Inflammatory biomarkers predict airflow obstruction after exposure to World Trade Center dust.
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ABSTRACT:
SUBMITTER: Nolan A
PROVIDER: S-EPMC3425337 | biostudies-other | 2012 Aug
REPOSITORIES: biostudies-other
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Project description:Respiratory ailments have plagued occupational and public health communities exposed to World Trade Center (WTC) dust since the September 11, 2001 attack on the Twin Towers in Lower Manhattan. We proposed that these ailments were proposed to be induced by inhalation exposure to WTC particulate matter (WTCPM), that was released during the collapse of the buildings and its subsequent resuspension during cleanup. We investigated this hypothesis using both an in vitro and an in vivo mouse intranasal (IN) exposure models to identify the inflammatory potential of WTCPM with specific emphasis on respiratory and endothelial tissue responses. The in vitro exposure studies found WTCPM exposure to be positively correlated with cytotoxicity and increased NO2- production in both BEAS-2B pulmonary epithelial cells and THP-1 macrophage cells. The in vivo C57BL/6 mouse studies found significant increases in inflammatory markers including increases in polymorphonuclear neutrophil (PMN) influx into nasal and bronchoalveolar lavage fluids (NLF and BALF), as well as increased levels of total protein and cytokine/chemokines levels. Concurrently, NLF, BALF, and serum NO2- levels exhibited significant homeostatic temporal deviations as well as temporal myograohic aortic dysfunction in myography studies. Respiratory exposure to- and evidence -based retention of- WTCPM may have contributed to chronic systemic effects in exposed mice that r resembled to observed effects in WTCPM-exposed human populations. Collectively, these findings are reflective of WTCPM exposure and its effect(s) on respiratory and aortic tissues, highlighting potential dysfunctional pathways that may precipitate inflammatory events, while simultaneously altering homeostatic balances. The tight interplay between these balances, when chronically altered, may contribute to- or result in- chronically diseased pathological states.
| S-EPMC7370403 | biostudies-literature
Project description:The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question.Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans.At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease.Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation.
| S-EPMC2832867 | biostudies-other
Project description:Rationale: The pathophysiologic mechanisms by which World Trade Center (WTC) dust exposure leads to pulmonary disease have not been established. Matrix metalloproteinase-12 (MMP-12) is involved in the development of pulmonary fibrosis and chronic obstructive pulmonary disease. We have previously shown that exposure of mice to WTC dust results in increased expression of matrix metalloproteinase 12 by alveolar macrophages. Matrix metalloproteinase 12 expression is regulated, in part, by oxidative stress, which is also increased after WTC dust exposure. A significant percentage of WTC dust–exposed individuals have concomitant obstructive sleep apnea, which is an added source of oxidative stress, through chronic intermittent hypoxia (CIH). Objectives: To determine if combined exposures of mice to WTC dust and CIH exacerbated matrix metalloproteinase 12 expression in alveolar macrophages. Methods: Male Balbc/J mice (12–24 wk) were treated intratracheally with phosphate-buffered saline (PBS) or WTC dust suspended in PBS, followed by CIH (cycles of 21 to 5% fraction of inspired oxygen, 2-min cycles) (CIH groups) or chronic intermittent air (CIA; cycles of 21 to 19% fraction of inspired oxygen, 2-min cycles) (CIA groups) 12 hours per day for 28 days. Histologic sections were then examined for macrophage expression of matrix metalloproteinase 12 by immunohistochemistry. Results: The mean number of positively stained alveolar macrophages from five fields per lobe was quantified. Mice exposed to WTC dust or CIH displayed increased macrophage expression of matrix metalloproteinase 12 compared with the control group. Exposure to WTC dust plus CIH was additive in effect (mean?±?SD, PBS/CIA: 20.8?±?5.2; PBS/CIH: 43.3?±?19.8; WTC/CIA: 43.3?±?12.5; WTC/CIH: 77.8?±?12.2). Conclusions: To our knowledge, this is the first study to suggest CIH increases macrophage matrix metalloproteinase 12 expression in mice. Combined exposures to WTC dust and CIH further increased macrophage matrix metalloproteinase 12 expression. Given the role of matrix metalloproteinase 12 in pulmonary fibrosis and chronic obstructive pulmonary disease pathogenesis, patients with obstructive sleep apnea who have been exposed to WTC dust may have added risk for pulmonary parenchymal disease.
| S-EPMC5955033 | biostudies-literature
Project description:BackgroundThe terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer's disease (AD) later in life.ObjectiveWe hypothesize that WTCPM dust exposure affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype.Methods5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR.ResultsMice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption.ConclusionThese studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR.
| S-EPMC9912736 | biostudies-literature
Project description:BackgroundThere is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer's disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown.ObjectiveIn a study of 3,997 WTC responders, polygenic scores for Alzheimer's disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD.ResultsPolygenic scores for Alzheimer's disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer's disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors.ConclusionThese results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer's disease, as genetic liability for Alzheimer's disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts.
| S-EPMC10648279 | biostudies-literature
Project description:STUDY OBJECTIVES:A relationship between obstructive sleep apnea (OSA) and exposure to the World Trade Center (WTC) dust and fumes has been suggested in responders but little is known about a possible relationship in community members. We characterized sleep studies performed in community members with WTC dust exposure to improve our understanding of the relationship between the diagnosis and severity of OSA and WTC dust exposure in this population. METHODS:Single-center, retrospective study of patients enrolled in a clinical treatment program for community members with WTC dust exposure. Patients were included if they had undergone sleep studies for evaluation of possible OSA through September 2016 and provided written informed consent. RESULTS:The total number of patients included in the analysis was 143. Patients were predominantly male (61%), never smokers (59%) and had a median body mass index of 31 kg/m2. Most reported upper and lower respiratory symptoms. An apnea-hypopnea index (AHI) ? 5 events/h was measured in 66% of the patients, and respiratory disturbance index was ? 5 events/h in 97%. The proportion of patients with moderate-severe OSA (defined by the AHI 4% criteria) was 50%. Multivariate logistic regression revealed that acute WTC dust cloud exposure was associated with severity but not diagnosis of OSA. CONCLUSIONS:We identified a high rate of OSA in the WTC community cohort who were referred for sleep studies. Exposure to the massive WTC dust cloud caused by the WTC collapse was independently associated with the severity of OSA in this population. This finding highlights the role that environmental exposures may play in the development of OSA.
| S-EPMC5940423 | biostudies-literature
Project description:The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.
| S-EPMC7558705 | biostudies-literature
Project description:An excess incidence of prostate cancer has been identified among World Trade Center (WTC) responders. In this study, we hypothesized that WTC dust, which contained carcinogens and tumor-promoting agents, could facilitate prostate cancer development by inducing DNA damage, promoting cell proliferation, and causing chronic inflammation. We compared expression of immunologic and inflammatory genes using a NanoString assay on archived prostate tumors from WTC Health Program (WTCHP) patients and non-WTC patients with prostate cancer. Furthermore, to assess immediate and delayed responses of prostate tissue to acute WTC dust exposure via intratracheal inhalation, we performed RNA-seq on the prostate of normal rats that were exposed to moderate to high doses of WTC dust. WTC prostate cancer cases showed significant upregulation of genes involved in DNA damage and G2-M arrest. Cell-type enrichment analysis showed that Th17 cells, a subset of proinflammatory Th cells, were specifically upregulated in WTC patients. In rats exposed to WTC dust, we observed upregulation of gene transcripts of cell types involved in both adaptive immune response (dendritic cells and B cells) and inflammatory response (Th17 cells) in the prostate. Unexpectedly, genes in the cholesterol biosynthesis pathway were also significantly upregulated 30 days after acute dust exposure. Our results suggest that respiratory exposure to WTC dust can induce inflammatory and immune responses in prostate tissue. IMPLICATIONS: WTC-related prostate cancer displayed a distinct gene expression pattern that could be the result of exposure to specific carcinogens. Our data warrant further epidemiologic and cellular mechanistic studies to better understand the consequences of WTC dust exposure.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/8/1605/F1.large.jpg.
| S-EPMC6684261 | biostudies-literature
Project description:DNA methylation has emerged as a promising target linking environmental exposures and cancer. The World Trade Center (WTC) responders sustained exposures to potential carcinogens, resulting in an increased risk of cancer. Previous studies of cancer risk in WTC-exposed responders were limited by the deficiency in quantitative and individual information on exposure to carcinogens. The current study introduces a new exposure-ranking index (ERI) for estimating cancer-related acute and chronic exposures, which aimed to improve the ability of future analyses to estimate cancer risk. An epigenome-wide association study based on DNA methylation and a weighted gene co-expression network analysis were carried out to identify cytosine-phosphate-guanosine (CpG) sites, modules of correlated CpG sites, and biological pathways associated with the new ERI. Methylation was profiled on blood samples using Illumina 450K Beadchip. No significant epigenome-wide association was found for ERI at a false discovery rate of 0.05. Several cancer-related pathways emerged in pathway analyses for the top ranking genes from epigenome-wide association study as well as enriched module from the weighted gene co-expression network analysis. The current study was the first DNA methylation study that aimed to identify methylation signature for cancer-related exposure in the WTC population. No CpG sites survived multiple testings adjustment. However, enriched gene sets involved in cancer, were identified in both acute and chronic ERIs, supporting the view that multiple genes play a role in this complex exposure.
| S-EPMC6329666 | biostudies-literature
Project description:Little is known about the mechanisms of persistent airflow obstruction that result from chronic occupational endotoxin exposure. We sought to analyze the inflammatory response underlying persistent airflow obstruction as a result of chronic occupational endotoxin exposure. We developed a murine model of daily inhaled endotoxin for periods of 5 days to 8 weeks. We analyzed physiologic lung dysfunction, lung histology, bronchoalveolar lavage fluid and total lung homogenate inflammatory cell and cytokine profiles, and pulmonary gene expression profiles. We observed an increase in airway hyperresponsiveness as a result of chronic endotoxin exposure. After 8 weeks, the mice exhibited an increase in bronchoalveolar lavage and lung neutrophils that correlated with an increase in proinflammatory cytokines. Detailed analyses of inflammatory cell subsets revealed an expansion of dendritic cells (DCs), and in particular, proinflammatory DCs, with a reduced percentage of macrophages. Gene expression profiling revealed the up-regulation of a panel of genes that was consistent with DC recruitment, and lung histology revealed an accumulation of DCs in inflammatory aggregates around the airways in 8-week-exposed animals. Repeated, low-dose LPS inhalation, which mirrors occupational exposure, resulted in airway hyperresponsiveness, associated with a failure to resolve the proinflammatory response, an inverted macrophage to DC ratio, and a significant rise in the inflammatory DC population. These findings point to a novel underlying mechanism of airflow obstruction as a result of occupational LPS exposure, and suggest molecular and cellular targets for therapeutic development.
| S-EPMC3423463 | biostudies-literature