Respiratory Health Associated With Systemic Metal Exposure in Post-9/11 Veterans in the Department of Veterans Affairs Toxic Embedded Fragment Registry.

Objective: Adverse respiratory outcomes in post-9/11 veterans with elevated urinary metal measures and enrolled in the VA's Toxic Embedded Fragment registry were compared to those without elevated urinary metals.

Methods: Veterans completed questionnaires, underwent pulmonary physiology tests (pulmonary function and oscillometry), and provided urine samples for analysis of 13 metals. Respiratory symptoms, diagnoses, and physiology measures were compared in veterans with ≥1 urine metal elevation to those without metal elevations, adjusted for covariates, including smoking.

Association of antiplatelet therapy with clinical outcomes in patients with peripheral artery disease.

Background: The beneficial role of dual anti-platelet therapy (DAPT) in coronary artery disease is well established. However, there is limited data describing the effects of DAPT in patients with atherosclerotic peripheral artery disease (PAD). The aim of this meta-analysis is to compare clinical outcomes associated with DAPT versus single anti-platelet therapy (SAPT) in patients with symptomatic PAD.

Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein.

ER stress in type II alveolar epithelial cells (AECs) is common in idiopathic pulmonary fibrosis (IPF), but the contribution of ER stress to lung fibrosis is poorly understood. We found that mice deficient in C/EBP homologous protein (CHOP), an ER stress-regulated transcription factor, were protected from lung fibrosis and AEC apoptosis in 3 separate models where substantial ER stress was identified. In mice treated with repetitive intratracheal bleomycin, we identified localized hypoxia in type II AECs as a potential mechanism explaining ER stress.

Endogenous PGI signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model.

Endogenous prostaglandin I (PGI) has inhibitory effects on immune responses against pathogens or allergens; however, the immunomodulatory activity of endogenous PGI signaling in endotoxin-induced inflammation is unknown. To test the hypothesis that endogenous PGI down-regulates endotoxin-induced lung inflammation, C57BL/6 wild type (WT) and PGI receptor (IP) KO mice were challenged intranasally with LPS. Urine 6-keto-PGF, a stable metabolite of PGI was significantly increased following the LPS-challenge, suggesting that endogenous PGI signaling modulates the host response to LPS-challenge.

Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung.

The development of radiation-induced pulmonary fibrosis represents a critical clinical issue limiting delivery of therapeutic doses of radiation to non-small cell lung cancer. Identification of the cell types whose injury initiates a fibrotic response and the underlying biological factors that govern that response are needed for developing strategies that prevent or mitigate fibrosis. C57BL/6 mice (wild type, Nrf2 null, Nrf2, and Nrf2; SPC-Cre) were administered a thoracic dose of 12Gy and allowed to recover for 250 days.

Clinical Characteristics and Angiographic Findings of Acute Myocardial Infarction Associated With Marijuana Use: Consecutive Case Series.

Background: Marijuana use has been increasingly legalized in the United States resulting in substantial rise in the number of users especially in the younger populations. While our group and others had described various metabolic effects of this drug, little is known about its association with acute myocardial infarction.

Objective: To present a series of 8 patients with 10 events of ST-elevation MI (STEMI) associated with marijuana use; highlighting their demographic, clinical presentation, laboratory results and angiographic characteristics.

Clinical Characteristics and Angiographic Findings of Myocardial Infarction among Marijuana Users and Non-Users.

Background: Marijuana use has been increasingly legalized in the United States resulting in substantial rise in the number of users especially in the younger populations. While our group and others had described various metabolic effects of this drug, little is known about its association with acute myocardial infarction (AMI).

Objective: This follow up study presents contemporaneous cohort of non-THC user patients at a single, urban center hospital diagnosed with ST-elevation AMI; highlighting and comparing demographic, clinical, laboratory and angiographic characteristics based on exposure to THC at time of presentation.

Secretory IgA Deficiency in Individual Small Airways Is Associated with Persistent Inflammation and Remodeling.

Rationale: Maintenance of a surface immune barrier is important for homeostasis in organs with mucosal surfaces that interface with the external environment; however, the role of the mucosal immune system in chronic lung diseases is incompletely understood.

Objectives: We examined the relationship between secretory IgA (SIgA) on the mucosal surface of small airways and parameters of inflammation and airway wall remodeling in chronic obstructive pulmonary disease (COPD).

Methods: We studied 1,104 small airways (<2 mm in diameter) from 50 former smokers with COPD and 39 control subjects.

Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome.

Alveolar epithelial cell (AEC) dysfunction underlies the pathogenesis of pulmonary fibrosis in Hermansky-Pudlak syndrome (HPS) and other genetic syndromes associated with interstitial lung disease; however, mechanisms linking AEC dysfunction and fibrotic remodeling are incompletely understood. Since increased macrophage recruitment precedes pulmonary fibrosis in HPS, we investigated whether crosstalk between AECs and macrophages determines fibrotic susceptibility. We found that AECs from HPS mice produce excessive MCP-1, which was associated with increased macrophages in the lungs of unchallenged HPS mice.

Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis.

Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH.

Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.

Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis.

Secretory IgA from submucosal glands does not compensate for its airway surface deficiency in chronic obstructive pulmonary disease.

Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported. However, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) fluid has not been consistently observed.

Percutaneous Ventricular Assist Devices and ECMO in the Management of Acute Decompensated Heart Failure.

The successful treatment of acute decompensated heart failure continues to evolve with an increasing utilization of nondurable mechanical support devices. Indications for acute support have broadened to include their use as a bridge to recovery or decision (for durable ventricular assist devices [VADs] or heart transplant). Available devices have improved in terms of effectiveness, ease of insertion, and reduction in complications.

Enhanced External Counterpulsation Is Cost-Effective in Reducing Hospital Costs in Refractory Angina Patients.

Background: Enhanced external counterpulsation (EECP) is effective in the treatment of refractory angina, a condition suffered by 1.7 million Americans. Declining cardiovascular mortality and appropriate use criteria may further increase this number.

Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown.

Telomerase deficiency delays renal recovery in mice after ischemia-reperfusion injury by impairing autophagy.

The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion.

Rare variants in RTEL1 are associated with familial interstitial pneumonia.

Rationale: Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

Objectives: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA.

Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

Rationale: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease.

Objectives: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset.

Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.

A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia.

Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified a kindred with FIP with short telomeres who did not carry a mutation in known FIP genes TERT or hTR . We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred.

Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease.

Background: Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease.

Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report.

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies.