D C Christiani

Harvard University, Cambridge, Massachusetts, United States

Are you D C Christiani?

Claim your profile

Publications (250)1145.9 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to characterise the cardiovascular inflammatory response to secondhand smoke (SHS) exposure among non-smoking construction workers.
    Occupational and environmental medicine. 06/2014; 71 Suppl 1:A31-2.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Whether cessation of exposure to endotoxin containing organic dusts leads to transient vs. sustained improvement of lung function is unknown.
    Occupational and environmental medicine. 06/2014; 71 Suppl 1:A3.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Workplace and contextual factors that may affect risk for worker injury are not well described. This study used results from an employee job satisfaction survey to construct aggregate indicators of the work environment and estimate the relative contribution of those factors to injury rates in a manufacturing cohort. Principal components analysis was used to construct four plant-level factors from responses to a 32 question survey of the entire workforce, administered in 2006. Multilevel Poisson regression was used to evaluate the relationship between injury rate, individual-level and plant-level risk factors, unionisation and plant type. Plant-level 'work stress' (incident rate ratio (IRR)=0.50, 95% CI 0.28 to 0.90) was significant in the multilevel model, indicating the rate of injury for an average individual in that plant was halved (conditional on plant) when job stress decreased by a tertile. 'Overall satisfaction', 'work environment' and 'perception of supervisor' showed the same trend but were not significant. Unionisation was protective (IRR=0.40, 95% CI 0.17 to 0.95) as was any plant type compared with smelter. We demonstrated utility of data from a human resources survey to construct indicators of the work environment. Our research suggests that aspects of the work environment, particularly work stress and unionisation, may have a significant effect on risk for occupational injury, emphasising the need for further multilevel studies. Our work would suggest monitoring of employee perceptions of job stress and the possible inclusion of stress management as a component of risk reduction programmes.
    Occupational and environmental medicine 04/2014; · 3.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in ~20% of intrahepatic cholangiocarcinoma (ICC) and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in ICC. We initially measured serum 2HG concentration in blood samples collected from 31 ICC patients in a Screening cohort. Findings were validated across 38 resected ICC patients from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden and a number of clinical variables. Circulating levels of 2HG in the Screening cohort were significantly elevated in patients with IDH1/2-mutant (median 478 ng/ml) versus IDH1/2-wild-type (median 118 ng/ml) tumors (p<0.001). This significance was maintained in the Validation cohort (343 ng/ml vs 55 ng/ml, p<0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (p<0.05). Serum 2HG levels >170 ng/ml could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regards to the levels of circulating 2HG. This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in ICC and that circulating 2HG levels may correlate directly with tumor burden.
    Clinical Cancer Research 01/2014; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: A recent genome-wide study (GWAS) has identified GPC5 as a promising susceptibility gene for Lung cancer in never smokers (LCINS). However, the most significant single nucleotide polymorphism (SNP) in this GWAS, rs2352028, has yielded controversial results. The aim of this study was to clarify the relationship between rs2352028 and LCINS. Considering that rs2352028 might be largely marker-SNP correlated to causative variants, two predicted functional SNPs, rs3759452 and rs7322083, were additionally investigated in this study. Methods: A hospital based case-control study including 298 cases and 599 controls in a never-smoking Chinese Han population was conducted, and then a meta-analysis combining our data and published data was performed to verify the findings. Results: The SNP rs3759452, predicted to potentially change transcription factor binding site of GPC5, was significantly associated with LCINS risk (odds ratio for dominant model=1.55, 95% confidence interval=1.14-2.12). Nevertheless, no significant evidence was showed for rs2352028, both in our case-control study and the meta-analysis including 13 studies of 2342 LCINS cases and 13,398 never-smoking controls. Further subgroup meta-analysis according to population ethnicity and cancer histology also reported no significant association of rs2352028. Conclusions: The association conferring rs3759452 further supports the value of GPC5 in susceptibility to LCINS. Nevertheless, comprehensive analyses are warranted to dissect the functional mechanism underpinning rs3759452.
    Cancer epidemiology. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well-known that metabolism of benzene is required for the induction of toxicity and consequent health problems. Therefore, genetic variation in benzene (BZ) metabolism genes can influence health outcomes. However, large population studies are needed to provide more evidence for such relationship. We have conducted a large population investigation (385 BZ-exposed shoe workers and 197 matched healthy controls) on the association between inheritance of certain BZ metabolizing genes and the expression of micronuclei (MN). The latter was based on the cytokinesis-blocked MN assay. We analyzed the polymorphisms of GSTM1, GSTT1, GSTP1 (rs1695), CYP2E1 (rs3813867), CYP2E1 (rs2031920), CYP2E1 (rs6413432), mEH exon 3 (rs1051740), mEH exon 4 (rs2234922). Univariate Poisson regression analysis demonstrated that the BZ-exposed workers had significantly increased MN frequency compared with the controls (FR = 1.84, 95% CI: 1.56-2.18; P < 0.001), and showed a cumulative exposure dose--response relationship. The CYP2E1 rs3813867 mutant allele (CC+ GC) (FR 1.15, 95% CI 1.02–1.29; P = 0. 020) and rs2031920 variant allele (CT + TT) (FR = 1.23, 95% CI: 1.09–1.37, P<0.01) was associated with higher MN frequency significantly compared with the wild genotype separately. Furthermore, the MN frequency in rs2031920 variant allele (CT + TT) (FR = 1.17, 95% CI: 1.04–1.31, P<0.01) was also higher than the wild genotype when the age, gender and cumulative exposure dose was adjusted in Poisson regression. In addition, the CYP2E1 (However, GSTM1null, GSTT1null, GSTP1 rs1695, rs6413432, rs1051740 and rs2234922 polymorphisms showed no association with MN frequency. Our results indicate that two promoter polymorphisms in the CYP2E1 gene, especially the rs2031920 variant allele, were involved with the BZ-induction of MN and may contribute to risk of cancer among exposed workers.
    International journal of hygiene and environmental health 01/2014; · 2.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND:Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization-defined severe pneumonia.METHODS:We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization- and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site.RESULTS:Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60-6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96-1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001).CONCLUSIONS:Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
    PEDIATRICS 10/2013; · 4.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although occupational exposure to cotton dust and endotoxin is associated with adverse respiratory health, associations with cancer are unclear. We investigated cancer mortality in relation to cotton dust and endotoxin exposure in the Shanghai textile workers cohort. We followed 444 cotton textile and a reference group of 467 unexposed silk workers for 30 years (26 777 person-years). HRs for all cancers combined (with and without lung cancer) and gastrointestinal cancer were estimated in Cox regression models as functions of cotton textile work and categories of cumulative exposure (low, medium, high), after adjustment for covariates including pack-years smoked. Different lag years accounted for disease latency. Risks of mortality from gastrointestinal cancers and all cancers combined, with the exclusion of lung cancer, were increased in cotton workers relative to silk workers. When stratified by category of cumulative cotton exposure, in general, risks were greatest for 20-year lagged medium exposure (all cancers HR=2.7 (95% CI 1.4 to 5.2); cancer excluding lung cancer HR=3.4 (1.7-7.0); gastrointestinal cancer HR=4.1 (1.8-9.7)). With the exclusion of lung cancer, risks of cancer were more pronounced. When stratified by category of cumulative endotoxin exposure, consistent associations were not observed for all cancers combined. However, excluding lung cancer, medium endotoxin exposure was associated with all cancers and gastrointestinal cancer in almost all lag models. Cotton dust may be associated with cancer mortality, especially gastrointestinal cancer, and endotoxin may play a causative role. Findings also indirectly support a protective effect of endotoxin on lung cancer.
    Occupational and environmental medicine 07/2013; · 3.64 Impact Factor
  • Jorunn Kirkeleit, Trond Riise, Tone Bjørge, David C Christiani
    [Show abstract] [Hide abstract]
    ABSTRACT: Use of the general population as a reference might cause serious underestimation of the risk of cancer in working populations because of the healthy worker effect. Using incidence rates, we studied how this underestimation varied according to subtypes of cancer by comparing a large cohort of randomly selected Norwegian workers hired between 1981 and 2003 (n = 366,114) with the general Norwegian population. The cohort was linked to the Cancer Registry of Norway, including all new cancer cases (n = 11,271) reported up to 2003. We found marked potential for the healthy worker effect for overall cancer incidence in male workers (standardized incidence ratio (SIR) = 0.91, 95% confidence interval: 0.89, 0.93) but not in female workers (SIR = 0.99, 95% confidence interval: 0.95, 1.03). A statistically significantly lower incidence was found among men for cancers of the head and neck (SIR = 0.78), lung (SIR = 0.81), prostate (SIR = 0.93), kidney (SIR = 0.83), and bladder (SIR = 0.77) and for leukemia (SIR = 0.80), whereas an increased incidence was found for malignant melanoma among both men (SIR = 1.09) and women (SIR = 1.29) and for ovarian cancer in women (SIR = 1.32). Depending on the type of cancer being studied, marked potential exists for both underestimation and overestimation of cancer risk when the general population is used as the reference for studies of worker populations.
    American journal of epidemiology 04/2013; · 5.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag (-/-) mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.
    PLoS Genetics 04/2013; 9(4):e1003413. · 8.52 Impact Factor
  • Peggy S Lai, David C Christiani
    [Show abstract] [Hide abstract]
    ABSTRACT: Over 60 million people worldwide work in the textile or clothing industry. Recent studies have recognized the contribution of workplace exposures to chronic lung diseases, in particular chronic obstructive pulmonary disease (COPD). Early studies in textile workers have focused on the relationship between hemp or cotton dust exposure and the development of a syndrome termed byssinosis. The purpose of this review is to evaluate the effect of long-term exposure to organic dust in textile workers on chronic respiratory disease in the broader context of disease classifications, such as reversible or irreversible obstructive lung disease (i.e. asthma or COPD), and restrictive lung disease. Cessation of exposure to cotton dust leads to improvement in lung function. Recent animal models have suggested a shift in the lung macrophage:dendritic cell population ratio as a potential mechanistic explanation for persistent inflammation in the lung due to repeated cotton dust-related endotoxin exposure. Other types of textile dust, such as silk, may contribute to COPD in textile workers. Textile dust-related obstructive lung disease has characteristics of both asthma and COPD. Significant progress has been made in the understanding of chronic lung disease due to organic dust exposure in textile workers.
    Current opinion in pulmonary medicine 03/2013; 19(2):152-7. · 3.12 Impact Factor
  • Crystal M North, David C Christiani
    [Show abstract] [Hide abstract]
    ABSTRACT: In the last 20 years, there has been an increased focus on gender differences in health and disease. The earliest studies of lung cancer enrolled mainly men, as the incidence of lung cancer among women was exceedingly low. As social patterns changed around World War II and women began to smoke more, the epidemiology of lung cancer has changed. The higher percentage of lung cancer in nonsmoking women as compared with nonsmoking men suggests that lung cancer behaves differently in women. Studies of lung cancer in women indicate that there are differences in risk factors, histology, pathophysiology, treatment outcomes, and prognosis as compared with men. The purpose of this review is to provide a concise summary of the literature on lung cancer as it pertains to women, with an emphasis on new areas of research and treatment options.
    Seminars in Thoracic and Cardiovascular Surgery 01/2013; 25(2):87-94.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development.
    PLoS ONE 01/2013; 8(5):e62910. · 3.53 Impact Factor
  • Source
    Human Molecular Genetics 01/2013; 22(1):184-201. · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: : Amplification of fibroblast growth factor receptor 1 (FGFR1) has been reported in squamous cell lung carcinoma and may be a molecular target for therapy. Little is known, however, about the clinical and demographic correlates of FGFR1 amplification. : The study is an Institutional Review Board approved retrospective analysis of 226 patients with squamous cell lung cancer seen at the Massachusetts General Hospital from 2005 to 2011. Clinical and demographic characteristics of all patients were obtained, as well as treatment details including surgery, radiation, and chemotherapy, and overall survival. fluorescence in situ hybridization was performed for FGFR1 on formalin-fixed paraffin-embedded tumor tissue. Clinical genotyping results were also reviewed where available. : Thirty-seven of 226 patients (16%) with squamous cell lung cancer were found positive for amplification using a definition of amplification of a gene to copy number control ratio of 2.2 or higher. FGFR1 amplification status was not associated with age, sex, stage, histologic subtype within squamous cell, smoking history, or pack-years of smoking. We found no significant difference in overall survival by FGFR1 amplification status as a whole; in the advanced stage subset, our findings are inconclusive because of the small sample size. : FGFR1 amplification was found in 16% of a clinical cohort of squamous cell lung cancer patients. The lack of any specific clinicodemographic features that correlates with FGFR1 amplification suggests that all squamous cell patients should be tested for this genomic change.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1775-80. · 4.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: SESSION TYPE: Pediatric Critical CarePRESENTED ON: Sunday, October 21, 2012 at 01:15 PM - 02:45 PMPURPOSE: Pneumonia is the leading cause of mortality in children under five years of age in developing nations. Factors that affect tissue delivery of oxygen (DO2) may contribute to severity of illness on presentation and treatment outcomes. We examined the effect of two of these factors, high altitude and anemia, on clinical severity at presentation and treatment outcomes in young children with WHO-classified very severe pneumonia.METHODS: We analyzed data from the Severe Pneumonia Evaluation Antimicrobial Research (SPEAR) study, a multinational WHO-funded RCT of chloramphenicol vs. ampicillin/gentamicin for very severe pneumonia among children 2-59 mo. in low-resource settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥ 2,000m) or low altitude (< 2,000m). Differences in clinical characteristics were compared using Student's T test and Pearson's chi-square. The effect of hemoglobin at high vs. low altitude was assessed using multivariate regression, adjusting for potential confounders and study site.RESULTS: Children at high altitude had significantly lower mean SpO2 on presentation (71% vs. 88%, p < .0001), higher proportion of cyanosis (94% vs. 8%, p < .0001), lower systolic blood pressure (86 mm Hg vs. 93 mm Hg, p < .0001), and higher mean hemoglobin (10.5 vs. 9.8, p < .0001). Interaction was observed between high altitude and hemoglobin (p = 0.001), indicating a different effect of hemoglobin at high and low altitudes. After adjusting for potential confounders, a lower hemoglobin predicted treatment failure at high altitude (RR = 0.68 [0.53, 0.86]) but not at low altitude. For every 1g/dL increase in hemoglobin, the risk of treatment failure was found to decrease by 32%.CONCLUSIONS: Children at high altitude present with significantly more severe hypoxemia and cyanosis than children at low altitude. Lower hemoglobin at high altitude increases the risk of treatment failure.CLINICAL IMPLICATIONS: Treatment of anemia should be a high priority in children at high altitude, and could reduce morbidity and mortality from very severe pneumonia.DISCLOSURE: The following authors have nothing to disclose: Peter Moschovis, Salem Banajeh, William MacLeod, Samir Saha, Douglas Hayden, David Christiani, Greta Mino, Mathuram Santosham, Donald Thea, Shamim Qazi, Patricia HibberdNo Product/Research Disclosure InformationMassachusetts General Hospital/Harvard Medical School, Boston, MA.
    Chest 10/2012; 142(4_MeetingAbstracts):764A. · 7.13 Impact Factor
  • Hu L, Wu C, Zhao X, Heist R, Su L, Zhao Y, Han B, Cao S, Chu M, Dai J, [......], Tan W, Ma H, Chen J, Jin G, Wu T, Lu D, Christiani DC, Lin D, Hu Z, Shen H
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Genetic variation may influence chemotherapy response and overall survival in cancer patients. Experimental design: We conducted a genome-wide scan in 535 advanced-stage non-small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA). RESULTS: Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10(-5) to 4.19 × 10(-7) in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population. CONCLUSION: In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients. Clin Cancer Res; 18(19); 5507-14. ©2012 AACR.
    Clinical Cancer Research 10/2012; · 7.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    American Journal of Respiratory Cell and Molecular Biology 04/2012; 47(2):209-17. · 4.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
    American Journal of Respiratory and Critical Care Medicine 03/2012; 185(11):1225-34. · 11.04 Impact Factor
  • David C Christiani
    [Show abstract] [Hide abstract]
    ABSTRACT: The study of disease variability in populations is a goal of modern epidemiology. Because most common diseases arise out of a combination of factors and events (exposures, heritability, comorbidities, and chance), developing simple models of characterizing joint events is a daunting task. Dr. Weinberg argues successfully in this issue of the Journal (Am J Epidemiol. 2012;175(7):602-605) that additive null models can capture pure forms of independent causal effects in studies of rare conditions. Moreover, the concept of exposure modification, which characterizes most gene-environment interactions reported to date, is introduced. More cross-talk between biologists and epidemiologists is needed to tackle key issues in chronic disease etiology, and the argument for the use of parsimonious joint models in epidemiology is convincing.
    American journal of epidemiology 02/2012; 175(7):606-8. · 5.59 Impact Factor

Publication Stats

5k Citations
1,145.90 Total Impact Points


  • 1993–2014
    • Harvard University
      • • Department of Environmental Health
      • • Department of Epidemiology
      Cambridge, Massachusetts, United States
  • 1987–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1997–2013
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 2011
    • Universidad Nacional Autónoma de México
      Ciudad de México, The Federal District, Mexico
  • 2008–2010
    • Fudan University
      • School of Public Health
      Shanghai, Shanghai Shi, China
  • 2009
    • University of Toronto
      • Department of Medical Biophysics
      Toronto, Ontario, Canada
    • University of Bergen
      • Department of Public Health and Primary Health Care
      Bergen, Hordaland Fylke, Norway
  • 1993–2009
    • Massachusetts General Hospital
      • • Department of Medicine
      • • Division of Pulmonary & Critical Care Medicine
      • • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2006
    • Liberty Mutual Research Institute for Safety
      • Center for Injury Epidemiology
      Boston, Massachusetts, United States
  • 2005
    • Texas A&M University - Galveston
      Galveston, Texas, United States
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      Chapel Hill, NC, United States
  • 2004
    • University of Texas MD Anderson Cancer Center
      • Department of Epidemiology
      Houston, TX, United States
  • 1998–2004
    • Brigham and Women's Hospital
      • • Division of Thoracic Surgery
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, MA, United States
  • 2003
    • Dana-Farber Cancer Institute
      • Center for Community-Based Research
      Boston, MA, United States
    • New York State
      New York City, New York, United States
    • Ewha Womans University
      • Department of Preventive Medicine
      Sŏul, Seoul, South Korea
  • 2001–2002
    • Inha University Hospital
      Sinhyeon, South Gyeongsang, South Korea
    • Cambridge Health Alliance
      Cambridge, Massachusetts, United States
  • 2000
    • Yonsei University
      • Department of Preventive Medicine and Public Health
      Seoul, Seoul, South Korea
    • Boston University
      • Department of Pediatrics
      Boston, MA, United States
  • 1999–2000
    • Shanghai Medical University
      • School of Public Health
      Shanghai, Shanghai Shi, China
    • National Yang Ming University
      • Department of Public Health
      T’ai-pei, Taipei, Taiwan
  • 1997–2000
    • Cambridge College
      Cambridge, Massachusetts, United States
  • 1991–1995
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Epidemiology and Biostatistics
      San Francisco, CA, United States
  • 1994
    • Yale University
      • Department of Internal Medicine
      New Haven, CT, United States