Biomedical subjects

Andrew Churg

Publications and source records attributed to Andrew Churg.

43 records · Page 3Linked to original sources

PubMed2002

Cigarette smoke induces rapid changes in gene expression in pulmonary arteries.

The pathogenesis of cigarette smoke-induced pulmonary hypertension is not well characterized. We used RT-PCR to examine gene expression of nitric oxide synthase 2 (NOS-2), nitric oxide synthase 3 (NOS-3), endothelin, and vascular endothelial growth factor (VEGF) and its flk-1 receptor (VEGF-R) in main pulmonary arteries and in intraparenchymal arteries microdissected from alcohol-fixed paraffin blocks. The main pulmonary artery and intraparenchymal vessels responded in a similar fashion, with up-regulation of endothelin, VEGF, and VEGF-R gene expression evident by 2 hours after smoke exposure. Up-regulation of gene expression was still present at 24 hours after exposure, and at this time there was also a small increase in NOS-2. As a comparison, we examined the trachea and microdissected intraparenchymal airways and found up-regulation of endothelin and NOS-2 at 2 hours and additional up-regulation of NOS-3 at 24 hours. These findings suggest that the pulmonary vasculature very rapidly responds to cigarette smoke with up-regulation of mediators that control vascular cell proliferation and vascular constriction. These changes support the idea that pulmonary hypertension in cigarette smokers reflects a direct effect of smoke on the vasculature. The pattern of response in the vessels is distinctly different from that in the airways.

Animals↗

PubMed2002

Iron loading makes a nonfibrogenic model air pollutant particle fibrogenic in rat tracheal explants.

To examine the potential role of particle iron in fibrogenicity, we loaded nonfibrogenic fine (0.12micro) TiO(2) with increasing amounts of Fe(II)-Fe(III) chloride. Dusts were applied to rat tracheal explants, which were maintained in air organ culture for 1 wk. Iron-loaded dust increased procollagen gene expression and tissue hydroxyproline. The active oxygen species (AOS) scavenger tetramethylthiourea prevented these effects. Iron loading caused nuclear factor (NF)-kappaB activation, decreased levels of total IkappaBalpha, but relatively increased levels of both IkappaBalpha-phosphoserine 32/36 and IkappaBalpha-phosphotyrosine. A citrate extract of iron-loaded dust increased procollagen expression. Gel shift using a probe consisting of the NF-kappaB consensus sequence from the prolyl-4-hydroxylase promoter and adjacent bases showed increased nuclear binding, and RT-PCR examination showed increased prolyl-hydroxylase alpha-chain gene expression after iron loading. We conclude that addition of surface iron can convert a nonreactive model air pollutant particle into a fibrogenic particle via AOS- and NF-kappaB-dependent pathways, probably through two different NF-kappaB activation pathways in two different anatomic compartments. This process may proceed in vivo through iron extracted from the dust into the cytoplasm. NF-kappaB activation may directly increase expression of prolyl hydroxylase, an enzyme involved in collagen synthesis. These findings suggest that air pollutant particles containing significant quantities of transition metals may produce airway wall fibrosis and lead to chronic obstructive pulmonary disease.

Air Pollutants↗

PubMed2002

Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice.

The cells/proteases responsible for the development of smoke-induced emphysema is an area of intense investigation. Mice with knockout of macrophage metalloelastase genes (MME(-/-)) do not develop emphysema after smoke exposure, but we also observed that neutrophils (PMN) in lavage appeared to be a requirement for acute connective tissue breakdown. In this study we exposed mice to cigarette smoke and examined lavage PMN, macrophages (MAC), desmosine (DES, a measure of elastin breakdown) and hydroxyproline (HP, a measure of collagen breakdown) 24 h afterwards. MME(+/+) mice exposed to smoke showed elevations in PMN, DES, and HP, but no elevations were seen in MME-deficient mice. Both PMN influx and increased levels of DES/HP could be restored by administering MAC from MME(+/+) mice to MME-deficient mice and then exposing them to smoke. RS113456, a metalloprotease inhibitor, also prevented PMN influx and connective tissue breakdown. Western blots against mouse alpha(1)-antitrypsin (alpha(1)AT) showed that alpha(1)AT was not protected in MME-deficient mice, nor by administration of RS113456. We conclude that, in mice, acute smoke-induced connective tissue breakdown, the precursor to emphysema, requires both PMN and MME, that PMN influx appears to be secondary to MAC activation, and that this process initially does not involve protection of alpha(1)AT from metalloprotease attack.

Animals↗

PubMed2002

A model of tobacco smoke-induced airflow obstruction in the guinea pig.

Animal models have proven to be extremely worthwhile in the investigations of cigarette smoke-induced lung disease. We have found the guinea pig to be useful, with a large number of advantages and few disadvantages when used in our experimental circumstances. Other animal models exist, however, and the investigator should select the model that is most suited to the hypothesis to be tested.

Animals↗

PubMed2002

Animal models of cigarette smoke-induced COPD.

OBJECTIVES: To review the animal models of COPD, and to compare these data to those found in humans. RESULTS: Smoke-induced animal models can produce emphysema, although the lesions are not generally close mimics of human emphysema, as well as increases in mucous-secreting cells and vascular changes including pulmonary hypertension. There is considerable species-to-species variation in the degree and/or presence of these different abnormalities, so that care has to be used in selecting a species to study. Remarkably little information is available about the biochemical and molecular changes induced by cigarette smoke in animal models. CONCLUSIONS: Great insights into the pathology of chronic obstructive lung disease have been made using various animal models.

Animals↗

PubMed2002

Airway wall remodeling induced by occupational mineral dusts and air pollutant particles.

OBJECTIVES: COPD has been reported in workers exposed to particulates, and there is increasing evidence that high levels of ambient particulate pollutants may also be associated with COPD. The studies here investigate the hypothesis that particulates, including air pollution particles, can induce airway wall fibrosis, a process that can lead to COPD. DESIGN: Rat tracheal explants were exposed to various occupationally encountered dusts, air pollution particles, and model air pollution particles. In some experiments, iron was loaded onto the particle surface. Gene expression and nuclear factor (NF)-kappaB activation were measured after 7 days of air culture. Adhesion to and uptake of dusts by the tracheal epithelium were also evaluated. RESULTS: Known fibrogenic dusts such as amosite asbestos produced increased gene expression of procollagen, transforming growth factor-beta, and platelet-derived growth factor, and increased hydroxyproline in the explants, and the addition of iron increased these effects. The addition of iron also converted nonfibrogenic TiO2 into a fibrogenic dust. Dusts with surface complexed iron activated NF-kappaB via an oxidant mechanism. However, an ultrafine TiO2 with very low iron was also fibrogenic. In separate experiments, exogenous tumor necrosis factor-alpha increased dust adhesion to, and exogenous ozone increased dust uptake by, tracheal epithelial cells. CONCLUSIONS: Mineral dusts can directly induce fibrosis in the airway wall. Exogenous inflammatory cells and exogenous agents are not required, but they probably exaggerate the fibrogenic effects. An iron-mediated oxidant mechanism underlies the fibrogenic effects of some, but not all, of these dusts. Particle-induced airway wall fibrosis may lead to COPD.

Air Pollutants↗

PubMedDate not supplied

Ferruginous bodies: implications in the mechanism of fiber and particle toxicity.

Exposures to fibers and particles can be associated with several different lung injuries including bronchitis, bronchiolitis, pneumonitis, pleuritis, pulmonary alveolar proteinosis, pneumoconiosis, mesotheliomas, and lung cancers. The mechanism of biological effect exerted by fibers and particles has not been exactly defined. Exposures to all fibers and particles introduce a solid-liquid interface into the lower respiratory tract. These surfaces all have some concentration of oxygen-containing functional groups that demonstrate a capacity to coordinate iron. Radical generation is catalyzed by this metal resulting in a cascade of cell signaling, transcription factor activation, and mediator release. We propose that the ferruginous body (i.e., a fiber or particle with a coating of both protein and iron) provides direct evidence of a participation of iron in the biological effect of both fibers and particles. It is recommended that an identification of ferruginous bodies in the lung be regarded as support for a metal-catalyzed oxidative stress in the mechanism of cell and tissue injury.

Animals↗