Biomedical subjects

Michael Weiden

Publications and source records attributed to Michael Weiden.

14 recordsLinked to original sources

PubMed2006

Pulmonary function after exposure to the World Trade Center collapse in the New York City Fire Department.

RATIONALE: On September 11, 2001, the World Trade Center collapse created an enormous urban disaster site with high levels of airborne pollutants. First responders, rescue and recovery workers, and residents have since reported respiratory symptoms and developed pulmonary function abnormalities. OBJECTIVES: To quantify respiratory health effects of World Trade Center exposure in the New York City Fire Department. MEASUREMENTS: Longitudinal study of pulmonary function in 12,079 New York City Fire Department rescue workers employed on or before 09/11/2001. Between 01/01/1997 and 09/11/2002, 31,994 spirometries were obtained and the FEV(1) and FVC were analyzed for differences according to estimated World Trade Center exposure intensity. Adjusted average FEV(1) during the first year after 09/11/2001 was compared with the 5 yr before 09/11/2001. Median time between 09/11/2001 and a worker's first spirometry afterwards was 3 mo; 90% were assessed within 5 mo. MAIN RESULTS: World Trade Center-exposed workers experienced a substantial reduction in adjusted average FEV(1) during the year after 09/11/2001 (372 ml; 95% confidence interval, 364-381 ml; p < 0.001) This exposure-related FEV(1) decrement equaled 12 yr of aging-related FEV(1) decline. Moreover, exposure intensity assessed by initial arrival time at the World Trade Center site correlated linearly with FEV(1) reduction in an exposure intensity-response gradient (p = 0.048). Respiratory symptoms also predicted a further FEV(1) decrease (p < 0.001). Similar findings were observed for adjusted average FVC. CONCLUSIONS: World Trade Center exposure produced a substantial reduction in pulmonary function in New York City Fire Department rescue workers during the first year after 09/11/2001.

Adult↗

PubMed2005

Interleukin-10 induces inhibitory C/EBPbeta through STAT-3 and represses HIV-1 transcription in macrophages.

Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN.

Animals↗

PubMed2005

Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the World Trade Center collapse.

BACKGROUND: The collapse of the World Trade Center (WTC) on September 11, 2001 created a large-scale disaster site in a dense urban environment. In the days and months thereafter, thousands of rescue/recovery workers, volunteers, and residents were exposed to a complex mixture of airborne pollutants. METHODS: We review current knowledge of aerodigestive inhalation lung injuries resulting from this complex exposure and present new data on the persistence of nonspecific bronchial hyperreactivity (methacholine PC20 < or =8 mg/mL) in a representative sample of 179 Fire Department of the City of New York (FDNY) rescue workers stratified by exposure intensity (according to arrival time) who underwent challenge testing at 1, 3, 6, and 12 months post-collapse. RESULTS: Aerodigestive tract inflammatory injuries, such as declines in pulmonary function, reactive airways dysfunction syndrome (RADS), asthma, reactive upper airways dysfunction syndrome (RUDS), gastroesophageal reflux disease (GERD), and rare cases of inflammatory pulmonary parenchymal diseases, have been documented in WTC rescue/recovery workers and volunteers. In FDNY rescue workers, we found persistent hyperreactivity associated with exposure intensity, independent of airflow obstruction. One year post-collapse, 23% of highly exposed subjects were hyperreactive as compared with only 11% of moderately exposed and 4% of controls. At 1 yr, 16% met the criteria for RADS. CONCLUSIONS: While it is too early to ascertain all of the long-term effects of WTC exposures, continued medical monitoring and treatment is needed to help those exposed and to improve our prevention, diagnosis, and treatment protocols for future disasters.

Air Pollutants↗

PubMed2004

Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages.

Opportunistic infections such as pulmonary tuberculosis (TB) increase local HIV-1 replication and mutation. As AIDS progresses, alteration of the HIV-1 gp120 V3 sequence is associated with a shift in viral coreceptor use from CCR5 (CD195) to CXCR4 (CD184). To better understand the effect of HIV/TB coinfection, we screened transcripts from bronchoalveolar lavage cells with high density cDNA arrays and found that CXCR4 mRNA is increased in patients with TB. Surprisingly, CXCR4 was predominately expressed on alveolar macrophages (AM). Mycobacterium tuberculosis infection of macrophages in vitro increased CXCR4 surface expression, whereas amelioration of disease reduced CXCR4 expression in vivo. Bronchoalveolar lavage fluid from TB patients had elevated levels of CCL4 (macrophage inflammatory protein-1beta), CCL5 (RANTES), and CX3CL1 (fractalkine), but not CXCL12 (stromal-derived factor-1alpha). We found that M. tuberculosis infection of macrophages in vitro increased viral entry and RT of CXCR4-using [corrected] HIV-1, but not of CCR5-using [corrected] HIV-1. Lastly, HIV-1 derived from the lung contains CD14, suggesting that they were produced in AM. Our results demonstrate that TB produces a permissive environment for replication of CXCR4-using virus by increasing CXCR4 expression in AM and for suppression of CCR5-using HIV-1 by increasing CC chemokine expression. These changes explain in part why TB accelerates the course of AIDS. CXCR4 inhibitors are a rational therapeutic approach in HIV/TB coinfection.

Amino Acid Sequence↗

PubMed2004

Posttranscriptional inhibition of gene expression by Mycobacterium tuberculosis offsets transcriptional synergism with IFN-gamma and posttranscriptional up-regulation by IFN-gamma.

Host defense against Mycobacterium tuberculosis requires the cytokine IFN-gamma and IFN regulatory factor 1 (IRF-1), a transcription factor that is induced to high levels by IFN-gamma. Therefore, we chose to study regulation of IRF-1 expression as a model for effects of M. tuberculosis on response to IFN-gamma. We found that IRF-1 mRNA abundance increased far more than transcription rate in human monocytic THP-1 cells stimulated by IFN-gamma, but less than transcription rate in cells infected by M. tuberculosis. IFN-gamma stimulation of infected cells caused a synergistic increase in IRF-1 transcription, yet IRF-1 mRNA abundance was similar in uninfected and infected cells stimulated by IFN-gamma, as was the IRF-1 protein level. Comparable infection by Mycobacterium bovis bacillus Calmette-Guérin failed to induce IRF-1 expression and had no effect on the response to IFN-gamma. We also examined the kinetics of transcription, the mRNA t(1/2), and the distribution of IRF-1 transcripts among total nuclear RNA, poly(A) nuclear RNA, and poly(A) cytoplasmic RNA pools in cells that were infected by M. tuberculosis and/or stimulated by IFN-gamma. Our data suggest that infection by M. tuberculosis inhibits RNA export from the nucleus. Moreover, the results indicate that regulated entry of nascent transcripts into the pool of total nuclear RNA affects IRF-1 expression and that this process is stimulated by IFN-gamma and inhibited by M. tuberculosis. The ability of infection by M. tuberculosis to limit the increase in IRF-1 mRNA expression that typically follows transcriptional synergism may contribute to the pathogenicity of M. tuberculosis.

Active Transport, Cell Nucleus↗

PubMed2004

Induced sputum assessment in New York City firefighters exposed to World Trade Center dust.

New York City Firefighters (FDNY-FFs) were exposed to particulate matter and combustion/pyrolysis products during and after the World Trade Center (WTC) collapse. Ten months after the collapse, induced sputum (IS) samples were obtained from 39 highly exposed FDNY-FFs (caught in the dust cloud during the collapse on 11 September 2001) and compared to controls to determine whether a unique pattern of inflammation and particulate matter deposition, compatible with WTC dust, was present. Control subjects were 12 Tel-Aviv, Israel, firefighters (TA-FFs) and 8 Israeli healthcare workers who were not exposed to WTC dust. All controls volunteered for this study, had never smoked, and did not have respiratory illness. IS was processed by conventional methods. Retrieved cells were differentially counted, and metalloproteinase-9 (MMP-9), particle size distribution (PSD), and mineral composition were measured. Differential cell counts of FDNY-FF IS differed from those of health care worker controls (p < 0.05) but not from those of TA-FFs. Percentages of neutrophils and eosinophils increased with greater intensity of WTC exposure (< 10 workdays or greater than or equal to 10 workdays; neutrophils p = 0.046; eosinophils p = 0.038). MMP-9 levels positively correlated to neutrophil counts (p = 0.002; r = 0.449). Particles were larger and more irregularly shaped in FDNY-FFs (1-50 microm; zinc, mercury, gold, tin, silver) than in TA-FFs (1-10 microm; silica, clays). PSD was similar to that of WTC dust samples. In conclusion, IS from highly exposed FDNY-FFs demonstrated inflammation, PSD, and particle composition that was different from nonexposed controls and consistent with WTC dust exposure.

Adult↗

PubMed2004

[Molecular pathogenesis in tuberculosis complicated with AIDS].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP beta, activated NF-kappaB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappaB, further enhancing the HIV-1 LTR.

AIDS-Related Opportunistic Infections↗

PubMed2003

Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center.

New York City Fire Department rescue workers experienced massive exposure to airborne particulates at the World Trade Center site. Aims of this longitudinal study were to (1) determine if bronchial hyperreactivity was present, persistent, and independently associated with exposure intensity, (2) identify objective measures shortly after the collapse that would predict persistent hyperreactivity and a diagnosis of reactive airways dysfunction 6 months post-collapse. A representative sample of 179 rescue workers stratified by exposure intensity (high, moderate, and control) without current smoking or prior respiratory disease was enrolled. Highly exposed workers arrived within 2 hours of collapse, moderately exposed workers arrived later on Days 1-2; control subjects were not exposed. Hyperreactivity at 1, 3, and 6 months post-collapse was associated with exposure intensity, independent of ex-smoking and airflow obstruction. Six months post-collapse, highly exposed workers were 6.8 times more likely than moderately exposed workers and control subjects to be hyperreactive (95% confidence interval, 1.8-25.2; p = 0.004), and hyperreactivity persisted in 55% of those hyperreactive at 1 and/or 3 months. In highly exposed subjects, hyperreactivity 1 or 3 months post-collapse was the sole predictor for reactive airways dysfunction (p = 0.021). In conclusion, development and persistence of hyperreactivity and reactive airways dysfunction were strongly and independently associated with exposure intensity. Hyperreactivity shortly post-collapse predicted reactive airways dysfunction at 6 months in highly exposed workers; this has important implications for disaster management.

Adult↗

PubMed2003

Recombinant gamma interferon stimulates signal transduction and gene expression in alveolar macrophages in vitro and in tuberculosis patients.

Tuberculosis is the seventh leading cause of morbidity and mortality in the world, with eight million cases per year. Animal and human studies demonstrate an enrichment of CD4 cells at sites of disease, with a more favorable clinical course when there is a Th1 response with the presence of gamma interferon (IFN-gamma). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-gamma (rIFN-gamma) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-gamma would induce signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) binding activity in alveolar macrophages (AM). AM treated in vitro showed clear upregulation of STAT-1 and IRF-1 by rIFN-gamma. STAT-1 was not activated and IRF-1 was only weakly induced after 1 day of infection by Mycobacterium tuberculosis TN913. In bronchoalveolar lavage (BAL) cells obtained from 10 of 10 tuberculosis patients 10 +/- 2 days post-antituberculosis treatment, there was no detectable STAT-1 or IRF-1 DNA-binding activity. After 4 weeks of treatment with rIFN-gamma aerosol in addition to the antituberculosis drugs, 10 of 10 patients had increased STAT-1, IRF-1, and/or IRF-9 DNA-binding activity in BAL cells from lung segments shown radiographically to be involved and in those shown to be uninvolved. Symptoms and chest radiographs improved, and amounts of macrophage inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) viral loads (in five of five HIV-1-coinfected patients) declined in the second BAL specimens. rIFN-gamma aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial.

AIDS-Related Opportunistic Infections↗

PubMed2003

Inhibition of response to alpha interferon by Mycobacterium tuberculosis.

We previously reported that infection by Mycobacterium tuberculosis, the causative agent of tuberculosis, leads to secretion of alpha/beta interferon (IFN-alpha/beta). While IFN-alpha/beta ordinarily stimulates formation of signal transducer and stimulator of transcription-1 (STAT-1) homodimers and IFN-stimulated gene factor-3 (ISGF-3), only ISGF-3 is found in infected human monocytes and macrophages. We have now investigated the basis for this unusual profile of transcription factor activation and its consequences for regulation of transcription, as well as the impact of infection on response to IFN-alpha. After infection, IFN-alpha stimulation of STAT-1 homodimers is inhibited in monocytes and macrophages, while stimulation of ISGF-3 increases in monocytes but tends to decline in macrophages. Effects of infection on the abundance of ISGF-3 subunits, STAT-1, STAT-2, and interferon regulatory factor 9, and on tyrosine phosphorylation of STAT-1 and STAT-2 explain the observed changes in DNA-binding activity, which correlate with increased or inhibited transcription of genes regulated by ISGF-3 and STAT-1. Infection by Mycobacterium bovis BCG does not inhibit IFN-alpha-stimulated tyrosine phosphorylation of STAT-1, formation of homodimers, or transcription of genes regulated by STAT-1 homodimers, suggesting that inhibition of the response to IFN-alpha/beta by M. tuberculosis is an aspect of pathogenicity. Thus, this well-known feature of infection by pathogenic viruses may also be a strategy employed by pathogenic bacteria.

Cell Line↗

PubMed2002

Acute eosinophilic pneumonia in a New York City firefighter exposed to World Trade Center dust.

We report a sentinel case of acute eosinophilic pneumonia in a firefighter exposed to high concentrations of World Trade Center dust during the rescue effort from September 11 to 24. The firefighter presented with a Pa(O2) of 53 mm Hg and responded to oxygen and corticosteroids. Computed tomography scan showed patchy ground glass density, thickened bronchial walls, and bilateral pleural effusions. Bronchoalveolar lavage recovered 70% eosinophils, with only 1% eosinophils in peripheral blood. Eosinophils were not degranulated and increased levels of interleukin-5 were measured in bronchoalveolar lavage and serum. Mineralogic analysis counted 305 commercial asbestos fibers/10(6) macrophages including those with high aspect ratios, and significant quantities of fly ash and degraded fibrous glass. Acute eosinophilic pneumonia is a rare consequence of acute high dust exposure. World Trade Center dust consists of large particle-size silicates, but fly ash and asbestos fibers may be found in bronchoalveolar lavage cells.

Acute Disease↗

PubMed2002

Cough and bronchial responsiveness in firefighters at the World Trade Center site.

BACKGROUND: Workers from the Fire Department of New York City were exposed to a variety of inhaled materials during and after the collapse of the World Trade Center. We evaluated clinical features in a series of 332 firefighters in whom severe cough developed after exposure and the prevalence and severity of bronchial hyperreactivity in firefighters without severe cough classified according to the level of exposure. METHODS: "World Trade Center cough" was defined as a persistent cough that developed after exposure to the site and was accompanied by respiratory symptoms severe enough to require medical leave for at least four weeks. Evaluation of exposed firefighters included completion of a standard questionnaire, spirometry, airway-responsiveness testing, and chest imaging. RESULTS: In the first six months after September 11, 2001, World Trade Center cough occurred in 128 of 1636 firefighters with a high level of exposure (8 percent), 187 of 6958 with a moderate level of exposure (3 percent), and 17 of 1320 with a low level of exposure (1 percent). In addition, 95 percent had symptoms of dyspnea, 87 percent had gastroesophageal reflux disease, and 54 percent had nasal congestion. Of those tested before treatment of World Trade Center cough, 63 percent of firefighters (149 of 237) had a response to a bronchodilator and 24 percent (9 of 37) had bronchial hyperreactivity. Chest radiographs were unchanged from precollapse findings in 319 of the 332 with World Trade Center cough. Among the cohort without severe cough, bronchial hyperreactivity was present in 77 firefighters with a high level of exposure (23 percent) and 26 with a moderate level of exposure (8 percent). CONCLUSIONS: Intense, short-term exposure to materials generated during the collapse of the World Trade Center was associated with bronchial responsiveness and the development of cough. Clinical and physiological severity was related to the intensity of exposure.

Adult↗

PubMed2002

Host defense responses to infection by Mycobacterium tuberculosis. Induction of IRF-1 and a serine protease inhibitor.

Alveolar macrophages and newly recruited monocytes are targets of infection by Mycobacterium tuberculosis. Therefore, we examined the expression of interferon regulatory factor 1 (IRF-1), which plays an important role in host defense against M. tuberculosis, in undifferentiated and differentiated cells. Infection induced IRF-1 in both. IRF-1 from undifferentiated, uninfected monocytic cell lines was modified during extraction to produce specific species that were apparently smaller than intact IRF-1. After infection by M. tuberculosis or differentiation, intact IRF-1 was recovered. Subcellular fractions were assayed for the ability to modify IRF-1 or inhibit its modification. A serine protease on the cytoplasmic surface of an organelle or vesicle in the "lysosomal/mitochondrial" fraction from undifferentiated cells was responsible for the modification of IRF-1. Thus, the simplest explanation of the modification is cleavage of IRF-1 by the serine protease. Recovery of intact IRF-1 correlated with induction of a serine protease inhibitor that was able to significantly reduce the modification of IRF-1. The inhibitor was present in the cytoplasm of M. tuberculosis-infected or -differentiated cells. It is likely that induction of both IRF-1 and the serine protease inhibitor in response to infection by M. tuberculosis represent host defense mechanisms.

Apoptosis↗

PubMed2002

Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines.

HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein beta (C/EBPbeta) transcription factor and activation of nuclear factor (NF)-kappaB. Since the cellular immune response in pulmonary TB requires lymphocyte--macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPbeta, activated NF-kappaB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPbeta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPbeta expression. However, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1--LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1--LTR stimulation was also achieved when IL-1beta, IL-6, and TNF-beta were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPbeta, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-kappaB, further enhancing the HIV-1 LTR.

Blotting, Western↗