Do Ambient Ozone or Other Pollutants Modify Effects of Controlled Ozone Exposure on Pulmonary Function?

In a previous trial (MOSES [Multicenter Ozone Study of oldEr Subjects]), 3 hours of controlled ozone (O) exposure caused concentration-related reductions in lung function with evidence of airway inflammation and injury, but without convincing evidence of effects on cardiovascular function. However, the subjects' exposures to indoor and outdoor air pollution in the hours and days before each controlled O exposure may have modified biomarker responses to the controlled O exposures. We sought to determine whether personal measures of nitrogen dioxide (NO) and O, or ambient concentrations of O, particulate matter ≤2.

Nasal Nitric Oxide Measurement in Primary Ciliary Dyskinesia. A Technical Paper on Standardized Testing Protocols.

Nasal nitric oxide concentrations are extremely low in primary ciliary dyskinesia (PCD), and measurement of this nasal gas is recommended as a PCD diagnostic test in cooperative patients aged 5 years and older. However, nasal nitric oxide measurements must be performed with chemiluminescence analyzers using a standardized protocol to ensure proper results, because nasal nitric oxide values can be influenced by various internal and external factors. Repeat nasal nitric oxide testing on separate visits is required to ensure that low diagnostic values are persistent and consistent with PCD.

Ozone effects on blood biomarkers of systemic inflammation, oxidative stress, endothelial function, and thrombosis: The Multicenter Ozone Study in oldEr Subjects (MOSES).

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol.

Tropospheric ozone assessment report: Global ozone metrics for climate change, human health, and crop/ecosystem research.

Assessment of spatial and temporal variation in the impacts of ozone on human health, vegetation, and climate requires appropriate metrics. A key component of the is the consistent calculation of these metrics at thousands of monitoring sites globally. Investigating temporal trends in these metrics required that the same statistical methods be applied across these ozone monitoring sites.

Cardiovascular function and ozone exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES).

Background: To date, there have been relatively few studies of acute cardiovascular responses to controlled ozone inhalation, although a number of observational studies have reported significant positive associations between both ambient ozone levels and acute cardiovascular events and long-term ozone exposure and cardiovascular mortality.

Objectives: We hypothesized that short-term controlled exposure to low levels of ozone in filtered air would induce autonomic imbalance, repolarization abnormalities, arrhythmia, and vascular dysfunction.

Methods: This randomized crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol, from June 2012 to April 2015.

Interleukin-13 stimulates production of nitric oxide in cultured human nasal epithelium.

The diversity and extent of signaling functions of nitric oxide (NO) in cell physiology as well as its presence and influence as a common component of ambient air pollution and tobacco smoke are gaining increasing research attention relative to both health and disease. While cellular NO production is typically associated with inflammatory cells and processes, the airway epithelium particularly of the paranasal sinuses, has been documented to be a rich source of excreted NO. Inasmuch as excreted NO derives from both mucosal and inflammatory cell sources, distinguishing the individual contribution of these compartments to total excreted cellular NO is potentially problematic.

Respiratory Responses to Ozone Exposure. MOSES (The Multicenter Ozone Study in Older Subjects).

Rationale: Acute respiratory effects of low-level ozone exposure are not well defined in older adults.

Objectives: MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults.

Methods: We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.

Temporal structure/function variation in cultured differentiated human nasal epithelium associated with acute single exposure to tobacco smoke or E-cigarette vapor.

Objective: Mucociliary clearance sustains a baseline functionality and an "on demand" capability to upregulate clearance upon irritant exposure involving mucus hypersecretion and accelerated ciliary beat frequency (CBF) modulated by nitric oxide (NO). This study characterized these elements as well as cellular and exogenous NO concentrations subsequent to a single exposure to tobacco smoke (TS) or e-cigarette vapor (EV) on cultured human airway epithelium.

Materials And Methods: Air-liquid interface (ALI) airway epithelial cultures per nonsmoking human subjects were subjected to single TS or EV exposures.

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents.

Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations.

Objectives: To define a statistically valid combination of systematically defined clinical features that strongly associates with PCD in children and adolescents.

Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype.

Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined.

Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype.

Methods: A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping.

Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.

Background: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

Methods: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations.

Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.

Rationale: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.

Objectives: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.

Methods: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing.

Pulmonary responses in current smokers and ex-smokers following a two hour exposure at rest to clean air and fine ambient air particles.

Background: Increased susceptibility of smokers to ambient PM may potentially promote development of COPD and accelerate already present disease.

Objectives: To characterize the acute and subacute lung function response and inflammatory effects of controlled chamber exposure to concentrated ambient fine particles (CAFP) with MMAD  ≤  2.5 microns in ex-smokers and lifetime smokers.

Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects.

Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia.

Rationale: Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized.

Objectives: To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites.

Methods: At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32).

Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive, genetically heterogeneous disorder characterized by ciliary dysfunction resulting in chronic oto-sino-pulmonary disease, respiratory distress in term neonates, laterality (situs) defects, and bronchiectasis. Diagnosis has traditionally relied on ciliary ultrastructural abnormalities seen by electron microscopy. Mutations in radial spoke head proteins occur in PCD patients with central apparatus defects.

Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities.

Objective: To determine whether individuals with primary ciliary dyskinesia (PCD) from unrelated Amish and Mennonite families harbor a single and unique founder mutation.

Study Design: Subjects from Amish and Mennonite communities in several states were enrolled in the study. All subjects were clinically characterized, and nasal nitric oxide levels were measured.

Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 14 genes, but they collectively account for only ~60% of all PCD. To identify mutations that cause PCD, we performed exome sequencing on six unrelated probands with ciliary outer dynein arm (ODA) defects.

Interferon γ stimulates accumulation of gas phase nitric oxide in differentiated cultures of normal and cystic fibrosis airway epithelial cells.

Background: Exhaled nitric oxide (NO) levels have been reported to be lower in patients with cystic fibrosis (CF) than in controls; however the mechanism(s) responsible and the effect on pathogenesis are unclear. The objective of these studies was to determine if the low levels of gas phase NO (gNO) could be reproduced in well-differentiated air-liquid interface (ALI) cultures of normal and CF cells.

Methods: Human bronchial epithelial (HBE) cells from CF and control tissues were cultured under ALI conditions that promote differentiation into a mostly ciliated, pseudostratified epithelium similar to that of the in vivo airway.

Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure.

Rationale: Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11).

Objectives: To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology.

Nasal nitric oxide and lifestyle exposure to tobacco smoke.

Objectives: Nitric oxide (NO) is a reactive gas generated by inflammatory cells and mucosal epithelial cells of the nose and paranasal sinuses and is an important mediator in nonspecific host defense against infectious agents. However, NO also mediates physiologic events such as vasodilation, mucus hypersecretion, and mucosal disruption that are associated with inflammatory conditions, and it is a regulator of ciliary beat frequency. In the present study, we hypothesized that lifestyle exposure to tobacco smoke, whether through active smoking or by inadvertent exposure to secondhand tobacco smoke, would result in higher detectable levels of nasal NO (nNO) than are found in well-documented nonsmokers.

Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours.

Rationale: Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm, close to the National Ambient Air Quality Standard for ground level ozone.

Objectives: To test whether airway effects occur below the current ozone standard and if they are more pronounced in potentially susceptible individuals, such as those deficient in the antioxidant gene glutathione S-transferase mu 1 (GSTM1).

An alternative form and level of the human health ozone standard.

Controlled human laboratory studies have shown that there is a disproportionately greater pulmonary function response from higher hourly average ozone (O3) concentrations than from lower hourly average values and thus, a nonlinear relationship exists between O3 dose and pulmonary function (FEV1) response. The nonlinear dose-response relationship affects the efficacy of the current 8-h O3 standard to describe adequately the observed spirometric response to typical diurnal O3 exposure patterns. We have reanalyzed data from five controlled human response to O3 health laboratory experiments as reported by Hazucha et al.