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Biomedical subjects

M D Roth

Publications and source records attributed to M D Roth.

At least 37 records · Page 2Linked to original sources
PubMed1997

Acute activation of circulating polymorphonuclear neutrophils following in vivo administration of cocaine. A potential etiology for pulmonary injury.

Crack cocaine has become a major drug of abuse in the United States and its use is associated with a broad spectrum of pulmonary complications. The present study was conducted to determine whether controlled in vivo administration of cocaine (inhaled or IV) alters the function of circulating inflammatory cells in a manner capable of contributing to acute lung injury. Subjects who regularly smoked crack cocaine were asked to abstain from illicit drug use for at least 8 h, and were then administered one of the following treatments on each of 4 study days: inhaled cocaine base (45 mg), inhaled placebo (4.5 mg cocaine base, a subphysiologic dose), IV cocaine HCl (0.35 to 0.50 mg/kg), or IV placebo (saline solution). Samples of blood were obtained from a peripheral venous catheter and blood cells were isolated before and 10 to 45 min after treatment. The administration of either cocaine base or cocaine HCl, but not their corresponding placebos, resulted in the activation of circulating polymorphonuclear neutrophils (PMNs). Exposure to cocaine in vivo enhanced the antibacterial activity of PMNs, as measured by their ability to kill Staphylococcus aureus. Antitumor activity, as measured in an antibody-dependent cell-mediated cytotoxicity assay, also increased following short-term administration of cocaine. Finally, short-term exposure to cocaine enhanced production of interleukin 8, a potent PMN chemoattractant and neutrophil-activating factor associated with both acute and chronic lung injury. These studies demonstrate that short-term in vivo exposure to cocaine activates the effector function and cytokine production of circulating PMNs. Therefore, it is possible that bursts of acute inflammatory activity resulting from crack use could contribute to lung injury.

Administration, Inhalation↗
PubMed1997

Tracheobronchial histopathology in habitual smokers of cocaine, marijuana, and/or tobacco.

BACKGROUND: Marijuana and alkaloidal cocaine ("crack") are the two most commonly smoked substances in the United States after tobacco. While regular tobacco smoking has been found to be associated with extensive microscopic alterations in bronchial mucosa, little information is available concerning the effect of crack cocaine and marijuana on tracheobronchial histopathology. STUDY OBJECTIVE: To determine the relative impact of smoked substances (cocaine, marijuana, and tobacco) alone and in combination on the histopathology of the tracheobronchial mucosa and to assess whether the effects of habitual smoking of two or more substances (cocaine, marijuana, and/or tobacco) are additive. DESIGN: Observational cohort study. SUBJECTS: Fifty-three nonsmoking control subjects (NS), 14 current, habitual smokers of crack cocaine only (CS), 40 current, regular smokers of marijuana only (MS), 31 regular smokers of tobacco only (TS), 16 current smokers of both cocaine and marijuana (CMS), 12 current smokers of both cocaine and tobacco (CTS), 44 current smokers of both marijuana and tobacco (MTS), and 31 current smokers of cocaine, marijuana, and tobacco (CMTS). METHODS: After preliminary screening evaluation, including a detailed respiratory and general health questionnaire and routine pulmonary function studies, subjects underwent fiberoptic bronchoscopy with endobronchial biopsies of the mucosa of the primary carina and randomly selected secondary or tertiary carinae. Biopsy specimens were processed for light microscopy, stained with hematoxylin-eosin or periodic acid-Schiff, and examined to assess epithelial, basement membrane, and submucosal alterations by one or two pathologists who were masked to the smoking status of the subject. RESULTS: Smokers of cocaine, marijuana, or tobacco alone all exhibited more frequent abnormalities than NS in 10 (CS) or all 11 (MS and TS) of the histopathologic features assessed. For most features, MS and TS showed significantly more frequent alterations than NS (p < or = 0.02), while CS showed significantly more frequent abnormalities than NS in only three features (p<0.05) and nearly significant differences from NS in two additional features (p < or = 0.09). Alterations were noted most frequently in CTS (six features) and MTS (three features), while abnormalities were relatively infrequent in CMS. For 10 features, MTS had more frequent alterations than MS and TS. With a single exception, CMTS did not show more frequent alterations than CTS or MTS. CONCLUSION: Marijuana and tobacco smoking each produces significant bronchial mucosal histopathology and the effects of marijuana and tobacco appear additive. Cocaine appears to lead to fewer significant bronchial mucosal alterations than marijuana or tobacco when smoked alone and does not add to the changes associated with marijuana. When smoked together with tobacco, however, cocaine appears to augment the bronchial injury caused by tobacco smoking.

Adult↗
PubMed1996

Human CD14+ leukocytes acquire the phenotype and function of antigen-presenting dendritic cells when cultured in GM-CSF and IL-4.

The combination of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) induces the growth of antigen-presenting cells (APC) from adherent peripheral blood leukocytes. These cells have been characterized as dendritic cells (DC), yet many questions exist regarding their relationship to other DC populations and the nature of their progenitors. To address these issues, we utilized a combination of immunomagnetic depletion, cell sorting, and cell culture to isolate four distinct APC populations; macrophages expressing high levels of CD14 (CD14bright macrophages), DC produced by culturing adherent cells in GM-CSF and IL-4 (cultured DC), and two different subsets of fresh DC that express low levels of CD14 (CD14dim DC). Each population exhibited a unique morphology and a unique profile of cell surface markers. In contrast to macrophages,all three DC populations expressed the DC marker CD83, as well as highlevels of MHC molecules and the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). In addition. all three DC populations presented soluble tetanus toxin antigen and stimulated T cell proliferation to levels far superior to that of macrophages. Blocking studies demonstrated a costimulatory role for B7-1, B7-2, and CD40 in antigen presentation, although B7-2 expression was the single most important factor. To identify the progenitors of cultured DC, we sorted the adherent fraction of PBMC into discrete subpopulations prior to exposure to GM-CSF and IL-4. DC activity derived entirely from CD14+ precursors and was equally demonstrable using either the CD14dim or CD14bright subsets. Although these DC precursors lost expression of CD14 in culture, they maintained most of their other myeloid features. We conclude that human CD14+ leukocytes acquire the phenotype and function of DC when cultured in GM-CSF and IL-4.

Antibodies↗
PubMed1995

Effects of smoking marijuana, tobacco or cocaine alone or in combination on DNA damage in human alveolar macrophages.

This study examined the role of marijuana smoking in the pathogenesis of human lung cancer by measuring DNA damage in alveolar macrophages (AM). The alkaline unwinding method was used to determine DNA single-strand breaks in AM lavaged from non-smokers [NS] and smokers of marijuana [MS], tobacco [TS] or cocaine [CS], either alone or in combination. DNA damage was related to superoxide anion (O2-) production by AM stimulated with phorbol myristate acetate (PMA) and to nitric oxide content of smoke using cellular nitrite (NO2-) concentrations. The percentage of double-stranded DNA present after alkaline unwinding was higher in AM of NS (41 +/- 5% [11]) and CS (41 +/- 4% [9]) versus that of MS (31 +/- 4% [8]), TS (35 +/- 3% [11]), MTS (26 +/- 4% [3]), and CTS (27 +/- 5%* [10]), mean +/- SEM [n], * = p < 0.1 vs. NS). PMA stimulated O2- production by AM from NS and CS was lower than that of other smokers, but the differences were not significant. O2- release, however, had an inverse correlation with DNA single-strand breaks (r = -0.38, p = 0.009). Nitrite content of AM from NS and CS was less than that of other smokers' cells (p < 0.1 for TS & CTS vs. NS), but DNA damage had no relationship to NO2- concentration. We conclude that AM recovered from MS, either alone or in combination with tobacco smoking, show a trend towards DNA damage. Studies utilizing a larger population should verify our findings and further define its relationship to enhanced oxidant production by macrophages.

Cocaine↗
PubMed1994

Interleukin 2 induces the expression of CD45RO and the memory phenotype by CD45RA+ peripheral blood lymphocytes.

The CD45RA and CD45RO isoforms of the leukocyte common antigen identify functionally distinct "naive" and "memory" T cell subsets. While antigenic and mitogenic stimuli are known to initiate transition from the naive to memory state, little is known about the role of cytokines in this process. This report demonstrates that in vitro exposure of purified CD45RA+/CD45RO- peripheral blood lymphocytes (PBL) to interleukin 2 (IL-2) promotes their conversion to the CD45RA-/CD45RO+ phenotype. Conversion to CD45RO occurs for both the CD3+ and CD3-/CD56+ lymphocyte subsets, but occurs more rapidly, and at lower IL-2 concentrations, in the CD3-/CD56+ population. Expression of CD45RO was observed only in response to IL-2 and was not observed during long-term culture in IL-4, IL-6, or IL-7. We also examined the effect of IL-2 on the expression of adhesion molecules by T cells. The expression of CD2, CD11a, and CDw29 increased, and expression of Leu-8 (LAM-1) decreased, on cultured CD45RA+/CD45RO- cells after they converted to expression of CD45RO. In contrast, lymphocytes that remained CD45RA+/CD45RO- after 10 d in culture exhibited no change from their baseline adhesion molecule profile. Finally, to test the role of endogenous IL-2 during T cell activation we stimulated CD45RA+/CD45RO- PBL with immobilized anti-CD3 in the presence of neutralizing anti-IL-2 antibody and/or cyclosporin A. Both agents significantly reduced the expression of CD45RO and the effect of cyclosporin A was reversed by exogenous IL-2. We conclude that IL-2 promotes CD45RA+ cells to express the memory phenotype and is a mediator of CD45RO expression after stimulation of the T cell receptor/CD3 complex.

Cells, Cultured↗
PubMed1993

Human pulmonary macrophages utilize prostaglandins and transforming growth factor beta 1 to suppress lymphocyte activation.

The ability to activate peripheral blood lymphocytes (PBLs) in vitro with interleukin-2 (IL-2) is suppressed by the presence of autologous human pulmonary alveolar macrophages (AMs). AMs suppress both IL-2-induced proliferation and the induction of lymphokine-activated killer cell (LAK) activity in a dose-dependent manner (79 +/- 6% suppression of LAK activity at a 0.25:1 AM/PBL ratio). Increasing the IL-2 concentration increased baseline LAK activity but did not prevent AM-mediated suppression. At least two different mechanisms of suppression were observed, one diffusible in nature and the other contact dependent. Indomethacin prevented the component of inhibition that diffused across porous polycarbonate membranes, indicating prostaglandins as the diffusible inhibitor. In contrast, indomethacin had no effect when added alone into conventional AM-PBL cocultures, but a combination of indomethacin and anti-transforming growth factor beta 1 (TGF-beta 1) antibody did prevent inhibition. This result suggests that TGF-beta 1 acts as an additional contact-dependent inhibitor. PBLs that were rendered unresponsive to IL-2 completely recovered their responsiveness within 4 days after removing AMs from the coculture. These features suggest that pulmonary macrophages have multiple mechanisms for locally suppressing IL-2 responses and lymphocyte activation.

Adult↗
PubMed1993

Expression of CD45 isoforms in fresh and IL-2-cultured tumor-infiltrating lymphocytes from basal cell carcinoma.

Immunohistochemistry and flow cytometry analyses were performed to characterize the specific T cell subpopulations infiltrating basal cell carcinomas (BCC) and to determine their phenotypic response to in vitro expansion with IL-2. Tumor-infiltrating lymphocytes (TIL) within BCC predominantly expressed the CD45RO (activated or "memory") phenotype (65 +/- 3%) and the percentage of TIL expressing CD45RO consistently increased when cultured in vitro with IL-2 (85 +/- 5%). In comparison, fresh normal peripheral blood lymphocytes predominantly expressed the CD45RA (naive) phenotype (79 +/- 4%), but shifted to the expression of CD45RO following in vitro expansion in IL-2 (86 +/- 6%). To determine whether IL-2 alone, in the absence of antigen or mitogen, can promote naive lymphocytes to convert from the expression of the CD45RA isoform to the CD45RO isoform, we cultured purified CD45RA+ lymphocytes in IL-2. After three weeks in culture, 90% of the lymphocytes expressed exclusively CD45RO. We conclude that tumor-infiltrating lymphocytes from BCC predominantly express CD45RO and that this expression may represent specific antigen stimulation and/or in situ activation by cytokines.

Adult↗
PubMed1993

Pulmonary macrophages suppress the proliferation and cytotoxicity of tumor-infiltrating lymphocytes.

Adoptive immunotherapy with interleukin-2 and tumor-infiltrating lymphocytes (TIL) is rarely effective in primary lung cancer. We hypothesize that pulmonary macrophages (PM), which are increased substantially in the lungs of smokers, might suppress TIL function. The addition of PM into the TIL cytotoxicity assay produced a concentration-dependent suppression of TIL cytotoxicity with up to 71% inhibition of autologous tumor killing at the 1:1 PM:TIL ratio. Inhibition was not target-specific, as killing of NK-sensitive (K562), NK-resistant (M14), and autologous tumor targets were equally suppressed. Nor was inhibition specific for lung TIL, as similar inhibition was observed with melanoma and renal TIL. Using a model system, we demonstrated that both CD3+ antigen-specific and CD56+ nonspecific lymphocytes are susceptible to the suppressive effects of the PM. Direct co-incubation of PM and TIL for 4 to 44 h resulted in progressive suppression of TIL proliferation and cytotoxicity. TIL cytotoxicity remained suppressed even if PM were removed from the co-culture after 24 h, but was restored if the separated TIL were re-incubated in interleukin-2. These results suggest that PM may locally regulate the proliferative and cytotoxic function of adoptively transferred TIL.

Cell Communication↗
PubMed1993

Pulmonary surfactant inhibits interleukin-2-induced proliferation and the generation of lymphokine-activated killer cells.

The generation of lymphokine-activated killer (LAK) cell activity and the proliferative response to human recombinant interleukin-2 (IL-2) were significantly reduced when either human peripheral blood lymphocytes (PBL) or purified CD56+/CD3- lymphocytes were cultured in the presence of pulmonary surfactant. Surfactant concentrations ranging between 30 and 500 micrograms/ml produced increasing levels of inhibition ranging from 20 to 95%. For any given concentration of surfactant, increasing the IL-2 concentration produced increasing levels of LAK activity but never overcame the suppressive effects of the surfactant. Time course studies demonstrated that surfactant is inhibitory only if added to PBL during the first 2 days of IL-2 culture, suggesting a preferential action during the induction phase of LAK activity. Pretreatment of PBL with surfactant for as little as 2 to 4 h inhibited their subsequent response to IL-2 culture, suggesting that inhibition is rapid, persistent, and directly due to alterations in PBL responsiveness. To determine if surfactant alters cell membrane function, we measured the effects of surfactant exposure on LAK:tumor binding. Binding of LAK cells to both K562 and M14 tumor targets was inhibited in a concentration-dependent manner. Concurrently, we observed a reduced expression of IL-2 alpha-chain receptors on surfactant-treated CD56+/CD3- cells and a dramatic reduction in the expression of adhesion molecules including CD2, LFA-1, LFA-3, and ICAM-1. We conclude that pulmonary surfactant has the potential to suppress cytotoxic and proliferative responses to IL-2, alters cell-to-cell interactions, and reduces the expression of activation and adhesion molecules on LAK cells.

Adult↗
PubMed1993

Inhibition of natural killer cell activity by therapeutic levels of theophylline.

Theophylline, as used for the treatment of asthma and chronic obstructive pulmonary disease, may have several effects, including direct bronchodilation, improvement in diaphragmatic and ciliary function, and possibly immune modulation. In this study, we quantified the capacity for theophylline to inhibit natural killer (NK) cells and investigated the mechanism(s) that mediate this inhibition. Theophylline at 10 micrograms/ml and 20 micrograms/ml inhibited the tumoricidal activity of isolated peripheral blood lymphocytes (PBL) by 19 +/- 5% and 36 +/- 6%, respectively (n = 6). Using fluorescence-activated cell sorting, we purified NK cells from PBL and tested theophylline's effects on the kinetics of tumor lysis (Vmax) and on tumor binding. Theophylline at 20 micrograms/ml reduced Vmax by 40 +/- 9% but had no effect on tumor binding. We compared the effects of theophylline, which is both a phosphodiesterase (PDE) inhibitor and an adenosine receptor (AdR) antagonist, with agents that range from relatively pure AdR antagonists to pure PDE inhibitors. Inhibition of NK activity occurred only with PDE inhibitors. We also extracted lymphocyte PDE and observed a direct correlation (r2 = 0.99) between theophylline's activity as a PDE inhibitor and its capacity to inhibit NK activity. These results suggest that theophylline inhibits NK cytotoxicity through its activity as a PDE inhibitor. The clinical relevance of these findings awaits further study.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Marijuana smoking, pulmonary function, and lung macrophage oxidant release.

Pulmonary alveolar macrophages lavaged from tobacco smokers release increased levels of oxidants and have been implicated in the pathophysiology of emphysema. It is unknown whether lung macrophages recovered from marijuana smokers also liberate excessive levels of oxidants. To evaluate this possibility, pulmonary alveolar macrophages were obtained by bronchoalveolar lavage from nonsmokers, smokers of marijuana only, smokers of tobacco only, and smokers of tobacco plus marijuana. Spontaneous and stimulated superoxide anion release was measured by the superoxide dismutase-inhibitable reduction of ferricytochrome c. These findings were correlated with recent lung function tests. Superoxide anion production by macrophages, studies of small airway integrity (closing volume, closing capacity, and the slope of Phase III of the single-breath nitrogen washout curve), and evaluation of alveolar gas exchange (diffusing capacity of carbon monoxide) were similar in both nonsmokers and marijuana smokers. However, tobacco smoking was associated with both significantly higher levels of superoxide anion release by pulmonary alveolar macrophages and significant abnormalities of small airway function and alveolar diffusing capacity. Based on the results of this study, pulmonary alveolar macrophages of marijuana-only smokers do not produce increased amounts of oxidants when compared to macrophages of non-smoking subjects. This observation may account for the absence of abnormalities in small airway function and alveolar diffusing capacity in marijuana-only smokers, in contrast to the presence of such findings in smokers of tobacco, regardless of marijuana use.

Adult↗
PubMed1991

Antimicrobial and respiratory burst characteristics of pulmonary alveolar macrophages recovered from smokers of marijuana alone, smokers of tobacco alone, smokers of marijuana and tobacco, and nonsmokers.

Rodent studies indicate that marijuana smoke can adversely affect the antimicrobial function of pulmonary alveolar macrophages (PAM). To evaluate whether marijuana smoke similarly affects human PAM, we compared phagocytosis, fungistatic/fungicidal activity, and superoxide anion (O2-) production of PAM recovered from marijuana smokers (MS), tobacco smokers (TS), marijuana and tobacco smokers (MTS), and nonsmokers (NS). Although PAM from the four groups were equally capable of ingesting Candida albicans, the macrophages from smokers differed from normal PAM in their ability to restrict intracellular yeast germination (ungerminated candida in smokers' PAM = 68 +/- 3% [46] versus NS = 54 +/- 6% [17], mean +/- SEM [n], p = 0.022). Despite heightened fungistatic activity, PAM from MS and TS destroyed significantly fewer intracellular yeast (28 +/- 2 and 29 +/- 2%, respectively) after 4 h than did macrophages recovered from NS (40 +/- 4%, p less than 0.05). Both basal and stimulated (dihydrocytochalasin B + opsonized zymosan or phorbol myristate acetate) O2- production were similar in PAM from MS and NS, but significantly increased in PAM from TS (p less than 0.05). Our findings indicate that marijuana smoking does not alter the phagocytic behavior or the respiratory burst of human PAM, but marijuana smoking does decrease the ability of human PAM to destroy ingested Candida albicans. These findings contrast with the effects of tobacco smoking, which not only decreases the fungicidal activity of human PAM but also increases their respiratory burst.

Adult↗
PubMed1989

Inhibition of lymphokine-activated killer cell function by human alveolar macrophages.

Tissue- and organ-specific factors may be important in the regulation of cytotoxic lymphocytes. We therefore examined the ability of human alveolar macrophages (AMs) to alter the tumoricidal function of lymphokine-activated killer cells (LAK cells). AMs, obtained by bronchoalveolar lavage from healthy volunteers, or peripheral blood monocytes were added to a standard 4-h chromium release LAK assay at varying concentrations. AMs severely inhibited the killing of both NK-sensitive (K562) and NK-resistant (M14) tumor cells [42 +/- 2.6% (SEM) inhibition of M14 killing at the 0.125:1 AM:LAK ratio and 83 +/- 2.3% inhibition at the 1:1 ratio, n = 9]. Peripheral blood monocytes, in contrast, were only one-eighth as inhibitory as AMs. A positive smoking history was associated with a 3- to 7-fold increase in the number of AMs recovered by bronchoalveolar lavage but had no effect on the inhibition produced per AM cell. The mechanism of inhibition was investigated. Formalin fixation produced an 8-fold reduction in the inhibitory capacity of AMs, suggesting the need for active metabolism or an intact cell membrane. No soluble mediator could be detected with a two-chamber Transwell system, in 24-h AM culture supernatants, or following blocking experiments with indomethacin, catalase, or superoxide dismutase. Binding studies demonstrated selective binding between LAK cells and AMs, yet AMs were not susceptible to LAK-mediated lysis under the usual assay conditions. In summary, AMs are potent inhibitors of in vitro LAK function. Inhibition requires direct cell contact and is independent of soluble reactive oxygen species, prostaglandins, or activation by tobacco smoking. Inhibition is not due to lysis of the AM as a competitive cold target. These results suggest that AMs may actively limit antitumor cytotoxic responses in the lung.

Cell Communication↗
PubMed1988

Gas flow through a bronchopleural fistula. Measuring the effects of high-frequency jet ventilation and chest-tube suction.

High-frequency jet ventilation (HFJV) is FDA-approved for ventilating patients with bronchopleural fistulae (BPF), yet little is known about its effect on the fistula airleak. We quantitated a patient's BPF airleak during both conventional volume-cycled ventilation and HFJV. The effect of chest-tube suction (CTS) on BPF flow was also studied. Despite a significant reduction in peak airway pressure, the HFJV resulted in a 50-70 percent increase in BPF flow. CTS also significantly increased the airleak. HFJV may not always be the preferential method for ventilating patients with BPF and we recommend measuring the fistula airleak when attempting to optimize a patient's ventilatory parameters.

Adult↗
PubMed1988

Maxillary dental arch dimensions following pharyngeal-flap surgery.

Pharyngeal-flap surgery (PFS) is a surgical procedure utilized in the treatment of hypernasal speech. The purpose of this study was to evaluate the effect of PFS on the maxillary dental arch. Sixteen patients who had undergone PFS between the ages of 5 and 7 years were selected from the longitudinal growth study of the Lancaster Cleft Palate Clinic. Eight points were marked on the occlusal surfaces of serial maxillary dental models to determine arch width and length. These data were compared to a matched sample of patients from the same growth study who did not undergo PFS. The flap group demonstrated significant reduction in both arch width (at cuspids and molars) and arch length development compared to the control sample, following PFS. These results are not inconsistent with an hypothesis of dental-arch form changes related to possible airway obstruction following PFS, although data on the latter were not available on this sample.

Airway Resistance↗