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Biomedical subjects

Joanne L Wright

Publications and source records attributed to Joanne L Wright.

At least 19 recordsLinked to original sources
PubMed2006

Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall.

BACKGROUND: Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers with chronic obstructive pulmonary disease, but the pathogenesis of SAR is not understood. OBJECTIVE: To determine whether smoke causes production of profibrotic growth factors in the airway wall. METHODS: We exposed C57Bl/6 mice to cigarette smoke for up to 6 mo and examined growth factor/procollagen gene expression in laser-capture microdissected small airways by real-time reverse transcription-polymerase chain reaction. RESULTS: With a single smoke exposure, increases in procollagen, connective tissue growth factor (CTGF), transforming growth factor (TGF)-beta(1), platelet-derived growth factor (PDGF)-A and -B expression were seen 2 h after the start of smoking and declined to baseline by 24 h. With repeated exposures and at killing of animals 24 h after the last exposure, increases in procollagen, CTGF, PDGF-B, and (minimally) PDGF-A expression persisted through 1 wk, 1 mo, and 6 mo. TGF-beta(1) gene expression declined over time; however, increased immunochemical staining for phopho-Smad 2 was present at all time points, indicating continuing TGF-beta downstream signaling. Morphometric analysis showed that the small airways in smoke-exposed mice had more collagen at 6 mo. CONCLUSIONS: These findings suggest that smoke can induce growth factor and procollagen production in small airways in a time frame that initially is too short for a significant inflammatory response and that profibrotic growth factor and procollagen gene expression become self-sustaining with repeated smoke exposures. These results imply that the pathogenesis of and possible treatment approaches to emphysema and small airway remodeling might be quite different.

Animals↗
PubMed2006

Chronic hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is traditionally divided on clinical grounds into acute, subacute, and chronic stages. Most biopsy specimens come from patients in the subacute stage, in which there is a relatively mild, usually peribronchiolar, chronic interstitial inflammatory infiltrate, accompanied in most cases by poorly formed interstitial granulomas or isolated giant cells. However, the pathologic features in the chronic, ie, fibrotic stage, are poorly defined in the literature. These features are important to recognize because the chronic stage of HP is often associated with a poor prognosis. We reviewed 13 cases of chronic HP. Where information was available, exposures to the sensitizing agent had generally occurred over a long period of time. Three patterns of fibrosis were seen: 1) predominantly peripheral fibrosis in a patchy pattern with architectural distortion and fibroblast foci resembling, microscopically, usual interstitial pneumonia (UIP); 2) relatively homogeneous linear fibrosis resembling fibrotic nonspecific interstitial pneumonia (NSIP); and 3) irregular predominantly peribronchiolar fibrosis. In some instances, mixtures of the UIP-like and peribronchiolar patterns were found. In all cases, the presence of scattered poorly formed granulomas, or isolated interstitial giant cells, or sometimes only Schaumann bodies indicated the correct diagnosis. In 7 cases, areas of typical subacute HP were present as well. High-resolution CT scans showed variable patterns ranging from severe fibrosis, in some instances with an upper zone predominance, to predominantly ground glass opacities with peripheral reticulation. We conclude that, at the level of morphology, chronic HP may closely mimic UIP or fibrotic NSIP. If no areas of subacute HP are evident, the presence of isolated giant cells, poorly formed granulomas, or Schaumann bodies is crucial to arriving at the correct diagnosis, and the finding of peribronchiolar fibrosis may be helpful. Despite the presence of extensive fibrosis, some patients responded to removal from exposure and steroid therapy.

Adolescent↗
PubMed2005

Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig.

The pathogenesis of pulmonary hypertension in patients with chronic obstructive pulmonary disease is not understood. We have previously shown increased levels of mediators that control vasoconstriction (endothelin-1), vascular cell proliferation (endothelin-1 and vascular endothelial growth factor), and vasodilation (endothelial nitric oxide synthase) in the intrapulmonary arteries of animals exposed to cigarette smoke. To determine whether these mediators could be implicated in the structural remodeling of the arterial vasculature and increased pulmonary arterial pressure caused by chronic cigarette smoke exposure, guinea pigs were exposed to daily cigarette smoke for 6 mo. Pulmonary arterial pressures were measured. Intrapulmonary artery structure was analyzed by morphometry, artery mediator protein expression by immunohistochemistry, and artery mediator gene expression by laser capture microdissection and real-time RT-PCR. We found that the smoke-exposed animals developed increases in pulmonary arterial pressure and increased muscularization of the small pulmonary arteries. Gene expression and protein levels of all three mediators were increased, and pulmonary arterial pressure correlated both with the levels of mediator production and with the degree of arterial muscularization. We conclude that chronic smoke exposure produces increased vasoactive mediator expression in the small intrapulmonary arteries and that these mediators are associated with vascular remodeling as well as increased pulmonary arterial pressure. These findings support the idea that hypertension in chronic obstructive pulmonary disease is a result of direct cigarette smoke-mediated effects on the vasculature and suggest that interference with endothelin and VEGF production and activity or augmentation of nitric oxide levels may be beneficial.

Animals↗
PubMed2005

Transforming growth factor-beta1 drives airway remodeling in cigarette smoke-exposed tracheal explants.

Small airway remodeling (SAR) is an important cause of airflow obstruction in cigarette smokers, but whether SAR represents a response to smoke-evoked inflammation or is directly mediated by smoke-induced growth factor production is disputed. To examine this process, we exposed rat tracheal explants, a model free of exogenous inflammatory cells, to cigarette smoke in vitro. Cigarette smoke caused release of active transforming growth factor (TGF)-beta1, and this was prevented by the oxidant scavenger tetramethythiourea. Nuclear immunostaining for phospho-Smad2, a TGF-beta downstream signaling molecule, was present in epithelial and interstitial cells within 1 h after exposure. Smoke caused upregulation of gene expression of connective tissue growth factor (CTGF), a mediator of TGF-beta fibrogenic effects, within 2 h, and upregulation of procollagen gene expression at 24 h; both changes could be prevented by the TGF-beta antagonist fetuin (alpha2-HS-glycoprotein). In a cell-free system, recombinant human TGF-beta latency-associated peptide was oxidized by cigarette smoke, and smoke released active TGF-beta1 from recombinant latent TGF-beta1 via an oxidant mechanism. These experiments suggest that SAR in cigarette smokers may be caused by direct, smoke-mediated, oxidant-driven induction of growth factor signaling in the airway wall, and that SAR does not necessarily require exogenous inflammatory cells.

Animals↗
PubMed2005

Proteases and emphysema.

PURPOSE OF REVIEW: The protease-antiprotease theory of emphysema is widely accepted, but exactly which cells/proteases play a role continues to be a controversial subject. RECENT FINDINGS: Reports in humans show increased metalloproteinase activity in emphysema, but the exact role of metalloproteinases remains unclear. In laboratory animals, neutrophils turn out to be crucial, and neutrophil influx correlates well with measurements of matrix destruction. Neutrophil influx is linked to metalloproteinase activity, and in mice MMP12-induced release of tumor necrosis factor-alpha drives neutrophil infiltration. Serine elastase inhibitors, knockout of neutrophil elastase, and interference with tumor necrosis factor-alpha signaling all provide significant protection against smoke-induced emphysema, but metalloproteinase inhibitors may yield greater protection. In genetically modified mice, emphysema can be produced by overexpression of mediators such as tumor necrosis factor-alpha, interferon-gamma, or interleukin-13, and these models show evidence of metalloproteinase, cysteine protease, and serine protease attack with complicated relationships among these mediators. Collagen breakdown also appears to be important in the genesis of emphysema. Pro-apoptotic agents produce emphysema as well, possibly via an elastolytic pathway. SUMMARY: The idea that a single protease or a single type of inflammatory cell is responsible for human emphysema is unlikely to be true; rather, there are complex interactions among proteases, and between proteases and other mediators. The problem at this time is attempting to sort out the numerous candidate effector agents and to determine which of the animal models are relevant to human disease, since there may be considerable discrepancies in the types of proteases and their roles between laboratory animals and humans. There is now good evidence from animal models that antiproteolytic therapy can be of benefit in ameliorating cigarette smoke-induced emphysema.

Animals↗
PubMed2005

Idiopathic pulmonary fibrosis: spectrum of high-resolution CT findings.

OBJECTIVE: Characteristic high-resolution CT (HRCT) findings of idiopathic pulmonary fibrosis (IPF) include reticulation, architectural distortion, and honeycombing involving mainly the lung periphery and the lower lobes. In 50% of IPF patients, HRCT is nonspecific. This article illustrates the HRCT findings of IPF correlating with the pathology. CONCLUSION: The spectrum of HRCT manifestations varies from typical findings that allow confident diagnosis to atypical patterns mimicking other diseases, including predominance of ground-glass opacity, consolidation, nodules, and atypical distribution of lesions.

Diagnosis, Differential↗
PubMed2004

Cigarette smoke induces persisting increases of vasoactive mediators in pulmonary arteries.

The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We previously reported that a single smoke exposure acutely but transiently upregulated gene expression of the vasoconstrictor/vasoproliferative agents endothelin (ET) and vascular endothelial growth factor in pulmonary arteries from rat lungs. To determine whether similar changes occurred with chronic smoke exposure, we exposed Hartley guinea pigs, an outbred strain that develops pulmonary hypertension, to smoke for 2, 4, or 12 wk. Small intrapulmonary artery branches were isolated using laser capture microdissection, and gene expression was determined by real-time polymerase chain reaction. In smoke-exposed animals, there were significantly elevated but variable increases in gene expression, with some animals demonstrating 30- to 50-fold increases. Increases in ET and vascular endothelial growth factor expression occurred early and persisted through the exposure period, whereas increases in expression of the vasodilator, endothelial nitric oxide synthase, developed more slowly. Protein levels of these mediators were also elevated by immunohistochemical staining and correlated with increases in gene expression levels. We conclude that, in some animals, cigarette smoke induces persisting and marked vascular production of mediators that control vascular muscularization and contraction/dilation. These changes may be important in the development of smoke-induced pulmonary hypertension.

Animals↗
PubMed2004

Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse.

Mice lacking tumor necrosis factor-alpha (TNF-alpha) receptors (TNFRKO mice) do not develop an inflammatory infiltrate or matrix breakdown after a single acute cigarette smoke exposure. To determine the role of TNF-alpha in the long-term development of emphysema, mice were exposed to smoke for 6 months. TNFRKO mice demonstrated an 11% increase in mean linear intercept; wild-type mice had a 38% increase. TNFRKO mice had 65% fewer neutrophils and no increase in macrophages in lavage fluid. Whole lung matrix metalloprotease (MMP)-2, MMP-9, MMP-12, MMP-13, and matrix type-1 (MT1)-MMP proteins were increased in wild-type mice, but smaller increases in MMP-12, MMP-13, and MT1-MMP were also seen in TNFRKO mice. Lavage matrix breakdown products were elevated in wild-type mice and only partially reduced by anti-neutrophil antibody, implying both neutrophil- and non-neutrophil-mediated matrix breakdown. We conclude that TNF-alpha-mediated processes, probably driving neutrophil influx, are responsible for approximately 70% of airspace enlargement and the majority of inflammatory cell influx/matrix breakdown in the mouse model. TNF-alpha causes increased MMP production, but some increased MMP activity is present even in TNFRKO mice. These findings imply a second TNF-alpha-independent process, possibly related to direct MMP attack on matrix, that produces the remaining 30% of airspace enlargement.

Animals↗
PubMed2003

Cigarette smoke produces airway wall remodeling in rat tracheal explants.

Small airway remodeling ("small airways disease") is a common finding in cigarette smokers and is an important cause of airflow obstruction. Airway remodeling is usually attributed to the effects of cigarette smoke-induced inflammation in the airway wall, but little is actually known about its pathogenesis. We exposed rat tracheal explants to cigarette smoke and then maintained them in air organ culture. At 24 hours after smoke exposure, there was a dose-dependent increase in gene expression of procollagen and a significant increase in tissue hydroxyproline, a measure of collagen content. Greater increases in procollagen gene expression were found with repeated smoke exposures. Increased procollagen gene expression could be prevented with SN50, a selective inhibitor of nuclear factor-kappaB activation, and superoxide dismutase, catalase, and tetramethylthiourea, scavengers of active oxygen species. AG1478, an inhibitor of epidermal growth factor receptor signaling, also prevented increased procollagen gene expression, but PD98059 and SB203580, inhibitors of mitogen-activated protein kinases, did not. These findings indicate that cigarette smoke can directly induce airway remodeling, specifically airway wall fibrosis, probably through active oxygen species-dependent transactivation of the epidermal growth factor receptor and subsequent nuclear factor-kappaB activation. Smoke-evoked inflammatory cells are not required for this process.

Animals↗
PubMed2003

alpha-1-Antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse.

Serine elastase inhibitors have been proposed as a treatment for cigarette smoke-induced emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic serine elastase inhibitor, ZD0892, provided some protection against emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human alpha-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette smoke for up to 6 months; some animals received 20 mg of human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and elastase inhibitory capacity and abolished smoke-induced elevations in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) measured from 2 to 30 days of smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (emphysema) and abolished smoke-mediated increases in plasma tumor necrosis factor-alpha. We conclude that A1AT therapy ameliorates smoke-induced inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to tumor necrosis factor-alpha suppression, and provides partial protection against emphysema.

Animals↗
PubMed2003

Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release.

The cells and proteases that mediate cigarette smoke-induced emphysema are controversial, with evidence favoring either neutrophils and neutrophil-derived serine proteases or macrophages and macrophage-derived metalloproteases as the important effectors. We recently reported that both macrophage metalloelastase (MMP-12) and neutrophils are required for acute cigarette smoke-induced connective tissue breakdown, the precursor of emphysema. Here we show how these disparate observations can be linked. Both wild-type (MMP-12 +/+) mice and mice lacking MMP-12 (MMP-12 -/-) demonstrated rapid increases in whole-lung nuclear factor-kappaB activation and gene expression of proinflammatory cytokines after cigarette smoke exposure, indicating that a lack of MMP-12 does not produce a global failure to upregulate inflammatory mediators. However, only MMP-12 +/+ mice demonstrated increased whole-lung tumor necrosis factor-alpha (TNF-alpha) protein or release of TNF-alpha from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole-lung E-selectin, an endothelial activation marker, were increased in only MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-alpha from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. TNF-alpha release may be a general mechanism whereby metalloproteases drive cigarette smoke-induced inflammation.

Acute Disease↗
PubMed2003

Bronchiolitis caused by occupational and ambient atmospheric particles.

Occupationally encountered mineral dusts such as asbestos, silica, silicates (talc, mica), and metals can produce a distinctive pattern of fibrosis and distortion of the small airways, particularly the distal membranous bronchioles (MB) and the respiratory bronchioles (RB). Recent reports show that the same types of changes, accompanied by considerable muscle hyperplasia, are found in individuals living in regions with high levels of particulate air pollutants (PM). Models and actual measurements suggest that these changes occur because the small airways are sites of high particle deposition, and inhaled and deposited particulates, including PM, enter the airway walls. Studies from our laboratory using a tracheal explant model have shown that, for many types of particles, entry into the airway wall causes expression of mediators that lead to airway wall fibrosis and airway wall smooth muscle hyperplasia, probably through oxidant mechanisms. These reactions are intrinsic properties of the particles and do not require exogenous inflammatory cells. There is considerable evidence that individuals with occupational exposure to a wide variety of mineral dusts, as well as individuals with chronic exposure to high levels of PM, develop chronic airflow obstruction. The type of small airway remodeling seen in particle-induced bronchiolitis appears to be one cause of chronic airflow obstruction in this setting.

Journal Article↗
PubMed2003

Chronic exposure to high levels of particulate air pollution and small airway remodeling.

Recent evidence suggests that chronic exposure to high levels of ambient particulate matter (PM) is associated with decreased pulmonary function and the development of chronic airflow obstruction. To investigate the possible role of PM-induced abnormalities in the small airways in these functional changes, we examined histologic sections from the lungs of 20 women from Mexico City, a high PM locale. All subjects were lifelong residents of Mexico City, were never-smokers, never had occupational dust exposure, and never used biomass fuel for cooking. Twenty never-smoking, non-dust-exposed subjects from Vancouver, British Columbia, Canada, a low PM region, were used as a control. By light microscopy, abnormal small airways with fibrotic walls and excess muscle, many containing visible dust, were present in the Mexico City lungs. Formal grading analysis confirmed the presence of significantly greater amounts of fibrous tissue and muscle in the walls of the airways in the Mexico City compared with the Vancouver lungs. Electron microscopic particle burden measurements on four cases from Mexico City showed that carbonaceous aggregates of ultrafine particles, aggregates likely to be combustion products, were present in the airway mucosa. We conclude that PM penetrates into and is retained in the walls of small airways, and that, even in nonsmokers, long-term exposure to high levels of ambient particulate pollutants is associated with small airway remodeling. This process may produce chronic airflow obstruction.

Aged↗
PubMed2002

Synthetic serine elastase inhibitor reduces cigarette smoke-induced emphysema in guinea pigs.

To test whether a serine elastase inhibitor could prevent or reduce emphysema, we exposed guinea pigs to cigarette smoke acutely, or daily for 6 months, and treated some animals with the neutrophil elastase inhibitor ZD0892. Acute smoke exposure increased lavage neutrophils and increased desmosine and hydroxyproline, measures of elastin and collagen breakdown; all these measures were reduced by ZD0892. Long-term smoke exposure produced emphysema and increases in lavage neutrophils, desmosine, hydroxyproline, and plasma tumor necrosis factor alpha (TNF-alpha). ZD0892 treatment returned lavage neutrophils, desmosine, and hydroxyproline levels to control values, and decreased airspace enlargement by 45% and TNF-alpha by 30%. Animals exposed to smoke for 4 months and then to smoke plus ZD0892 for 2 months were not protected against emphysema. Mice exposed to smoke showed increases in gene expression of neutrophil chemoattractant macrophage inflammatory protein-2, macrophage chemoattractant protein-1, and TNF-alpha at 2 hours along with increased plasma TNF-alpha; ZD0892 prevented the increases in macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 expression and reduced plasma TNF-alpha levels to baseline. These data demonstrate that a serine elastase inhibitor ameliorates the inflammatory and destructive effects of cigarette smoke, and that these effects are mediated in part by neutrophils and by smoke-driven TNF-alpha production.

Animals↗
PubMed2002

Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown.

The role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of cigarette smoke-induced disease is controversial. We exposed mice with knocked-out p55/p75 TNF-alpha receptors (TNF-alpha-RKO mice) to cigarette smoke and compared them with control mice. Two hours after smoke exposure, increases in gene expression of TNF-alpha, neutrophil chemoattractant, macrophage inflammatory protein-2, and macrophage chemoattractant, protein-1 were seen in control mice. By 6 hours, TNF-alpha, macrophage inflammatory protein-2, and macrophage chemoattractant protein-1 gene expression levels had returned to control values in control mice and stayed at control values through 24 hours. In TNF-alpha-RKO mice, no changes in gene expression of these mediators were seen at any time. At 24 hours, control mice demonstrated increases in lavage neutrophils, macrophages, desmosine (a measure of elastin breakdown), and hydroxyproline (a measure of collagen breakdown), whereas TNF-alpha-RKO mice did not. In separate experiments, pure strain 129 mice, which produce low levels of TNF-alpha, showed no inflammatory response to smoke at 24 hours or 7 days. We conclude that TNF-alpha is central to acute smoke-induced inflammation and resulting connective tissue breakdown, the precursor of emphysema. The findings support the idea that TNF-alpha promoter polymorphisms may be of importance in determining who develops smoke-induced chronic obstructive pulmonary disease.

Analysis of Variance↗
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

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↗