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1.
Article in English | MEDLINE | ID: mdl-31207973

ABSTRACT

Environmental justice is a rising social movement throughout the world. Research is beginning to define the movement and address the disparities that exist among communities exposed to pollution. North Birmingham, a community made up of six neighborhoods in Jefferson County, Alabama, in the United States, is a story of environmental injustice. Heavy industry, including the 35th Avenue Superfund Site, has caused significant environmental pollution over time, leaving residents concerned that their health and well-being are at risk from continued exposure. For years, pollution has impacted the community, and residents have fought and challenged industry and government. The United States (U.S.) Environmental Protection Agency (EPA), the U.S. Agency for Toxic Substances and Disease Registry (ATSDR), and the Jefferson County Department of Health (JCDH) in Alabama have historically played a role in working with the community regarding their health concerns. In this manuscript, we describe a city entrenched in environmental injustice. We provide the history of the community, the responsible parties named for the contamination, the government's involvement, and the community's response to this injustice. Through this manuscript, we offer insight into a global concern that challenges local communities on a daily basis.


Subject(s)
Environmental Exposure , Social Justice , Alabama , Environmental Pollution , Federal Government , Hazardous Substances , Humans , Industry , United States
2.
JCI Insight ; 3(1)2018 01 11.
Article in English | MEDLINE | ID: mdl-29321377

ABSTRACT

The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr-/- (KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities. The KO rat exhibits decreased periciliary depth, hyperacidic pH, and increased mucus solid content percentage; however, the transport rates and viscoelastic properties of the mucus are unaffected until the KO rat ages. Airway submucosal gland hypertrophy develops in the KO rat by 6 months of age. Only then does it induce increased mucus viscosity, collapse of the periciliary layer, and delayed mucociliary transport; stimulation of gland secretion potentiates this evolution. These findings could be reversed by bicarbonate repletion but not pH correction without counterion donation. These studies demonstrate that abnormal surface epithelium in CF does not cause delayed mucus transport in the absence of functional gland secretions. Furthermore, abnormal bicarbonate transport represents a specific target for restoring mucus clearance, independent of effects on periciliary collapse. Thus, mature airway secretions are required to manifest the CF defect primed by airway dehydration and bicarbonate deficiency.


Subject(s)
Cystic Fibrosis/therapy , Mucus/metabolism , Respiratory Mucosa/metabolism , Animals , Bicarbonates/metabolism , Biological Transport , Cystic Fibrosis/pathology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Disease Models, Animal , Female , Gene Knockout Techniques , Ion Transport , Male , Mucociliary Clearance , Rats , Respiratory Mucosa/pathology , Surface Properties
3.
Am J Respir Cell Mol Biol ; 56(3): 383-392, 2017 03.
Article in English | MEDLINE | ID: mdl-27870560

ABSTRACT

Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D-deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D-deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency-associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies.


Subject(s)
Trachea/pathology , Vitamin D Deficiency/pathology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Animals , Animals, Newborn , Female , Mice, Inbred C57BL , Pregnancy , Respiratory Function Tests , Trachea/diagnostic imaging , Trachea/drug effects , Trachea/physiopathology , Vitamin D/pharmacology , Vitamin D Deficiency/physiopathology
4.
MCN Am J Matern Child Nurs ; 40(3): 180-5, 2015.
Article in English | MEDLINE | ID: mdl-25919211

ABSTRACT

BACKGROUND: Pregnancy is a particularly vulnerable time for exposure to indoor air pollutants, such as formaldehyde (FA), which is linked to spontaneous abortion, congenital malformations, and premature birth. PURPOSE: To determine personal exposure to FA during pregnancy, and to identify the relationship between FA exposure levels and potential residential sources of FA. STUDY DESIGN AND METHODS: The study sample consisted of 140 pregnant women recruited from obstetrical clinics in Huntsville, Alabama. Formaldehyde exposure was measured by FA vapor monitor badges. Questionnaires were administered to participants to identify potential residential sources of FA. Urine cotinine, a surrogate for tobacco smoke exposure, was also used as an indicator of a possible source of residential exposure to FA. RESULTS: The mean level of FA exposure by vapor monitor badge was 0.04 parts per million (ppm) (SD = 0.06; range 0.003-0.54 ppm). Minimum risk levels of 0.03 and higher were found in 36.4% of participants. Exposure levels of FA were higher in spring than winter (p < 0.001). Exposure levels of FA were correlated with indoor temperature of dwellings (p < 0.02), installation of new carpet within last 5 years (p < 0.04), and use of nail polish (p < 0.01). No relationship was found between FA exposure and urine cotinine levels. CLINICAL IMPLICATIONS: Formaldehyde exposure may increase at various times in the lives of women; however, it is of particular concern during pregnancy because of perinatal risk to the exposed fetus.


Subject(s)
Air Pollutants/adverse effects , Formaldehyde/adverse effects , Maternal Exposure , Adult , Air Pollution, Indoor/prevention & control , Alabama , Cross-Sectional Studies , Female , Housing , Humans , Maternal Exposure/statistics & numerical data , Obstetric Nursing , Pregnancy , Surveys and Questionnaires , Tobacco Smoke Pollution/prevention & control , Young Adult
5.
PLoS One ; 9(3): e91253, 2014.
Article in English | MEDLINE | ID: mdl-24608905

ABSTRACT

Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/-) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR-/-) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR-/- rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR-/- males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR-/- animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/deficiency , Gene Knockout Techniques , Organogenesis , Animals , Base Sequence , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Dentition , Epithelium/metabolism , Female , Humans , Ileum/growth & development , Ileum/physiology , Ion Channel Gating , Ion Transport , Male , Membrane Potentials , Microinjections , Molecular Sequence Data , Mucus/metabolism , Nose/physiology , Rats, Sprague-Dawley , Trachea/anatomy & histology , Trachea/physiology , Vas Deferens/abnormalities
6.
Am J Physiol Lung Cell Mol Physiol ; 303(12): L1079-86, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23087018

ABSTRACT

Pulmonary dendritic cells (DCs) are among the first responders to inhaled environmental stimuli such as ozone (O(3)), which has been shown to activate these cells. O(3) reacts with epithelial lining fluid (ELF) components in an anatomically site-specific manner dictated by O(3) concentration, airway flow patterns, and ELF substrate concentration. Accordingly, the anatomical distribution of ELF reaction products and airway injury are hypothesized to produce selective DC maturation differentially within the airways. To investigate how O(3) affects regional airway DC populations, we utilized a model of O(3)-induced pulmonary inflammation, wherein C57BL/6 mice were exposed to 0.8 ppm O(3) 8 h/day for 1, 3, and 5 days. This model induced mild inflammation and no remarkable epithelial injury. Tracheal, but not more distant airway sites, and mediastinal lymph node (MLN) DC numbers were increased significantly after the third exposure day. The largest increase in each tissue was of the CD103(+) DC phenotype. After 3 days of exposure, fewer DCs expressed CD80, CD40, and CCR7, and, at this same time point, total MLN T cell numbers increased. Together, these data demonstrate that O(3) exposure induced site-specific and phenotype changes in the pulmonary and regional lymph node DC populations. Possibly contributing to ozone-mediated asthma perturbation, the phenotypic changes to DCs within pulmonary regions may alter responses to antigenic stimuli. Decreased costimulatory molecule expression within the MLN suggests induction of tolerance mechanisms; increased tracheal DC number may raise the potential for allergic sensitization and asthmatic exacerbation, thus overcoming O(3)-induced decrements in costimulatory molecule expression.


Subject(s)
Antigens, CD/metabolism , CD11b Antigen/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Environmental Exposure , Integrin alpha Chains/metabolism , Oxidants, Photochemical/pharmacology , Ozone/toxicity , Animals , Antigens, CD/analysis , B7-1 Antigen/analysis , CD11b Antigen/analysis , CD40 Antigens/analysis , Integrin alpha Chains/analysis , Lung/drug effects , Lymph Nodes/drug effects , Lymphocyte Count , Male , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Receptors, CCR7/analysis , Trachea/drug effects
7.
Free Radic Biol Med ; 53(7): 1431-9, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22917977

ABSTRACT

Cl(2) gas toxicity is complex and occurs during and after exposure, leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl(2) exposure can occur in diverse situations encompassing mass casualty scenarios, highlighting the need for postexposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we assessed the efficacy of a single dose of nitrite (1 mg/kg) to decrease ALI when administered to rats via intraperitoneal (ip) or intramuscular (im) injection 30 min after Cl(2) exposure. Exposure of rats to Cl(2) gas (400 ppm, 30 min) significantly increased ALI and caused RAS 6-24h postexposure as indexed by BAL sampling of lung surface protein and polymorphonucleocytes (PMNs) and increased airway resistance and elastance before and after methacholine challenge. Intraperitoneal nitrite decreased Cl(2)-dependent increases in BAL protein but not PMNs. In contrast im nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase-dependent manner. Histological evaluation of airways 6h postexposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl(2)-exposed rats. Both ip and im nitrite improved airway histology compared to Cl(2) gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with im compared to ip nitrite. Airways were rendered more sensitive to methacholine-induced resistance and elastance after Cl(2) gas exposure. Interestingly, im nitrite, but not ip nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of im and ip therapy showed a twofold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl(2) exposure-dependent increases in circulating leukocytes. Halving the im nitrite dose resulted in no effect in PMN accumulation but significant reduction of BAL protein levels, indicating a distinct nitrite dose dependence for inhibition of Cl(2)-dependent lung permeability and inflammation. These data highlight the potential for nitrite as a postexposure therapeutic for Cl(2) gas-induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics.


Subject(s)
Acute Lung Injury/prevention & control , Lung/drug effects , Neutrophils/drug effects , Sodium Nitrite/pharmacology , Acute Lung Injury/chemically induced , Acute Lung Injury/immunology , Acute Lung Injury/pathology , Animals , Bronchial Provocation Tests , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Chlorine , Inhalation Exposure , Injections, Intramuscular , Injections, Intraperitoneal , Lung/immunology , Lung/pathology , Male , Methacholine Chloride/administration & dosage , Neutrophils/immunology , Neutrophils/pathology , Rats , Rats, Sprague-Dawley , Sodium Nitrite/therapeutic use
8.
Toxicol Sci ; 128(2): 500-16, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22584687

ABSTRACT

Computational fluid dynamics (CFD) models are useful for predicting site-specific dosimetry of airborne materials in the respiratory tract and elucidating the importance of species differences in anatomy, physiology, and breathing patterns. We improved the imaging and model development methods to the point where CFD models for the rat, monkey, and human now encompass airways from the nose or mouth to the lung. A total of 1272, 2172, and 135 pulmonary airways representing 17±7, 19±9, or 9±2 airway generations were included in the rat, monkey and human models, respectively. A CFD/physiologically based pharmacokinetic model previously developed for acrolein was adapted for these anatomically correct extended airway models. Model parameters were obtained from the literature or measured directly. Airflow and acrolein uptake patterns were determined under steady-state inhalation conditions to provide direct comparisons with prior data and nasal-only simulations. Results confirmed that regional uptake was sensitive to airway geometry, airflow rates, acrolein concentrations, air:tissue partition coefficients, tissue thickness, and the maximum rate of metabolism. Nasal extraction efficiencies were predicted to be greatest in the rat, followed by the monkey, and then the human. For both nasal and oral breathing modes in humans, higher uptake rates were predicted for lower tracheobronchial tissues than either the rat or monkey. These extended airway models provide a unique foundation for comparing material transport and site-specific tissue uptake across a significantly greater range of conducting airways in the rat, monkey, and human than prior CFD models.


Subject(s)
Respiratory Physiological Phenomena/drug effects , Acrolein/pharmacokinetics , Acrolein/pharmacology , Aged , Aged, 80 and over , Animals , Female , Humans , Macaca mulatta , Male , Rats , Rats, Sprague-Dawley , Tissue Distribution
9.
J Appl Physiol (1985) ; 112(10): 1659-69, 2012 May.
Article in English | MEDLINE | ID: mdl-22403348

ABSTRACT

Low concentrations of inhaled hydrogen sulfide (H(2)S) induce hypometabolism in mice. Biological effects of H(2)S in in vitro systems are augmented by lowering O(2) tension. Based on this, we hypothesized that reduced O(2) tension would increase H(2)S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H(2)S at 21% O(2) or 10.5% O(2) for 6 h followed by 1 h recovery at room air. Rats exposed to H(2)S in 10.5% O(2) had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H(2)S administered under both O(2) levels and did not return to preexposure levels after 1 h recovery. Inhaled H(2)S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H(2)S on prosurvival signaling was also measured in heart and liver. H(2)S in 21% O(2) increased Akt-P(Ser473) and GSK-3ß-P(Ser9) in the heart whereas phosphorylation was decreased by H(2)S in 10.5% O(2), indicating O(2) dependence in regulating cardiac signaling pathways. Inhaled H(2)S and low O(2) had no effect on liver Akt. In summary, we found that lower O(2) was needed for H(2)S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H(2)S. Inhaled H(2)S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H(2)S. In conclusion, these findings demonstrate the importance of O(2) in influencing physiological and signaling effects of H(2)S in mammalian systems.


Subject(s)
Hydrogen Sulfide/administration & dosage , Hypoxia/metabolism , Myocardium/metabolism , Oxygen/metabolism , Signal Transduction/drug effects , Administration, Inhalation , Animals , Body Temperature Regulation/drug effects , Creatine Kinase, MB Form/blood , Disease Models, Animal , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Heart Rate/drug effects , Hydrogen Sulfide/toxicity , Hypoxia/pathology , Hypoxia/physiopathology , Liver/drug effects , Liver/metabolism , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/physiopathology , Male , Myocardium/pathology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Respiration/drug effects , Serine , Time Factors
10.
Am J Respir Cell Mol Biol ; 46(5): 599-606, 2012 May.
Article in English | MEDLINE | ID: mdl-22162906

ABSTRACT

We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gas-induced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorine-exposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the post-exposure administration of ascorbate and deferoxamine.


Subject(s)
Antioxidants/therapeutic use , Bronchi/pathology , Chlorine/toxicity , Trachea/pathology , Animals , Antioxidants/pharmacology , Ascorbic Acid/metabolism , Bronchi/drug effects , Bronchial Provocation Tests , Chlorine/administration & dosage , Glutathione/metabolism , Hyperplasia/prevention & control , Inhalation Exposure , Lung/pathology , Male , Rats , Rats, Sprague-Dawley , Trachea/drug effects
11.
Toxicol Sci ; 124(2): 472-86, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21914721

ABSTRACT

Over a quarter of the U.S. population is exposed to harmful levels of airborne particulate matter (PM) pollution, which has been linked to development and exacerbation of respiratory diseases leading to morbidity and mortality, especially in susceptible populations. Young children are especially susceptible to PM and can experience altered anatomic, physiologic, and biological responses. Current studies of ambient PM are confounded by the complex mixture of soot, metals, allergens, and organics present in the complex mixture as well as seasonal and temporal variance. We have developed a laboratory-based PM devoid of metals and allergens that can be replicated to study health effects of specific PM components in animal models. We exposed 7-day-old postnatal and adult rats to a single 6-h exposure of fuel-rich ultrafine premixed flame particles (PFPs) or filtered air. These particles are high in polycyclic aromatic hydrocarbons content. Pulmonary cytotoxicity, gene, and protein expression were evaluated at 2 and 24 h postexposure. Neonates were more susceptible to PFP, exhibiting increased lactate dehydrogenase activity in bronchoalveolar lavage fluid and ethidium homodimer-1 cellular staining in the lung in situ as an index of cytotoxicity. Basal gene expression between neonates and adults differed for a significant number of antioxidant, oxidative stress, and proliferation genes and was further altered by PFP exposure. PFP diminishes proliferation marker PCNA gene and protein expression in neonates but not adults. We conclude that neonates have an impaired ability to respond to environmental exposures that increases lung cytotoxicity and results in enhanced susceptibility to PFP, which may lead to abnormal airway growth.


Subject(s)
Air Pollutants/toxicity , Fires , Inhalation Exposure/adverse effects , Lung/drug effects , Soot/toxicity , Air Pollutants/chemistry , Animals , Animals, Newborn , Antioxidants/metabolism , Cell Survival/drug effects , Cell Survival/genetics , Gene Expression/drug effects , Gene Expression Profiling , Lung/growth & development , Lung/metabolism , Lung/pathology , Male , Microscopy, Electron, Transmission , Oxidative Stress/drug effects , Oxidative Stress/genetics , Particle Size , Proliferating Cell Nuclear Antigen/genetics , Rats , Rats, Sprague-Dawley , Soot/chemistry , Surface Properties
12.
Am J Physiol Lung Cell Mol Physiol ; 300(3): L362-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21148791

ABSTRACT

Nitrite (NO(2)(-)) has been shown to limit injury to the heart, liver, and kidneys in various models of ischemia-reperfusion injury. Potential protective effects of systemic NO(2)(-) in limiting lung injury or enhancing repair have not been documented. We assessed the efficacy and mechanisms by which postexposure intraperitoneal injections of NO(2)(-) mitigate chlorine (Cl(2))-induced lung injury in rats. Rats were exposed to Cl(2) (400 ppm) for 30 min and returned to room air. NO(2)(-) (1 mg/kg) or saline was administered intraperitoneally at 10 min and 2, 4, and 6 h after exposure. Rats were killed at 6 or 24 h. Injury to airway and alveolar epithelia was assessed by quantitative morphology, protein concentrations, number of cells in bronchoalveolar lavage (BAL), and wet-to-dry lung weight ratio. Lipid peroxidation was assessed by measurement of lung F(2)-isoprostanes. Rats developed severe, but transient, hypoxemia. A significant increase of protein concentration, neutrophil numbers, airway epithelia in the BAL, and lung wet-to-dry weight ratio was evident at 6 h after Cl(2) exposure. Quantitative morphology revealed extensive lung injury in the upper airways. Airway epithelial cells stained positive for terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL), but not caspase-3. Administration of NO(2)(-) resulted in lower BAL protein levels, significant reduction in the intensity of the TUNEL-positive cells, and normal lung wet-to-dry weight ratios. F(2)-isoprostane levels increased at 6 and 24 h after Cl(2) exposure in NO(2)(-)- and saline-injected rats. This is the first demonstration that systemic NO(2)(-) administration mitigates airway and epithelial injury.


Subject(s)
Inhalation Exposure , Lung Injury/pathology , Lung Injury/prevention & control , Sodium Nitrite/administration & dosage , Sodium Nitrite/pharmacology , Animals , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Chlorine , F2-Isoprostanes/metabolism , In Situ Nick-End Labeling , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/physiopathology , Lung Injury/chemically induced , Lung Injury/physiopathology , Male , Nitrogen Dioxide/metabolism , Oxygen/metabolism , Rats , Rats, Sprague-Dawley , Respiration/drug effects
13.
Am J Physiol Lung Cell Mol Physiol ; 300(3): L462-71, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21131396

ABSTRACT

Early life is a dynamic period of growth for the lung and immune system. We hypothesized that ambient ozone exposure during postnatal development can affect the innate immune response to other environmental challenges in a persistent fashion. To test this hypothesis, we exposed infant rhesus macaque monkeys to a regimen of 11 ozone cycles between 30 days and 6 mo of age; each cycle consisted of ozone for 5 days (0.5 parts per million at 8 h/day) followed by 9 days of filtered air. Animals were subsequently housed in filtered air conditions and challenged with a single dose of inhaled LPS at 1 yr of age. After completion of the ozone exposure regimen at 6 mo of age, total peripheral blood leukocyte and polymorphonuclear leukocyte (PMN) numbers were reduced, whereas eosinophil counts increased. In lavage, total cell numbers at 6 mo were not affected by ozone, however, there was a significant reduction in lymphocytes and increased eosinophils. Following an additional 6 mo of filtered air housing, only monocytes were increased in blood and lavage in previously exposed animals. In response to LPS challenge, animals with a prior history of ozone showed an attenuated peripheral blood and lavage PMN response compared with controls. In vitro stimulation of peripheral blood mononuclear cells with LPS resulted in reduced secretion of IL-6 and IL-8 protein in association with prior ozone exposure. Collectively, our findings suggest that ozone exposure during infancy can result in a persistent effect on both pulmonary and systemic innate immune responses later in life.


Subject(s)
Lipopolysaccharides/pharmacology , Lung/drug effects , Macaca mulatta/blood , Ozone/pharmacology , Aging/drug effects , Animals , Animals, Newborn , Bronchoalveolar Lavage Fluid/cytology , Cytokines/metabolism , Inflammation/pathology , Inhalation Exposure , Leukocyte Count , Leukocytes/cytology , Leukocytes/drug effects , Lung/metabolism , Male
14.
Inhal Toxicol ; 22 Suppl 2: 70-83, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20961279

ABSTRACT

Current studies of particulate matter (PM) are confounded by the fact that PM is a complex mixture of primary (crustal material, soot, metals) and secondary (nitrates, sulfates, and organics formed in the atmosphere) compounds with considerable variance in composition by sources and location. We have developed a laboratory-based PM that is replicable, does not contain dust or metals and that can be used to study specific health effects of PM composition in animal models. We exposed both neonatal (7 days of age) and adult rats to a single 6-h exposure of laboratory generated fine diffusion flame particles (DFP; 170 µg/m(3)), or filtered air. Pulmonary gene and protein expression as well as indicators of cytotoxicity were evaluated 24 h after exposure. Although DFP exposure did not alter airway epithelial cell composition in either neonates or adults, increased lactate dehydrogenase activity was found in the bronchoalveolar lavage fluid of neonates indicating an age-specific increase in susceptibility. In adults, 16 genes were differentially expressed as a result of DFP exposure whereas only 6 genes were altered in the airways of neonates. Glutamate cysteine ligase protein was increased in abundance in both DFP exposed neonates and adults indicating an initiation of antioxidant responses involving the synthesis of glutathione. DFP significantly decreased catalase gene expression in adult airways, although catalase protein expression was increased by DFP in both neonates and adults. We conclude that key airway antioxidant enzymes undergo changes in expression in response to a moderate PM exposure that does not cause frank epithelial injury and that neonates have a different response pattern than adults.


Subject(s)
Antioxidants/metabolism , Inhalation , Lung/pathology , Particulate Matter/toxicity , Respiratory System/pathology , Soot/toxicity , Administration, Inhalation , Age Factors , Animals , Animals, Newborn , Bronchoalveolar Lavage Fluid , Catalase/metabolism , Gene Expression , Glutamate-Cysteine Ligase/metabolism , Male , Particle Size , Rats , Rats, Sprague-Dawley , Respiratory System/metabolism
15.
J Appl Physiol (1985) ; 109(4): 1115-24, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20634362

ABSTRACT

Increasing numbers of epidemiologic studies associate air pollution exposure in children with decreased lung function development. The objective of this study was to examine the effects of exposure to combustion-generated fine [230 and 212 nm number mean aerodynamic particle diameter (NMAD)] to ultrafine (73 nm NMAD) particles differing in elemental (EC) and organic (OC) carbon content on postnatal airway development in rats. Neonatal Sprague-Dawley rats were exposed from postnatal day 7 through 25, and lung function and airway architecture were evaluated 81 days of age. In a separate group of rats, cell proliferation was examined after a single particle exposure at 7 days of age. Early life exposure to 73 nm high OC/EC particles altered distal airway architecture and resulted in subtle changes in lung mechanics. Early life exposure to 212 nm high OC/EC particles did not alter lung architecture but did alter lung mechanics in a manner suggestive of central airway changes. In contrast, early life exposure to 230 nm low OC/EC particles did not alter lung architecture or mechanics. A single 6-h exposure to 73 nm high OC/EC particle decreased airway cell proliferation, whereas 212 nm high OC/EC particles increased it and 230 nm low OC/EC particles did not. The early life exposure to ultrafine, high OC/EC particles results in persistent alterations in distal airway architecture that is characterized by an initial decrease in airway cell proliferation.


Subject(s)
Carbon/toxicity , Lung/drug effects , Particulate Matter/toxicity , Age Factors , Animals , Animals, Newborn , Bronchial Provocation Tests , Bronchoconstriction/drug effects , Cell Proliferation/drug effects , Immunohistochemistry , Inhalation Exposure , Lung/diagnostic imaging , Lung/growth & development , Lung/metabolism , Particle Size , Proliferating Cell Nuclear Antigen/metabolism , Rats , Rats, Sprague-Dawley , Respiratory Mechanics/drug effects , X-Ray Microtomography
16.
Anat Rec (Hoboken) ; 293(6): 947-54, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20503389

ABSTRACT

The basement membrane zone (BMZ) appears as three component layers: the lamina lucida, lamina densa, and lamina reticularis. The laminas lucida and densa are present during all stages of development. The lamina reticularis appears during postnatal development. Collagens I, III, and V form heterogeneous fibers that account for the thickness of the lamina reticularis. Additionally, there are three proteoglycans considered as integral components of the BMZ: perlecan, collagen XVIII, and bamacan. Perlecan is the predominant heparan sulfate proteoglycan in the airway BMZ. It is responsible for many of the functions attributed to the BMZ, in particular, trafficking of growth factors and cytokines between epithelial and mesenchymal cells. Growth factor binding sites on perlecan include FGF-1, FGF-2, FGF-7, FGF-10, PDGF, HGF, HB-EGF, VEGF, and TGF-beta. Growth factors pass through the BMZ when moving between the epithelial and mesenchymal cell layers. They move by rapid reversible binding with sites on both the heparan sulfate chains and core protein of perlecan. In this manner, perlecan regulates movement of growth factors between tissues. Another function of the BMZ is storage and regulation of FGF-2. FGF-2 has been shown to be involved with normal growth and thickening of the BMZ. Thickening of the BMZ is a feature of airway remodeling in asthma. It may have a positive effect by protecting against airway narrowing and air trapping. Conversely, it may have a negative effect by influencing trafficking of growth factors in the epithelial mesenchymal trophic unit. However, currently the significance of BMZ thickening is not known.


Subject(s)
Basement Membrane/growth & development , Primates/growth & development , Respiratory Mucosa/growth & development , Respiratory System/growth & development , Animals , Animals, Newborn/anatomy & histology , Animals, Newborn/growth & development , Basement Membrane/anatomy & histology , Humans , Lung Diseases/pathology , Lung Diseases/physiopathology , Primates/anatomy & histology , Respiratory Mucosa/anatomy & histology , Respiratory System/anatomy & histology , Trachea/anatomy & histology , Trachea/growth & development
17.
Comput Med Imaging Graph ; 34(7): 572-8, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20382502

ABSTRACT

Developing detailed lung airway models is an important step towards understanding the respiratory system. While modern imaging and airway casting approaches have dramatically improved the potential detail of such models, challenges have arisen in image processing as the demand for greater detail pushes the image processing approaches to their limits. Airway segmentations with proper topology have neither loops nor invalid voxel-to-voxel connections. Here we describe a new technique for segmenting airways with proper topology and apply the approach to an image volume generated by magnetic resonance imaging of a silicone cast created from an excised monkey lung.


Subject(s)
Bronchi/anatomy & histology , Image Processing, Computer-Assisted , Imaging, Three-Dimensional , Magnetic Resonance Imaging , Animals , Bronchi/physiology , Hydrodynamics , Macaca mulatta , Male , Models, Anatomic , Rats
18.
Am J Physiol Lung Cell Mol Physiol ; 298(4): L543-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20139177

ABSTRACT

Collagen VII anchoring fibrils in the basement membrane zone (BMZ) are part of a supracellular anchoring network that attaches the epithelium to the BMZ. Sloughing of airway epithelium in asthmatics (creola bodies) is a pathology associated with the supracellular anchoring network. In a rhesus monkey model of house dust mite (HDM)-induced allergic asthma, we found increased deposition of collagen I in the BMZ. In this study, we determine whether HDM also affected deposition of collagen VII in the BMZ. In the developing airway of rhesus monkeys, the width of collagen VII anchoring fibrils in the BMZ was 0.02 +/- 0.04 microm at 1 mo of age. At 6 mo the width had increased to 1.28 +/- 0.34 microm and at 12 mo 2.15 +/- 0.13 microm. In animals treated with HDM, we found a 42.2% reduction in the width of collagen VII layer in the BMZ at 6 mo (0.74 +/- 0.15 microm; P < 0.05). During recovery, the rate of collagen VII deposition returned to normal. However, the amount of collagen VII lost was not recovered after 6 mo. We concluded that normal development of the collagen VII attachment between the epithelium and BMZ occurs in coordination with development of the BMZ. However, in HDM-treated animals, the collagen VII attachment with the epithelium was significantly reduced. Such a reduction in collagen VII may weaken the supracellular anchoring network and be associated with sloughing of the epithelium and formation of creola bodies in asthmatics.


Subject(s)
Basement Membrane/pathology , Collagen Type VII/metabolism , Fibrillar Collagens/metabolism , Macaca mulatta/parasitology , Pyroglyphidae/physiology , Trachea/pathology , Animals , Animals, Newborn , Basement Membrane/metabolism , Basement Membrane/parasitology , Immunohistochemistry , Trachea/growth & development , Trachea/metabolism , Trachea/parasitology
19.
Anat Rec (Hoboken) ; 291(8): 916-26, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18561195

ABSTRACT

Rats are widely used for studies of pulmonary toxicology and lung disease. Several studies suggest nominal geometric parameters describing the architecture of the rat airway. However, intersubject variance has never been reported due to the huge effort and time to take these manual measurements. In this study, we present statistics of the branching pattern of six healthy male Sprague Dawley rats by automatically analyzing computed tomography images of silicon casts of their airways. Details of branching characteristics and also intersubject variance are presented. In addition, this study shows that mean and standard deviation of many geometric parameters insufficiently represent pulmonary architecture because some, such as diameter-asymmetry, are not normally distributed. Detailed statistics including inter- and intrasubject variance and distribution of the geometric parameters will aid in constructing more realistic airway models for particle transport and studies of normal and abnormal respiratory physiology.


Subject(s)
Lung/anatomy & histology , Lung/physiology , Animals , Lung/diagnostic imaging , Lung Diseases/pathology , Lung Diseases/physiopathology , Male , Models, Biological , Rats , Rats, Sprague-Dawley , Reference Values , Tomography, X-Ray Computed
20.
J Theor Biol ; 253(2): 381-7, 2008 Jul 21.
Article in English | MEDLINE | ID: mdl-18430440

ABSTRACT

Analyses of human airway architecture based on calculations of airflow resistance or energy dissipation suggest that the branching pattern is not optimized for minimizing energy loss by flow dissipation during respiration. Airway flow dissipates only a few percent of the total body work during normal breathing, so branching patterns deviate from minimum energy loss to also optimize other physiological needs. Studies of airway performance often record some measure of expiration, such as FEV1 (Forced Expiratory Volume in 1s), because airway constriction during expiration limits the rate of rapid respiration. We posit that lung structure is optimized for the rate of expiration as well as minimum energy loss. By increasing the daughter-to-parent airway diameter ratio (h) from 0.794 (corresponding to the energy minimum for symmetrically branching airways) to 0.85 (the observed value in humans) luminal pressures at airway generations 4-15 were substantially increased during exercise (a 4.5 and 15 cmH2O increase during moderate and heavy exercise, respectively). Values of h somewhat larger than 0.794 help airways remain open during expiration by increasing both viscous pressure drop and convective acceleration pressure drop. Asymmetric bifurcations also exhibit higher proximal airway pressures than symmetric ones, but the improvement was not large.


Subject(s)
Airway Resistance/physiology , Exhalation/physiology , Lung/anatomy & histology , Models, Biological , Exercise/physiology , Forced Expiratory Volume/physiology , Humans , Lung/physiology
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