Anna Nolan, M.D.

Pulmonary Disability Evaluations In Fdny Rescue Workers Exposed To Wtc Particulates: A Pilot Study
Comfort AL; Weiden M; Naveed B; Ferrier N; Webber MP; Berger KI; Rom WN; Prezant DJ; Nolan A
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137900, year: 2011, vol: 183, page: ?, stat: Journal Article,

Low Serum Iga And Igg4 Levels Predict Accelerated Decline In Lung Function Of WTC Dust Exposed Firefighters
Ferrier NV; Nolan A; Naveed B; Rom WN; Comfort AL; Prezant DJ; Weiden MD
2011 ;183:?-? #A4773, American journal of respiratory & critical care medicine
— id: 137903, year: 2011, vol: 183, page: ?, stat: Journal Article,

Neutrophils Activate Alveolar Macrophages by Producing Caspase-6-Mediated Cleavage of IL-1 Receptor-Associated Kinase-M
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Hoshino, Yoshihiko; Segal, Leopoldo N; Fujita, Yoko; Rom, William N; Weiden, Michael D
2011 Jan 1;186(1):403-410, Journal of immunology
Alveolar macrophages (AMs) are exposed to respirable microbial particles. Similar to phagocytes in the gastrointestinal tract, AMs can suppress inflammation after exposure to nonpathogenic organisms. IL-1R-associated kinase-M (IRAK-M) is one inhibitor of innate immunity, normally suppressing pulmonary inflammation. During pneumonia, polymorphonuclear neutrophils (PMNs) are recruited by chemotactic factors released by AMs to produce an intense inflammation. We report that intact IRAK-M is strongly expressed in resting human AMs but is cleaved in patients with pneumonia via PMN-mediated induction of caspase-6 (CASP-6) activity. PMN contact is necessary and PMN membranes are sufficient for CASP-6 induction in macrophages. PMNs fail to induce TNF-alpha fully in macrophages expressing CASP-6 cleavage-resistant IRAK-M. Without CASP-6 expression, PMN stimulation fails to cleave IRAK-M, degrade IkappaBalpha, or induce TNF-alpha. CASP-6(-/-) mice subjected to cecal ligation and puncture have impaired TNF-alpha production in the lung and decreased mortality. LPS did not induce or require CASP-6 activity demonstrating that TLR2/4 signaling is independent from the CASP-6 regulated pathway. These data define a central role for CASP-6 in PMN-driven macrophage activation and identify IRAK-M as an important target for CASP-6. PMNs de-repress AMs via CASP-6-mediated IRAK-M cleavage. This regulatory system will blunt lung inflammation unless PMNs infiltrate the alveolar spaces
— id: 116209, year: 2011, vol: 186, page: 403, stat: Journal Article,

Biomarkers of metabolic syndrome predict accelerated decline of lung function in NYC firefighters that were exposed to world trade center particulates
Naveed B.; Comfort A.; Ferrier N.; Kwon S.; Rom W.N.; Prezant D.J.; Weiden M.D.; Nolan A.
2011 ;4(2):99-99, Clinical & Translational Science
OBJECTIVES/SPECIFIC AIMS: The first year post 9/11/2001, the FEV1 of FDNY rescue workers declined 439 mL, stabilizing to a 25 ml/yr decline in the subsequent 7 years. Airflow obstruction predominated in firefighters who sought a subspecialty pulmonary evaluation for treatment. We are investigating the relationship between biomarkers of metabolic syndrome (MS) and decline in lung function. METHODS/ STUDY POPULATION: Treatment cohort (N = 1720) was stratified by FEV1 into obstructed, FEV1 < 76% predicted (LLN), or normal airflow, FEV1>76%. A pilot analysis assayed 41 patients' serum drawn 5 months post 9/11 for 15 biomarkers of MS by Luminex, (obstructed N = 10, normal N = 31). All patients had normal pre-9/11 lung function. Serum cholesterol (CHOL) and triglycerides (TG) were available on 157 patients, 20/157 were obstructed. Data presented as means +/- SD; p values -0.05 by t-test considered significant. RESULTS/ANTICIPATED RESULTS: BMIs at time of serum sampling were no different between normal and obstructed individuals. At subspecialty PFT, obstructed patients had higher BMIs with an accelerated decline in lung function post 9/11, increased airway reactivity, and evidence of air trapping based on elevated RV when compared to normals. Obstructed subjects had significantly greater CHOL and CHOL/HDL ratios; higher levels of sE-Selectin, tPAI-1, and s-ICAM; and a trend towards elevated levels of TG and C-peptide. DISCUSSION/SIGNIFICANCE OF IMPACT: Blood drawn post-WTC exposure identified a subgroup of patients with markers of MS. This subgroup had subsequent increased weight gain and decline in lung function. The finding of MS biomarkers prior to lung function decline raises the possibility that the combination of irritant exposure and mediators of MS interact and promote lung injury
— id: 142066, year: 2011, vol: 4, page: 99, stat: Journal Article,

Biomarkers Of Metabolic Syndrome Predict Accelerated Decline Of Lung Function In NYC Firefighters That Were Exposed To Wtc Particulates
Naveed B; Comfort AL; Ferrier N; Kasturiarachchi KJ; Rom WN; Prezant DJ; Weiden MD; Nolan A
2011 ;183:?-? #A4795, American journal of respiratory & critical care medicine
— id: 137902, year: 2011, vol: 183, page: ?, stat: Journal Article,

WTC Dust Induces Gm-Csf In Serum Of Fdny Rescue Workers With Accelerated Decline Of Lung Function And In Cultured Alveolar Macrophages
Naveed B; Comfort AL; Ferrier N; Segal LN; Kasturiarachchi KJ; Kwon S; Chen LC; Gordon T; Cohen MD; Prophete C; Rom WN; Prezant DJ; Nolan A; Weiden M
2011 ;183:?-? #A4770, American journal of respiratory & critical care medicine
— id: 137901, year: 2011, vol: 183, page: ?, stat: Journal Article,

Metabolic Syndrome Biomarkers Predict Lung Function Impairment: A Nested Case-Control Study
Naveed B; Weiden MD; Kwon S; Gracely EJ; Comfort AL; Ferrier N; Kasturiarachchi KJ; Cohen HW; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Nolan A
2011 Nov 17;:?-? #, American journal of respiratory & critical care medicine
RATIONALE: Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function. OBJECTIVE: Define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure. METHODS: A nested case-control study of FDNY personnel with normal pre-9/11 FEV1 and who presented for subspecialty pulmonary evaluation before 3/10/2008. We correlated metabolic syndrome biomarkers obtained within six months of World Trade Center Dust exposure with subsequent FEV1. FEV1 at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV1<lower limit of normal (LLN) while controls had FEV1>/=LLN. MEASUREMENTS: Clinical data and serum sampled at the first monitoring exam within six months of 9/11/2001 assessed BMI, heart rate, serum glucose, Triglycerides/High Density Lipoprotein (HDL), Leptin, Pancreatic Polypeptide and Amylin. MAIN RESULTS: Cases and controls had significant differences in HDL<40 mg/dL with Triglycerides >/=150 mg/dL, heart rate >/=66 bpm, and Leptin >/=10,300 pg/mL. Each increased the odds of abnormal FEV1 at pulmonary evaluation by more than 2 fold, while Amylin >/=116 pg/mL decreased the odds by 84%, in a multi-biomarker model adjusting for age, race, BMI and WTC arrival time. This model had a sensitivity of 41%, a specificity of 86% and a ROC AUC of 0.77. CONCLUSION: Abnormal triglycerides and HDL, elevated heart rate and Leptin are independent risk factors of greater susceptibility to lung function impairment after 9/11/2001 while elevated Amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation
— id: 149814, year: 2011, vol: , page: ?, stat: Journal Article,

Inflammatory Biomarkers Predict Airflow Obstruction After Exposure to World Trade Center Dust
Nolan A; Naveed B; Comfort AL; Ferrier N; Hall CB; Kwon S; Kasturiarachchi KJ; Cohen HW; Zeig-Owens R; Glaser MS; Webber MP; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Weiden MD
2011 Oct 13;:?-? #, Chest
Abstract BACKGROUND:The World Trade Center (WTC) collapse produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-9/11. METHODS:In a cohort of 801 never smokers with normal pre-9/11 FEV(1), we correlated inflammatory biomarkers and complete blood counts at monitoring entry within 6 months of 9/11/2001 with a median FEV(1) at SPE (34 months, IQR 25-57). Cases of airflow obstruction had FEV(1) < LLN (100/801; 70/100 had serum) while controls had FEV(1) >/= LLN (153/801; 124/153 had serum). RESULTS:From monitoring entry to SPE, years later, FEV(1) declined 12% in cases and increased 3% in controls. Cases had elevated serum MDC, GM-CSF, G-CSF and IP-10. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) < LLN by 2.5 fold (95% CI; 1.2-5.3) and 3.0 fold (1.4-6.1) in a logistic model adjusted for exposure, BMI, age on 9/11, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI 27-51), specificity of 88% (80-93). CONCLUSIONS:Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure
— id: 138730, year: 2011, vol: , page: ?, stat: Journal Article,

Regulatory t cells and th17 cells in bronchoalveolar lavage
Segal L; Kulkarni R; Nolan A; Weiden MD; Tse DB; Rom WN
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137898, year: 2011, vol: 183, page: ?, stat: Journal Article,

HIV-1 and Bacterial Pneumonia in the Era of Antiretroviral Therapy
Segal, Leopoldo N; Methe, Barbara A; Nolan, Anna; Hoshino, Yoshihiko; Rom, William N; Dawson, Rod; Bateman, Eric; Weiden, Michael D
2011 Jun;8(3):282-287, Proceedings of the American Thoracic Society
Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4(+) cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4(+) cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response
— id: 134318, year: 2011, vol: 8, page: 282, stat: Journal Article,

Azithromycin suppresses inflammatory cytokines and induces inhibatory transcription factors in alveolar macrophages
Segal, Leopoldo; Kulkarni, Rohan; Fujita, Yoko; Nolan, Anna; Rom, William N; Weiden, Michael
2011 ;183:?-? #A2853, American journal of respiratory & critical care medicine
— id: 137899, year: 2011, vol: 183, page: ?, stat: Journal Article,

Physician-Diagnosed Respiratory Conditions and Mental Health Symptoms Seven to Nine Years Following the World Trade Center Disaster
Webber MP; Glaser MS; Weakley J; Soo J; Ye F; Zeig-Owens R; Weiden MD; Nolan A; Aldrich TK; Kelly K; Prezant D
2011 Sep 1;54(9):661-671, American journal of industrial medicine
BACKGROUND: This study examines the prevalence of physician-diagnosed respiratory conditions and mental health symptoms in firefighters and emergency medical service workers up to 9 years after rescue/recovery efforts at the World Trade Center (WTC). METHODS: We analyzed FDNY physician and self-reported diagnoses by WTC exposure and quintiles of pulmonary function (FEV1%predicted). We used screening instruments to assess probable PTSD and probable depression. RESULTS: FDNY physicians most commonly diagnosed asthma (8.8%) and sinusitis (9.7%). The highest prevalence of physician-diagnosed obstructive airway disease (OAD) was in the lowest FEV1%predicted quintile. Participants who arrived earliest on 9/11 were more likely to have physician-diagnosed asthma (OR=1.4). 7% had probable PTSD. 19.4% had probable depression. CONCLUSIONS: Self-reported and physician-diagnosed respiratory conditions remain common, especially among those who arrived earliest at the WTC site. OAD was associated with the lowest pulmonary function. Since respiratory and mental health conditions remain prevalent, ongoing monitoring and treatment is important
— id: 137897, year: 2011, vol: 54, page: 661, stat: Journal Article,

Similar Exposure To World Trade Center (WTC) Dust Produced Variable Lung Function Decline: Defining Most And Least Effected Subgroups In The FDNY Cohort
Ferrier, Natalia; Nolan, Anna; Rom, Wiliam N; Comfort, Ashley L; Prezant, David J; Weiden, Michael D
2010 ;181:- #A1252, American journal of respiratory & critical care medicine
— id: 113679, year: 2010, vol: 181, page: , stat: Journal Article,

Neutrophils Activate Alveolar Macrophages By Producing Caspase-6 Mediated Cleavage Of Interleukin-1 Associated Kinase-M (IRAK-M) In Tuberculosis
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Comfort, Ashley L; Rom, William N; Hoshino, Yoshihiko; Weiden, Michael D
2010 ;181:- #A3221, American journal of respiratory & critical care medicine
— id: 113677, year: 2010, vol: 181, page: , stat: Journal Article,

WTC PM2.5 stimulates a more intense inflammatory response in human BAL cells than other ambient PM2.5 from NYC and surrounding environs
Naveed B.; Weiden M.D.; Rom W.N.; Prezant D.J.; Comfort A.; Chen L.; Kwon S.; Chen Y.; Gordon T.; Nolan A.
2010 ;3(2):S48-S48, Clinical & Translational Science
OBJECTIVES: Particulate matter (PM) exposure causes adverse health effects. The WTC collapse led to significant PM exposure and lung injury (Weiden et al. Chest 2009). The mechanism by which WTC PM causes pulmonary morbidity is not understood. We are investigating the differential cytokine effects on human alveolar cells, comparing ambient PM of WTC to ambient PM from NYC, South Bronx (SB) and Sterling Forest (SF), a rural area northwest of NYC. METHODS AND POPULATION: AM were obtained from Bronchoalveolar lavage (BAL) by adherence overnight. AM were exposed to 50mug/mL suspensions of WTC, SB, and SF PM2.5. Media alone was the negative control and 40 ng/mL of LPS was the positive control. After 24hrs, supernatants were collected and analyzed in duplicate using Human Cytokine Panel I (Millipore) on a Luminex-200. RESULTS: Fold induction of mediators was expressed as ratios of PM exposure/media alone. Exposure to WTC PM was markedly more inflammatory than SB and SF. The most significant inductions were of the leukocyte growth factors (GM-CSF, G-CSF), a promoter of angiogenesis (VEGF), the chemokine (RANTES) and the potent multifunctional cytokine IL-6. LPS caused a greater induction for all of the analytes when compared to WTC PM except for IL-1ra. SIGNIFICANCE OF STUDY: WTC PM2.5 produces a marked inflammatory effect in comparison to PM2.5 from both NYC, SB and rural sites. The large number of cytokines induced by WTC PM may drive airway injury and may be biomarkers for lung injury. WTC PM has been observed in induced sputum obtained 9 months after 9/11/2001 and so the elaboration of cytokines may underlie the severe and long lasting health effects produced by exposure to WTC PM
— id: 111408, year: 2010, vol: 3, page: S48, stat: Journal Article,

Microparticle Activity Is Increased In Murine Polymicrobial Sepsis
Naveed, Bushra; Weiden, Michael D; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Rom, William N; Nolan, Anna
2010 ;181:- #1375, American journal of respiratory & critical care medicine
— id: 113680, year: 2010, vol: 181, page: , stat: Journal Article,

WTC PM2.5 Stimulates A More Intense Inflammatory Response In Human BAL Cells Than Other Ambient PM2.5 From NYC And Surrounding Environs
Naveed, Bushra; Weiden, Michael D; Rom, William N; Prezant, David J; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Chen, Lung Chi; Gordon, Terry; Nolan, Anna
2010 ;181:- #A1158, American journal of respiratory & critical care medicine
— id: 113678, year: 2010, vol: 181, page: , stat: Journal Article,

Obstructive airways disease with air trapping among firefighters exposed to World Trade Center dust
Weiden, Michael D; Ferrier, Natalia; Nolan, Anna; Rom, William N; Comfort, Ashley; Gustave, Jackson; Zeig-Owens, Rachel; Zheng, Shugi; Goldring, Roberta M; Berger, Kenneth I; Cosenza, Kaitlyn; Lee, Roy; Webber, Mayris P; Kelly, Kerry J; Aldrich, Thomas K; Prezant, David J
2010 Mar;137(3):566-574, Chest
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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
— id: 109029, year: 2010, vol: 137, page: 566, stat: Journal Article,

Caspase 6 cleaves the macrophage inhibitor IRAK-M in contact dependent innate immune activation
Kobayashi H; Nolan A; Naveed B; Hoshino Y; Hoshino S; Rom WN; Weiden MD
2009 April;179:A5689-A5689, American journal of respiratory & critical care medicine
— id: 101390, year: 2009, vol: 179, page: A5689, stat: Journal Article,

CD80 mediates the innate inflammatory response in murine polymicrobial sepsis
Naveed B; Nolan A; Weiden WN; Rom WN; Gold JA
2009 April;179:A1142-A1142, American journal of respiratory & critical care medicine
— id: 101392, year: 2009, vol: 179, page: A1142, stat: Journal Article,

Costimulatory molecules in the inflammatory response to PM2.5 exposure
Naveed B; Weiden MD; Nolan A; Kang GS; Rom WN; Chen LC
2009 April;179:A3138-A3138, American journal of respiratory & critical care medicine
— id: 101389, year: 2009, vol: 179, page: A3138, stat: Journal Article,

Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis
Nolan, Anna; Kobayashi, Hiroshi; Naveed, Bushra; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Karulf, Matthew R; Rom, William N; Weiden, Michael D; Gold, Jeffrey A
2009 ;4(8):e6600-e6600, PLoS ONE
BACKGROUND: Inflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86(-/-) mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis. METHODOLOGY/PRINCIPAL FINDINGS: CD80(-/-) mice had improved survival after CLP when compared to WT or CD86(-/-) mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80(-/-) mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-kappaB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model. CONCLUSIONS: In conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80
— id: 101388, year: 2009, vol: 4, page: e6600, stat: Journal Article,

World Trade Center collapse produced airway injury and air trapping
Weiden MD; Ferrier N; Nolan A; Rom WN; Comfort A; Gustave J; Zheng S; Goldring R; Berger K; Cosenz K; Beringer A; Glass L; Lee R; Zeig-Owens R; Webber M; Prezant DJ
2009 ;179:A5852-A5852, American journal of respiratory & critical care medicine
— id: 101391, year: 2009, vol: 179, page: A5852, stat: Journal Article,

CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis
Nolan, Anna; Weiden, Michael; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Mehta, Nehal; Gold, Jeffrey A
2008 Feb 1;177(3):301-308, American journal of respiratory & critical care medicine
RATIONALE: Costimulatory molecules, including the CD40-CD154 and CD80/86-CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well. OBJECTIVES: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans. METHODS: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86(-/-) mice, and novel CD40/80/86(-/-) mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry. MEASUREMENTS AND MAIN RESULTS: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86(-/-) mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86(-/-) mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived. CONCLUSIONS: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients
— id: 78804, year: 2008, vol: 177, page: 301, stat: Journal Article,

Gene expression profiles of bronchoalveolar cells in pulmonary TB
Raju, Bindu; Hoshino, Yoshihiko; Belitskaya-Levy, Ilana; Dawson, Rod; Ress, Stanley; Gold, Jeffrey A; Condos, Rany; Pine, Richard; Brown, Stuart; Nolan, Anna; Rom, William N; Weiden, Michael D
2008 Jan;88(1):39-51, Tuberculosis (Edinburgh, Scotland)
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity
— id: 74211, year: 2008, vol: 88, page: 39, stat: Journal Article,

The CD80/86-CD28 interaction is significant to mortality in murine polymicrobial sepsis
Chitkara N; Ardilles EE; Gold JA; Weiden MD; Nolan A
2007 ;:A443-A443, American journal of respiratory & critical care medicine
— id: 101394, year: 2007, vol: , page: A443, stat: Journal Article,

Treatment with -1 antitrypsin confers protection from mortality in murine polymicrobial sepsis
Chitkara N; Ardilles EE; Gold JA; Weiden MD; Nolan A
2007 ;:A443-A443, American journal of respiratory & critical care medicine
— id: 101395, year: 2007, vol: , page: A443, stat: Journal Article,

Role of combined costimulatory molecule inhibition in sepsis
Gold JA; Nolan AM; Weiden MD
2007 ;:A900-A900, American journal of respiratory & critical care medicine
— id: 101393, year: 2007, vol: , page: A900, stat: Journal Article,

Benzodiazepine administration and need for mechanical ventilation in delirium tremens - Reply
Gold, JA; Nolan, A; Rimal, B; Nelson, L
2007 JUL ;35(7):1811-1812, Critical care medicine
— id: 73415, year: 2007, vol: 35, page: 1811, stat: Journal Article,

Exogenous interferon-alpha and interferon-gamma increase lethality of murine inhalational anthrax
Gold, Jeffrey A; Hoshino, Yoshihiko; Jones, Marcus B; Hoshino, Satomi; Nolan, Anna; Weiden, Michael D
2007 ;2(1):e736-e736, PLoS ONE
BACKGROUND: Bacillus anthracis, the etiologic agent of inhalational anthrax, is a facultative intracellular pathogen. Despite appropriate antimicrobial therapy, the mortality from inhalational anthrax approaches 45%, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Type I and Type II Interferons (IFN) are prominent members of the host innate immune response and are required for control of intracellular pathogens. We have previously described a protective role for exogenous Type I and Type II IFNs in attenuating intracellular B.anthracis germination and macrophage cell death in vitro. METHODOLOGY AND PRINCIPAL FINDINGS: We sought to extend these findings in an in vivo model of inhalational anthrax, utilizing the Sterne strain (34F2) of B.anthracis. Mice devoid of STAT1, a component of IFN-alpha and IFN-gamma signaling, had a trend towards increased mortality, bacterial germination and extrapulmonary spread of B.anthracis at 24 hrs. This was associated with impaired IL-6, IL-10 and IL-12 production. However, administration of exogenous IFN-gamma, and to a lesser extent IFN-alpha, at the time of infection, markedly increased lethality. While IFNs were able to reduce the fraction of germinated spores within the lung, they increased both the local and systemic inflammatory response manifest by increases in IL-12 and reductions in IL-10. This was associated with an increase in extrapulmonary dissemination. The mechanism of IFN mediated inflammation appears to be in part due to STAT1 independent signaling. CONCLUSIONS: In conclusion, while endogenous IFNs are essential for control of B.anthracis germination and lethality, administration of exogenous IFNs appear to increase the local inflammatory response, thereby increasing mortality
— id: 73818, year: 2007, vol: 2, page: e736, stat: Journal Article,

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens
Gold, Jeffrey A; Rimal, Binaya; Nolan, Anna; Nelson, Lewis S
2007 Mar;35(3):724-730, Critical care medicine
OBJECTIVE: Patients with severe alcohol withdrawal and delirium tremens are frequently resistant to standard doses of benzodiazepines. Case reports suggest that these patients have a high incidence of requiring intensive care and many require mechanical ventilation. However, few data exist on treatment strategies and outcomes for these subjects in the medical intensive care unit (ICU). Our goal was a) to describe the outcomes of patients admitted to the medical ICU solely for treatment of severe alcohol withdrawal and b) to determine whether a strategy of escalating doses of benzodiazepines in combination with phenobarbital would improve outcomes. DESIGN: Retrospective cohort study. SETTING: Inner-city municipal hospital. PATIENTS: Subjects admitted to the medical ICU solely for the treatment of severe alcohol withdrawal. INTERVENTIONS: Institution of guidelines emphasizing escalating doses of diazepam in combination with phenobarbital. MEASUREMENTS AND MAIN RESULTS: Preguideline (n = 54) all subjects were treated with intermittent boluses of diazepam with an average total and maximal individual dose of 248 mg and 32 mg, respectively; 17% were treated with phenobarbital. Forty-seven percent required intubation due to inability to achieve adequate sedation and need for constant infusion of sedative-hypnotics. Intubated subjects had longer length of stay (5.6 vs. 3.4 days; p = .09) and higher incidence of nosocomial pneumonia (42 vs. 21% p = .08). Postguideline (n = 41) there were increases in maximum individual dose of diazepam (32 vs. 86 mg; p = .001), total amount of diazepam (248 vs. 562 mg; p = .001), and phenobarbital use (17 vs. 58%; p = .01). This was associated with a reduction in the need for mechanical ventilation (47 vs. 22%; p = .008), with trends toward reductions in ICU length of stay and nosocomial pneumonia. CONCLUSIONS: Patients admitted to a medical ICU solely for treatment of severe alcohol withdrawal have a high incidence of requiring mechanical ventilation. Guidelines emphasizing escalating bolus doses of diazepam, and barbiturates if necessary, significantly reduced the need for mechanical ventilation and showed trends toward reductions in ICU length of stay and nosocomial infections
— id: 71814, year: 2007, vol: 35, page: 724, stat: Journal Article,

Macrophage expressed co-stimulatory molecules CD80/86 in murine polymicrobial sepsis
Ardilles EE; Gold JA; Weiden MD; Nolan A
2006 ;:A648-A648, American journal of respiratory & critical care medicine
— id: 101396, year: 2006, vol: , page: A648, stat: Journal Article,

Blockade of CD80/86 improves survival in a murine model of polymicrobial sepsis
Gold JA; Nolan A; Mehta NL; Weiden MD
2006 ;:A644-A644, American journal of respiratory & critical care medicine
— id: 101397, year: 2006, vol: , page: A644, stat: Journal Article,

A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces need for mechanical ventilation in delirium tremens
Gold JA; Rimal B; Nolan A; Nelson LN
2006 ;:A735-A735, American journal of respiratory & critical care medicine
— id: 101398, year: 2006, vol: , page: A735, stat: Journal Article,

Role of macrophage costimulatory molecules in human sepsis
Mehta NL; Shih P; Nolan A; Weiden MD; Hoshino Y; Gold JA
2005 ;:A522-A522, American journal of respiratory & critical care medicine
— id: 101399, year: 2005, vol: , page: A522, stat: Journal Article,

Role of interferons in an in vivo model of inhalational anthrax
Gold JA; Jones MB; Levy DE; Hoshino Y; Nolan A; Weiden MD
2004 ;169:A230-A230, American journal of respiratory & critical care medicine
— id: 101401, year: 2004, vol: 169, page: A230, stat: Journal Article,

Exogenous gamma and alpha/beta interferon rescues human macrophages from cell death induced by Bacillus anthracis
Gold, Jeffrey A; Hoshino, Yoshihiko; Hoshino, Satomi; Jones, Marcus B; Nolan, Anna; Weiden, Michael D
2004 Mar;72(3):1291-1297, Infection & immunity
During the recent bioterrorism-related outbreaks, inhalational anthrax had a 45% mortality in spite of appropriate antimicrobial therapy, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Alveolar macrophages are likely the first immune cells exposed to inhalational anthrax, and the interferon (IFN) response of these cells comprises an important arm of the host innate immune response to intracellular infection with Bacillus anthracis. Furthermore, IFNs have been used as immunoadjuvants for treatment of another intracellular pathogen, Mycobacterium tuberculosis. We established a model of B. anthracis infection with the Sterne strain (34F(2)) which contains lethal toxin (LeTx). 34F(2) was lethal to murine and human macrophages. Treatment with IFNs significantly improved cell viability and reduced the number of germinated intracellular spores. Infection with 34F(2) failed to induce the latent transcription factors signal transducer and activators of transcription 1 (STAT1) and ISGF-3, which are central to the IFN response. Furthermore, 34F(2) reduced STAT1 activation in response to exogenous alpha/beta IFN, suggesting direct inhibition of IFN signaling. Even though 34F(2) has LeTx, there was no mitogen-activated protein kinase kinase 3 cleavage and p38 was normally induced, suggesting that these early effects of B. anthracis infection in macrophages are independent of LeTx. These data suggest an important role for both IFNs in the control of B. anthracis and the potential benefit of using exogenous IFN as an immunoadjuvant therapy
— id: 42240, year: 2004, vol: 72, page: 1291, stat: Journal Article,

Vascular endothelial growth factor blockade reduces serum cytokines in a murine model of polymicrobial sepsis
Nolan A; Thurston G; Weiden MD; Gold JA
2004 ;169:A118-A118, American journal of respiratory & critical care medicine
— id: 101400, year: 2004, vol: 169, page: A118, stat: Journal Article,

Cd40 but not CD154 knockout mice have reduced inflammatory response in polymicrobial sepsis: a potential role for Escherichia coli heat shock protein 70 in CD40-mediated inflammation in vivo
Nolan, Anna; Weiden, Michael D; Hoshino, Yoshihiko; Gold, Jeffrey A
2004 Dec;22(6):538-542, Shock
The CD40-CD154 system controls various aspects of the host inflammatory response in models of cellular and humoral immunity. Recently, we described a role for CD40 in the innate immune response in polymicrobial sepsis. However, recent data suggests that CD40 maybe activated by CD154 or directly via bacterial heat shock protein (HSP) 70. Therefore, we decided to test the mechanism of CD40 activation in murine polymicrobial sepsis. Wild-type (WT), CD40, and CD154 underwent cecal ligation and puncture (CLP). Compared with WT mice, CD40 had improved survival in association with attenuated production of IL-12, TNF-alpha, and IL-6. In contrast, CD154 mice behaved similar to WT mice with regard to mortality and cytokine production. The differential response of CD40 and CD154 mice to CLP was not due to a general attenuated response to inflammatory stimuli, as all three strains had similar survival after LPS administration, and CD40 macrophages had normal production of IL-12 in response to lipopolysaccharide. In contrast, CD40 macrophages had attenuated IL-12 production in response to Escherichia coli HSP70 (DnaK). Furthermore, intraperitoneal administration of DnaK resulted in a 4-fold increase in IL-12 in WT mice, which was absent in CD40 mice. This data demonstrates CD154-independent CD40 activation in polymicrobial sepsis and suggests that bacterial HSP70 is capable of stimulating CD40 in vitro and in vivo
— id: 55783, year: 2004, vol: 22, page: 538, stat: Journal Article,

Vascular endothelial growth factor blockade reduces plasma cytokines in a murine model of polymicrobial sepsis
Nolan, Anna; Weiden, Michael D; Thurston, Gavin; Gold, Jeffrey A
2004 Oct;28(5):271-278, Inflammation
Numerous cytokines, including vascular endothelial growth factor (VEGF), are implicated in the pathogenesis of sepsis. While overexpression of VEGF produces pulmonary capillary leak, the role of VEGF in sepsis is less clear. We investigated VEGF in sepsis, utilizing a VEGF trap (VEGF(T)). Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP) and resulted in significantly increased plasma VEGF levels (234 vs. 46 pg/mL; p = 0.03). Inhibition of VEGF had no effect on mortality or lung leak but did attenuate plasma IL-6 (120 vs. 236 ng/mL; p = 0.02) and IL-10 (16 vs. 41 ng/mL; p = 0.03). These alterations in inflammatory cytokines were associated with increased levels of the dominant negative inhibitory C/EBPbeta. In vitro, VEGF stimulated IL-6, IL-10 and reduced the inhibitory isoform of C/EBPbeta in cultured macrophages. Together these data suggest VEGF can regulate inflammatory cytokine production in murine polymicrobial sepsis, via regulation of C/EBPbeta
— id: 58737, year: 2004, vol: 28, page: 271, stat: Journal Article,

Role of CD 40 ligand in early sepsis
Shih PH; Nolan A; Tse D; Doshi AM; Weiden MD; Gold JA
2004 ;169:A635-A635, American journal of respiratory & critical care medicine
— id: 101402, year: 2004, vol: 169, page: A635, stat: Journal Article,

CD40 contributes to lethality in acute sepsis: in vivo role for CD40 in innate immunity
Gold, Jeffrey A; Parsey, Merdad; Hoshino, Yoshihiko; Hoshino, Satomi; Nolan, Anna; Yee, Herman; Tse, Doris B; Weiden, Michael D
2003 Jun;71(6):3521-3528, Infection & immunity
Sepsis induces an early inflammatory cascade initiated by the innate immune response. This often results in the development of multisystem organ failure. We examined the role of CD40, a costimulatory molecule that is integral in adaptive immunity, by using a murine model of polymicrobial sepsis. CD40 knockout (KO) mice had delayed death and improved survival after cecal ligation and puncture (CLP). In addition, they had less remote organ injury as manifested by reduced pulmonary capillary leakage. The improvements in survival and remote organ dysfunction in CD40 KO mice were associated with reduced interleukin-6 (IL-6) and IL-10 levels in serum and bronchoalveolar lavage fluid compared to the levels in wild-type (WT) controls. Furthermore, in contrast to WT mice, CD40 KO mice had no induction of the Th1 cytokines IL-12 and gamma interferon in serum or lungs after CLP. The alterations in cytokine production in CD40 KO mice were associated with similar changes in transcription factor activity. After CLP, CD40 KO mice had attenuated activation of nuclear factor kappaB and signal transducer and activator of transcription 3 in both the lung and the liver. Finally, WT mice had increased expression of CD40 on their alveolar macrophages. These data highlight the importance of CD40 activation in the innate immune response during polymicrobial sepsis and the subsequent development of remote organ dysfunction
— id: 39222, year: 2003, vol: 71, page: 3521, stat: Journal Article,

CD40 is integral to the innate immune response during polymicrobial sepsis
Nolan A; Parsey M; Hoshino Y; Yee H; Tse DT; Weiden MD; Gold JA
2003 ;167:A556-A556, American journal of respiratory & critical care medicine
— id: 101404, year: 2003, vol: 167, page: A556, stat: Journal Article,

Severe alcohol withdrawal in the ICU, treatments and complications
Rimal B; Nolan A; Gold JA
2003 ;167:A250-A250, American journal of respiratory & critical care medicine
— id: 101403, year: 2003, vol: 167, page: A250, stat: Journal Article,

Correlation of PPD status of immunocompetent tuberculosis patients and bronchoalveolar lavage (BAL) cell differential
Nolan A; Rom WN; Condos R; Raju B
2002 ;165:A288-A288, American journal of respiratory & critical care medicine
— id: 101405, year: 2002, vol: 165, page: A288, stat: Journal Article,