exposures to amphotericin B (AmB) inhibited the induction of new Candida germ tubes and the lengthening of partially induced germ tubes. Blastoconidia with germ tubes were more susceptible to AmB killing, and this varied directly with the induction period and the AmB exposure period. AmB did not preferentially affect germ tube adherence to fibrin matrices.
Respiratory secretions provide an efficient method for protecting the large surface area of the lower respiratory tract. To determine whether lung secretions contribute to antifungal defenses, we tested bronchoalveolar lavage fluid for fungicidal activity. Candida albicans (blastoconidia) was incubated in unconcentrated cell-free lavage fluid from Swiss Webster mice and then cultured quantitatively to measure residual viability. In control buffer the residual fractions of viable fungi were 1.03 +/- 0.12 at 60 min and 0.84 +/- 0.05 at 120 min, whereas the residual fractions in lavage fluid were 0.64 +/- 0.07 and 0.23 +/- 0.05, respectively (P less than 0.05 by t tests). This activity was trypsin sensitive and heat stable (56 degrees C) and did not require divalent cations. It did not sediment with the surfactant fraction of lung lavage fluid. Unconcentrated lavage fluid reduced the adherence of C. albicans to serum-coated glass tubes to 2.3 +/- 1.5% of that of control Candida suspensions (n = 5, P less than 0.05 by t test). It did not alter Candida ingestion or intracellular processing by alveolar macrophages. Lavage fluid also killed clinical isolates of Candida tropicalis and Torulopsis glabrata but did not kill Candida krusei or Candida parapsilosis. Lavage fluid was concentrated and passed through an acrylamide-agarose gel matrix. The chromatogram indicated that the candidacidal activity eluted in a peak with a molecular weight range of 29,000 to 40,000. After electrophoresis on 15% sodium dodecyl sulfate-polyacrylamide gels, these fractions resolved into three bands. These were transferred to nitrocellulose and then eluted with Triton X-100; this procedure permitted the isolation of a single band of candidacidal activity with a molecular weight of 29,000. In summary, murine lavage fluid contains a heat-stable protein with direct antifungal activity. This soluble factor may contribute to lung defense processes by reducing fungal viability and adherence to tissue surfaces.
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Alveolar macrophages obtained by bronchoalveolar lavage (BAL) were evaluated by electron dispersive microanalysis (EDX) for the presence of elemental gold. EDX revealed gold in 90% (9/10) of patients with RA who were currently receiving chrysotherapy or who had discontinued chrysotherapy less than 24 months before BAL. All patients who had discontinued chrysotherapy more than 24 months before BAL (range: 3-14 years) were EDX negative (4/4), as were patients with RA who had never received gold therapy (5/5). Seven patients with RA (7/19) had clinical evidence of interstitial lung disease and 12 patients (12/19) had no interstitial lung disease. There was no correlation between chrysotherapy and the development of interstitial lung disease. These results demonstrate that gold is retained for prolonged periods in pulmonary tissue macrophages but do not identify any relationship between gold and chronic rheumatoid lung disease.
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Because sublethal concentrations of antibodies can have important effects on bacteria and may aid host defenses, even in the absence of direct microbial killing, the effect of brief sublethal exposures to amphotericin B on Candida albicans blastoconidia was evaluated. Amphotericin B (0.01-1.0 micrograms/ml for 60 min) inhibited germ tube formation and yeast adherence to both serum-coated plastic surfaces and fibrin matrices. These effects were not reversed by cation (K+ or Mg++) supplementation. Amphotericin B pretreatment accelerated clearance of C. albicans from the peritoneal surfaces of mice and reduced the inflammatory stimulus associated with this clearance, at least as measured by neutrophil influx. However, pretreatment did not facilitate killing of C. albicans by either neutrophils or monocytes in vitro. Thus sublethal concentrations of amphotericin B inhibit two activities of C. albicans that probably contribute to surface colonization and tissue invasion. These results provide one explanation for the clinical benefits observed with short courses of amphotericin B therapy for surface-limited candidal infections (e.g., esophagitis).
Chlorpromazine was tested for antifungal activity by using Candida albicans and standard assays. The MIC of chlorpromazine was 35 micrograms/ml; the minimal fungicidal concentration was also 35 micrograms/ml. The minimal effective concentration was 2.2 to 3.5 micrograms/ml (using assays based on quantitative cultures and growth). There was a slight positive interaction between chlorpromazine and amphotericin B but no interaction between chlorpromazine and rifampin. Chlorpromazine also inhibited C. krusei, C. parapsilosis, C. tropicalis, and Torulopsis glabrata. We conclude that phenothiazines have direct anti-Candida activity and that these drugs appear to have a broad antimicrobial spectrum.
To further delineate the mechanisms underlying murine pulmonary defenses against bacterial infection, we studied the effects of antioxidant enzymes and hydroxyl radical scavengers on pulmonary clearance processes. Intratracheal injection of catalase and superoxide dismutase resulted in prolonged intraalveolar residence of the enzymes, but caused no decrease in rates of clearance of either Staphylococcus aureus 502A or Pseudomonas aeruginosa PAO1. In contrast, dimethylsulfoxide and dimethylthiourea caused significant depression of clearance of P. aeruginosa without altering clearance of S. aureus. These results provide further differentiation between clearance processes affecting gram-negative and gram-positive bacteria and suggest that murine clearance of gram-negative organisms may be in part mediated by reactions which generate hydroxyl anion. In vivo administration of agents which inhibit hydrogen peroxide-, superoxide-, or hydroxyl anion-mediated reactions do not alter normal clearance of S. aureus.
Alveolar macrophages were isolated by bronchoalveolar lavage from normal subjects to determine whether these cells can be activated to produce interferon. Macrophages were incubated for 24 h, and the supernatants were assayed for interferon using a plaque reduction assay (vesicular stomatitis virus and human amnion cells). The macrophages did not spontaneously release detectable amounts of interferon, but macrophages stimulated with either mitogens or classic inducers did release antiviral activity (titer range, 32 to 962 units/ml). Interferon activity was detectable after 4h incubation. In general, macrophages that responded to one stimulating agent responded to all tested, and concanavalin A (25 micrograms/ml) produced the highest titer (mean, 335 units/ml). Peripheral blood lymphocytes at cell densities (1 X 10(5)/ml) comparable to that present in the macrophage suspension did not produce detectable amounts of interferon using identical culture and assay conditions. There was no difference between monocytes and alveolar macrophages in the amounts of interferon produced after 24 h, and there was also no apparent effect of cigarette smoking on the production of interferon by alveolar macrophages. Alveolar macrophages appeared to release gamma-interferon with mitogen stimulation (Con A) and alpha-interferon with UV-inactivated influenza A virus stimulation. We conclude that stimulated human alveolar macrophages can secrete both alpha- and gamma-interferon. This capacity for interferon production by alveolar macrophages may have important implications for antiviral defenses in the lung and may modulate certain pulmonary inflammatory and immune processes.