Living in environmental justice areas worsens asthma severity and control: Differential interactions with disease duration, age at onset, and pollution.

Background: Impoverished and historically marginalized communities often reside in areas with increased air pollution.

Objective: We evaluated the association between environmental justice (EJ) track and asthma severity and control as modified by traffic-related air pollution (TRAP).

Methods: We performed a retrospective study of 1526 adult asthma patients in Allegheny County, Pa, enrolled in an asthma registry during 2007-20.

PM and constituent component impacts on global DNA methylation in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) whose outcomes are worsened with air pollution exposures. DNA methylation (DNAm) patterns are altered in lungs and blood from patients with IPF, but the relationship between air pollution exposures and DNAm patterns in IPF remains unexplored. This study aimed to evaluate the association of PM and constituent components with global DNAm in patients with IPF.

Association of Particulate Matter Exposure With Lung Function and Mortality Among Patients With Fibrotic Interstitial Lung Disease.

Importance: Particulate matter 2.5 μm or less in diameter (PM2.5) is associated with adverse outcomes for patients with idiopathic pulmonary fibrosis, but its association with other fibrotic interstitial lung diseases (fILDs) and the association of PM2.

Impact of a pollution breach at a coke oven factory on asthma control in nearby vulnerable adults.

Background: Previous studies have related sulfur dioxide (SO) exposure to asthma exacerbations. We utilized the University of Pittsburgh Asthma Institute registry to study associations of asthma exacerbations between 2 geographically distinct populations of adults with asthma.

Objective: Our objective was to examine whether asthma symptoms worsened following a significant fire event that destroyed pollution control equipment at the largest coke works in the United States.

Genetic determinants of ammonia-induced acute lung injury in mice.

In this study, a genetically diverse panel of 43 mouse strains was exposed to ammonia, and genome-wide association mapping was performed employing a single-nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was used to help resolve the genetic determinants of ammonia-induced acute lung injury. The encoded proteins were prioritized based on molecular function, nonsynonymous SNP within a functional domain or SNP within the promoter region that altered expression.

A risk-based model to assess environmental justice and coronary heart disease burden from traffic-related air pollutants.

Background: Communities need to efficiently estimate the burden from specific pollutants and identify those most at risk to make timely informed policy decisions. We developed a risk-based model to estimate the burden of black carbon (BC) and nitrogen dioxide (NO) on coronary heart disease (CHD) across environmental justice (EJ) and non-EJ populations in Allegheny County, PA.

Methods: Exposure estimates in census tracts were modeled via land use regression and analyzed in relation to US Census data.

Nickel inhibits mitochondrial fatty acid oxidation.

Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2.

Secreted phosphoprotein 1 is a determinant of lung function development in mice.

Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding.

Quantitative method of measuring phosphatidylserine externalization during apoptosis using electron paramagnetic resonance (EPR) spectroscopy and annexin-conjugated iron.

We present here the application of a novel assay that measures the absolute amount of PS externalized on the surface of cells. While based on the same annexin binding principle as the fluorescent flow cytometry assay, we use paramagnetic iron as the ultimate reporter molecule, establishing a linear relationship between signal amplitude and amount of PS on the cell surface, allowing a quantitative assay of PS externalization over a wide dynamic range. The application of this technique, alone and in concert with the PS oxidation method presented in the previous chapter, will greatly aid in studying the mechanistic connection between lipid peroxidation and translocation events during apoptosis.

Quantification of selective phosphatidylserine oxidation during apoptosis.

Membrane phospholipids are gaining increasing attention as important mediators in a variety of signal transduction processes. Oxidation and changes in membrane topography of lipids are likely important elements in the regulation of phospholipid-dependent signaling. Phosphatidylserine (PS), in particular, is implicated in the regulation of macrophage-dependent clearance of apoptotic cell "corpses" in a pathway likely mediated by selective oxidation and translocation of PS in the plasma membrane.

Functional genomic assessment of phosgene-induced acute lung injury in mice.

In this study, a genetically diverse panel of 43 mouse strains was exposed to phosgene and genome-wide association mapping performed using a high-density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was also used to improve the genetic resolution in the identification of genetic determinants of phosgene-induced acute lung injury (ALI). We prioritized the identified genes based on whether the encoded protein was previously associated with lung injury or contained a nonsynonymous SNP within a functional domain.

Role of hypoxia-inducible factor 1, α subunit and cAMP-response element binding protein 1 in synergistic release of interleukin 8 by prostaglandin E2 and nickel in lung fibroblasts.

Numerous epidemiological studies have linked exposure to particulate matter (PM) air pollution with acute respiratory infection and chronic respiratory and cardiovascular diseases. We have previously shown that soluble nickel (Ni), a common component of PM, alters the release of CXC chemokines from cultured human lung fibroblasts (HLF) in response to microbial stimuli via a pathway dependent on disrupted prostaglandin (PG)E2 signaling. The current study sought to identify the molecular events underlying Ni-induced alterations in PGE2 signaling and its effects on IL-8 production.

Integrative assessment of chlorine-induced acute lung injury in mice.

The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling.

Integrative metabolome and transcriptome profiling reveals discordant energetic stress between mouse strains with differential sensitivity to acrolein-induced acute lung injury.

Scope: This investigation sought to better understand the metabolic role of the lung and to generate insights into the pathogenesis of acrolein-induced acute lung injury. A respiratory irritant, acrolein is generated by overheating cooking oils or by domestic cooking using biomass fuels, and is in environmental tobacco smoke, a health hazard in the restaurant workplace.

Methods And Results: Using SM/J (sensitive) and 129X1/SvJ (resistant) inbred mouse strains, the lung metabolome was integrated with the transcriptome profile before and after acrolein exposure.

Multiple protein kinase pathways mediate amplified IL-6 release by human lung fibroblasts co-exposed to nickel and TLR-2 agonist, MALP-2.

Microbial stimuli and atmospheric particulate matter (PM) interact to amplify the release of inflammatory and immune-modulating cytokines. The basis of this interaction, however, is not known. Cultured human lung fibroblasts (HLF) were used to determine whether various protein kinase pathways were involved in the release of IL-6 following combined exposure to the PM-derived metal, Ni, and M.

Nickel and the microbial toxin, MALP-2, stimulate proangiogenic mediators from human lung fibroblasts via a HIF-1alpha and COX-2-mediated pathway.

Hypoxia-inducible factor (HIF-1alpha) and cyclooxygenase-2 (COX-2) have been implicated in the regulation of inflammatory-like processes that lead to angiogenesis and fibrotic disorders. Here we demonstrate that in human lung fibroblasts (HLFs) treated with mixed exposures to chemical and microbial stimuli, HIF-1alpha stabilization plays a pivotal role in the induction of COX-2 mRNA and protein, driving the release of vascular endothelial growth factor (VEGF) and proangiogenic and profibrotic chemokines. Upon costimulation with Ni and the mycoplasma-derived lipopeptide macrophage-activating lipopeptide-2 (MALP-2), there was a synergistic induction of CXCL1 and CXCL5 mRNA and protein release from HLF, as well as an enhanced response in VEGF compared to either stimulus alone.

Sequential exposure to carbon nanotubes and bacteria enhances pulmonary inflammation and infectivity.

Carbon nanotubes (CNT), with their applications in industry and medicine, may lead to new risks to human health. CNT induce a robust pulmonary inflammation and oxidative stress in rodents. Realistic exposures to CNT may occur in conjunction with other pathogenic impacts (microbial infections) and trigger enhanced responses.

Nickel alterations of TLR2-dependent chemokine profiles in lung fibroblasts are mediated by COX-2.

Particulate matter air pollution (PM) has been linked with chronic respiratory diseases. Real-life exposures are likely to involve a mixture of chemical and microbial stimuli, yet little attention has been paid to the potential interactions between PM components (e.g.

Mycoplasma fermentans and TNF-beta interact to amplify immune-modulating cytokines in human lung fibroblasts.

Mycoplasma can establish latent infections and are associated with arthritis, leukemia, and chronic lung disease. We developed an experimental model in which lung cells are deliberately infected with Mycoplasma fermentans. Human lung fibroblasts (HLF) were exposed to live M.

Quantitative method of measuring phosphatidylserine externalization during apoptosis using electron paramagnetic resonance spectroscopy and annexin-conjugated iron.

We present here the application of a novel assay that measures the absolute amount of phosphatidylserine (PS) externalized on the surface of cells. Although the assay is based on the same annexin binding principle as the fluorescent flow cytometry assay, we use paramagnetic iron as the ultimate reporter molecule, establishing a linear relationship between signal amplitude and amount of PS on the cell surface, allowing a quantitative assay of PS externalization over a wide dynamic range. The application of this technique, alone and in concert with the PS oxidation method presented in the previous chapter, will greatly aid in studying the mechanistic connection between lipid peroxidation and translocation events during apoptosis.

Quantification of selective phosphatidylserine oxidation during apoptosis.

Membrane phospholipids are gaining increasing attention as important mediators in a variety of signal transduction processes. Oxidation and changes in membrane topography of lipids are probably important elements in the regulation of phospholipid-dependent signaling. Phosphatidylserine (PS), in particular, is implicated in the regulation of macrophage-dependent clearance of apoptotic cell "corpses" in a pathway probably mediated by selective oxidation and translocation of PS in the plasma membrane.

Microbial stimulation by Mycoplasma fermentans synergistically amplifies IL-6 release by human lung fibroblasts in response to residual oil fly ash (ROFA) and nickel.

Mycoplasma (MP), such as the species M. fermentans, possess remarkable immunoregulatory properties and can potentially establish chronic latent infections with little signs of disease. Atmospheric particulate matter (PM) is a complex and diverse component of air pollution associated with adverse health effects.

The plasma membrane is the site of selective phosphatidylserine oxidation during apoptosis: role of cytochrome C.

Phosphatidylserine (PS) externalization, a functional end point of apoptosis that triggers phagocytic recognition of dying cells, may be modulated by oxidative stress in biological membranes. We previously observed selective oxidation of PS during apoptosis, but the intracellular location and molecular mechanisms responsible for PS oxidation remain to be described. Peroxidation in individual classes of cellular phospholipids was monitored in whole cells and various subcellular fractions obtained from HL-60 cells undergoing apoptosis in response to tert-butyl hydroperoxide (t-BuOOH) after metabolic acylation of phospholipids with the oxidation-sensitive fluorescent fatty acid, cis-parinaric acid.

Quantification of oxidative/nitrosative modification of CYS(34) in human serum albumin using a fluorescence-based SDS-PAGE assay.

The SH group represented by cysteine in proteins is fundamental to the redox regulation of protein structure and function. Albumin is the most abundant serum protein whose redox modification modulates its physiologic function, as well as serves as a biomarker of oxidative stress. Measurement of selective Cys modification (S-oxidation/nitrosation, electrophilic substitution) on specific proteins, however, is problematic within complex biological mixtures such as plasma.