Faculty Bibliography

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment

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

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

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

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

BACKGROUND: The terrorist attacks on the World Trade Center on September 11, 2001, exposed thousands of Fire Department of New York City (FDNY) rescue workers to dust, leading to substantial declines in lung function in the first year. We sought to determine the longer-term effects of exposure. METHODS: Using linear mixed models, we analyzed the forced expiratory volume in 1 second (FEV(1)) of both active and retired FDNY rescue workers on the basis of spirometry routinely performed at intervals of 12 to 18 months from March 12, 2000, to September 11, 2008. RESULTS: Of the 13,954 FDNY workers who were present at the World Trade Center between September 11, 2001, and September 24, 2001, a total of 12,781 (91.6%) participated in this study, contributing 61,746 quality-screened spirometric measurements. The median follow-up was 6.1 years for firefighters and 6.4 years for emergency-medical-services (EMS) workers. In the first year, the mean FEV(1) decreased significantly for all workers, more for firefighters who had never smoked (a reduction of 439 ml; 95% confidence interval [CI], 408 to 471) than for EMS workers who had never smoked (a reduction of 267 ml; 95% CI, 263 to 271) (P<0.001 for both comparisons). There was little or no recovery in FEV(1) during the subsequent 6 years, with a mean annualized reduction in FEV(1) of 25 ml per year for firefighters and 40 ml per year for EMS workers. The proportion of workers who had never smoked and who had an FEV(1) below the lower limit of the normal range increased during the first year, from 3% to 18% for firefighters and from 12% to 22% for EMS workers, stabilizing at about 13% for firefighters and 22% for EMS workers during the subsequent 6 years. CONCLUSIONS: Exposure to World Trade Center dust led to large declines in FEV(1) for FDNY rescue workers during the first year. Overall, these declines were persistent, without recovery over the next 6 years, leaving a substantial proportion of workers with abnormal lung function.