Joanne L Wright

Publications (45)239.15 Total impact

• Article: Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease.

  Andrew Churg, Caroline V Marshall, Don D Sin, Sarah Bolton, Steven Zhou, Katherine Thain, Elaine B Cadogan, Justine Maltby, Matthew G Soars, Philip R Mallinder, Joanne L Wright
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  ABSTRACT: Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation. To determine the role of MPO in COPD. We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure. At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding. We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.
  American Journal of Respiratory and Critical Care Medicine 01/2012; 185(1):34-43. · 11.08 Impact Factor
• Source

  Available from: PubMed Central

  Article: Regional heterogeneity in murine lung fibroblasts from normal mice or mice exposed once to cigarette smoke.

  Olena Preobrazhenska, Joanne L Wright, Andrew Churg
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  ABSTRACT: Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure.
  PLoS ONE 01/2012; 7(6):e39761. · 4.09 Impact Factor
• Article: The complex relationship of serum adiponectin to COPD outcomes.

  Hoil Yoon, Yuexin Li, S F Paul Man, Donald Tashkin, Robert A Wise, John E Connett, Nicholas A Anthonisen, Andrew Churg, Joanne L Wright, Don D Sin
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  ABSTRACT: ABSTRACT BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder with high risk of cardiovascular morbidity and mortality. Adiponectin is a hormone that has anti-inflammatory, anti-diabetic, and anti-atherogenic activities. We investigated the relationship of serum adiponectin to health outcomes in COPD. METHODS:We measured adiponectin levels in serum samples from participants of the Lung Health Study (LHS), who were smokers with mild to moderate airflow limitation. We determined the relationship of serum adiponectin to hospitalization and mortality using Cox proportional hazards model and to baseline lung function measurements and to bronchial reactivity using multiple regression methods. RESULTS:Serum adiponectin concentrations were inversely related to hospitalizations and mortality from coronary heart disease (hazard ratio, HR, 0.73; 95% CI, 0.62 to 0.86) and to cardiovascular disease (HR, 0.83; 95% CI, 0.73 to 0.94) and positively related to deaths from respiratory causes (HR, 2.09; 95% CI, 1.41 to 3.11). However, serum adiponectin concentrations were not significantly related to total mortality (HR, 1.10; 95% CI, 0.93 to 1.29) or cancer-related mortality (HR, 1.11; 95% 0.92 to 1.34). Serum adiponectin concentrations were significantly related to increased bronchial reactivity and an accelerated decline in lung function (both p<.0001). Smoking status had no material influence on serum adiponectin concentrations. CONCLUSIONS:Adiponectin is a complex serum biomarker in COPD, which is associated with decreased risk of cardiovascular events but increased risk of respiratory mortality. Because serum adiponectin is not significantly influenced by smoking status, it is a very promising biomarker of cardiovascular outcomes in COPD.
  Chest 12/2011; · 5.25 Impact Factor
• Article: AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.

  T Stevens, K Ekholm, M Gränse, M Lindahl, V Kozma, C Jungar, T Ottosson, H Falk-Håkansson, A Churg, J L Wright, H Lal, A Sanfridson
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  ABSTRACT: N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1β. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.
  Journal of Pharmacology and Experimental Therapeutics 08/2011; 339(1):313-20. · 3.83 Impact Factor
• Article: Everything prevents emphysema: are animal models of cigarette smoke-induced chronic obstructive pulmonary disease any use?

  Andrew Churg, Don D Sin, Joanne L Wright
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  ABSTRACT: There is a very large number of experimental approaches that prevent cigarette smoke-induced emphysema in laboratory animals, but the few similar treatments that have been tried in humans have had minimal effects, leading to questions of whether animal models of chronic obstructive pulmonary disease (COPD) are of any use in developing treatments for human disease. We review possible reasons for this problem. First, humans usually get treated when they have severe (Global Initiative for Chronic Obstructive Lung Disease III/IV) COPD, but animal models only produce mild (Global Initiative for Chronic Obstructive Lung Disease I/II) disease that never progresses after smoking cessation, and never develops spontaneous exacerbations (i.e., animal models are not models of severe human disease, and probably can't be used to model treatment of severe disease). Second, animal models have concentrated on emphysema and largely ignored small airway remodeling, but small airway remodeling is an equally important cause of airflow obstruction. In addition, small airway remodeling and emphysema are independent responses to smoke, and some experimental animal treatments prevent both lesions, but many do not. Third, animal models are typically Day 1 of smoke exposure "prevention" models, but humans are always treated well along in the course of their disease; thus, any human treatment will be an intervention, and not a prevention. We propose that animal models should examine both emphysema and small airway remodeling, and that experiments should include a relatively late intervention arm. This approach, combined with the realization that human COPD probably needs early rather than late treatment, may make development of treatments based on animal models more relevant.
  American Journal of Respiratory Cell and Molecular Biology 06/2011; 45(6):1111-5. · 5.13 Impact Factor
• Article: Desquamative interstitial pneumonia.

  Henry D Tazelaar, Joanne L Wright, Andrew Churg
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  ABSTRACT: Desquamative interstitial pneumonia (DIP) is one of the rarest of the idiopathic interstitial pneumonias. It is characterized by the accumulation of macrophages in large numbers in the alveolar spaces associated with interstitial inflammation and/or fibrosis. The macrophages frequently contain light brown pigment, and because of their association with smoking have been called 'smoker's macrophages'. Lymphoid nodules are common, as is a sparse but distinct eosinophil infiltrate. Most cases of DIP are caused by cigarette smoking, but drugs and other inhaled agents, including marijuana smoke, can also produce the same disease. Although respiratory bronchiolitis-interstitial lung disease (RB-ILD) is a closely related process, there are prognostic reasons for continuing to separate it from DIP when possible. The proposed relationship of DIP to fibrotic non-specific interstitial pneumonia (NSIP) remains uncertain. The prognosis of DIP appears to be significantly better than that of fibrotic NSIP, so while there can be morphological overlap between the two, merging them into one disease may hide important prognostic information. Although the majority of DIP patients improve on treatment, some patients develop progressive irreversible fibrosis.
  Histopathology 03/2011; 58(4):509-16. · 3.08 Impact Factor
• Article: Fibrosis with emphysema.

  Joanne L Wright, Henry D Tazelaar, Andrew Churg
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  ABSTRACT: The concept of fibrosis with emphysema is confused by the existence of two very different clinical/pathological scenarios: first, cases in which a diffuse fibrosing interstitial pneumonia, most commonly usual interstitial pneumonia (UIP), occurs in a patient with emphysema. This combination is largely of clinical interest because of its effects on pulmonary function and pulmonary hypertension, but can produce unusual appearances in surgical lung biopsies when the fibrotic areas are wrapped around emphysematous spaces. However, the underlying morphology of emphysema and UIP or other interstitial lung disease remains unchanged. Radiological consultation is often helpful to show that the patient has both lesions; secondly, cases in which there is localized fibrosis that is part of emphysema, or related to respiratory bronchiolitis, or both. These lesions have been called 'respiratory bronchiolitis' (RB), 'respiratory bronchiolitis-interstitial lung disease' (RB-ILD), 'airspace enlargement with fibrosis', 'RB-ILD with fibrosis' and 'clinically occult interstitial fibrosis in smokers', but are probably all the same entity. Such changes are associated only rarely with the physiological or radiological features of an interstitial lung disease. Care should be taken when describing these lesions in biopsies so as not to give the impression that a diffuse interstitial lung disease is present.
  Histopathology 03/2011; 58(4):517-24. · 3.08 Impact Factor
• Article: Acute exacerbations of fibrotic interstitial lung disease.

  Andrew Churg, Joanne L Wright, Henry D Tazelaar
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  ABSTRACT: An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy.
  Histopathology 03/2011; 58(4):525-30. · 3.08 Impact Factor
• Article: Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling.

  Joanne L Wright, Steven Zhou, Olena Preobrazhenska, Caroline Marshall, Don D Sin, Ismail Laher, Saeid Golbidi, Andrew M Churg
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  ABSTRACT: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.
  American Journal of Respiratory and Critical Care Medicine 01/2011; 183(1):50-8. · 11.08 Impact Factor
• Article: Animal models of cigarette smoke-induced chronic obstructive pulmonary disease.

  Joanne L Wright, Andrew Churg
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  ABSTRACT: Chronic exposure of laboratory animals to cigarette smoke reproduces many of the anatomic/physiologic lesions (emphysema, small-airway remodeling and pulmonary hypertension) of human chronic obstructive pulmonary disease, although smoke-exposed laboratory animals are not good models of chronic bronchitis or acute exacerbations, as these are conditions based upon symptoms that are not recapitulated in animals. Many types of antiproteolytic and anti-inflammatory interventions, such as use of drugs or genetic modifications, are highly effective in preventing emphysema in these models, and some also prevent small-airway remodeling and pulmonary hypertension. However, the few attempts to translate these therapies into humans have been unsuccessful, probably because the animal models typically start therapy from day 1 of smoke exposure, whereas most humans are treated late in the course of their disease. Recent data from our laboratory suggest that the parenchyma can repair smoke-induced damage for some period, but then switches to a mode where it fails to repair; these observations suggest that the timing of an intervention in humans may be crucial to its success. The various different anatomic lesions induced by smoke appear to be largely independent effects and may require different therapeutic approaches.
  Expert Review of Respiratory Medicine 12/2010; 4(6):723-34.
• Article: Respiratory bronchiolitis/interstitial lung disease: fibrosis, pulmonary function, and evolving concepts.

  Andrew Churg, Nestor L Müller, Joanne L Wright
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  ABSTRACT: The concept of respiratory bronchiolitis/interstitial lung disease (RBILD) was introduced to explain the presence of interstitial lung disease in individuals whose only finding on surgical lung biopsy was smoker's respiratory bronchiolitis (RB). Over time, the diagnostic criteria for RBILD have become progressively more confused. To review the diagnostic criteria for RBILD. The review was based on the literature and personal experience. The concept of RBILD has changed over time with the recognition that, histologically and radiologically, RB and RBILD are usually indistinguishable. Most authors accept mild alveolar wall fibrosis extending away from the respiratory bronchioles as a part of both RB and RBILD, and occasional cases show quite marked, but probably localized, interstitial fibrosis. What has not been appreciated is that RB is not only an extremely common disease in cigarette smokers but also is ordinarily associated with airflow obstruction. Further, interstitial fibrosis is sometimes found in centrilobular emphysema, and this phenomenon has probably lead to some cases of centrilobular emphysema being misclassified as RB or RBILD. Despite the presence of fibrosis, centrilobular emphysema is still associated with airflow obstruction. We suggest that RBILD be restricted to the clinical setting in which cigarette smokers have a restrictive or mixed obstructive and restrictive functional abnormality, have a marked decrease in diffusing capacity with minimal evidence of airflow obstruction, or have imaging studies showing ground glass opacities/centrilobular nodules plus reticulation and no other lesion besides RB on biopsy to account for these changes. In this setting, the presence of RB-associated interstitial fibrosis probably causes the functional changes.
  Archives of pathology & laboratory medicine 01/2010; 134(1):27-32. · 2.58 Impact Factor
• Article: Modification of the rat airway explant transcriptome by cigarette smoke.

  Yolanda S López-Boado, Jun U Li, Chris L Clayton, Joanne L Wright, Andrew Churg
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  ABSTRACT: Although a number of animal model studies have addressed changes in gene expression in the parenchyma and their relationship to emphysema, much less is known about the pathogenesis of cigarette smoke-induced small airway remodeling. In this study the authors exposed rat tracheal explants, a model of the airway wall, to whole smoke for 15 min, and then cultured the explants in air. The airway transcriptome was evaluated using RAE 230_2 gene chips. By 2 h after starting smoke exposure, expression levels of 502 genes were differentially expressed by more than 1.5 times (p < .01 or less) and by 24 h 1870 genes were significantly changed up or down. These included genes involved in antioxidant protection, epithelial defense and remodeling, inflammatory mediators and transcription factors, and a number of unexpected genes, including the matrix metalloproteinase (MMP)-12 inducer, tachykinin-1 (substance P). Pretreatment of the explants with 1 x 10(-7) M dexamethasone reduced the number of significantly changed genes by approximately 47% at 2 h and 68% at 24 h and in almost all instances reduced the magnitude of the smoke-induced changes. The authors conclude that even a very brief exposure to cigarette smoke can lead to rapid changes in the expression of a large number of genes in rat tracheal explants, and that these effects are directly mediated by smoke, without a need for exogenous inflammatory cells. Steroids, contrary to the usual belief, are able to ameliorate many of these changes, at least in this very acute model.
  Inhalation Toxicology 11/2009; 22(3):234-44. · 1.92 Impact Factor
• Article: Testing drugs in animal models of cigarette smoke-induced chronic obstructive pulmonary disease.

  Andrew Churg, Joanne L Wright
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  ABSTRACT: Animal models of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) provide potentially useful ways to test drug therapies, either by direct administration of the treatment of interest, or by use of genetically modified animals that mimic the actions of the drug of interest. Evaluation of the potential effects of a drug in animal models requires a long-term (generally 6-mo) smoke exposure to produce/prevent lesions because acute models do not completely predict chronic events. There are now more than 30 chronic studies in the literature which, in aggregate, show that antiproteolytic therapies, antiinflammatory therapies, and antioxidant therapies substantially or completely prevent emphysema, small airway remodeling, and pulmonary hypertension in laboratory animals. However, the few corresponding trials in humans (anti-TNF-alpha therapy, PDE4 inhibitors) have produced only minor improvements or failed to prevent disease progression. New data from our laboratory indicates that, at least for murine emphysema, the development of disease goes through different phases, with early repair and late failure to repair smoke-induced damage. These observations suggest that the potential effects of drug treatment in humans may vary depending on the stage of the disease and that treatment may be more effective in relatively early disease. An additional complicating factor is that interventions that ameliorate emphysema may or may not prevent small airway remodeling and/or pulmonary hypertension, suggesting that different therapeutic approaches may be needed for the various different anatomic lesions of COPD.
  Proceedings of the American Thoracic Society 10/2009; 6(6):550-2.
• Source

  Available from: pnas.org

  Article: alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice.

  Eli C Lewis, Mark Mizrahi, Michel Toledano, Nathaniel Defelice, Joanne L Wright, Andrew Churg, Leland Shapiro, Charles A Dinarello
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  ABSTRACT: Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor alpha1-antitrypsin (AAT) possesses antiinflammatory properties and reduces cytokine-mediated islet damage. In the present study, diabetic mice were grafted with allogeneic islets and treated with AAT monotherapy (n = 24). After 14 days of treatment, mice remained normoglycemic and islet allografts were functional for up to 120 treatment-free days. After graft removal and retransplantation, mice accepted same-strain islets but rejected third-strain islets, thus confirming that specific immune tolerance had been induced. Explanted grafts exhibited a population of T regulatory cells in transplant sites. According to RT-PCR, grafts contained high levels of mRNA for foxp3, cytotoxic T lymphocyte antigen-4, TGF-beta, IL-10, and IL-1 receptor antagonist; expression of proinflammatory mediators was low or absent. After implantation of skin allografts, AAT-treated mice had greater numbers of foxp3-positive cells in draining lymph nodes (DLNs) compared with control treatment mice. Moreover, dendritic cells in DLNs exhibited an immature phenotype with decreased CD86 activation marker. Although the number of CD3 transcripts decreased in the DLNs, AAT did not affect IL-2 activity in vitro. Thus, AAT monotherapy provides allografts with antiinflammatory conditions that favor development of antigen-specific T regulatory cells. Because AAT treatment in humans is safe, its use during human islet transplantation may be considered.
  Proceedings of the National Academy of Sciences 11/2008; 105(42):16236-41. · 9.68 Impact Factor
• Article: The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling.

  Andrew Churg, Steven Zhou, Xiaoshan Wang, Rona Wang, Joanne L Wright
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  ABSTRACT: Interleukin-1beta (IL-1beta), a proinflammatory cytokine, is elevated in cigarette smokers. To determine whether IL-1beta plays a role in the pathogenesis of cigarette smoke-induced emphysema and small airway remodeling, IL-1 receptor knockout (IL1RKO), TNF-alpha receptor knockout (TNFRKO), or C57Bl/6 (control) mice were exposed to cigarette smoke acutely or for up to 6 months. With a single acute exposure, smoke elevated IL-1beta in C57Bl/6 mice. IL1RKO mice were protected against acute smoke-mediated increases in lavage inflammatory cells and matrix breakdown. In C57Bl/6 mice, acute smoke-mediated increases in inflammatory cells, serum IL-1beta, and serum TNF-alpha were blocked by z-VAD-fmk, a pan-caspase inhibitor, or z-WEHD-fmk, a caspase-1 (IL-1-converting enzyme, [ICE]) inhibitor. With 6 months of exposure, IL-1beta was no longer increased, but IL-18 was elevated. After 6 months of exposure, IL1RKO mice were 65% protected against emphysema, whereas TNFRKO mice were 83% protected. Both strains were completely protected against small airway remodeling. Lavage desmosine, hydroxyproline, and hyaluronan, matrix breakdown markers, were elevated in C57 but not IL1RKO mice. We conclude that IL-1beta plays a significant role in induction of murine emphysema and small airway remodeling, and is comparable to TNF-alpha in its effects. The protective effects of caspase inhibitors appear to be related to inhibition of ICE and raise the question of whether models that ameliorate emphysema with caspase inhibitors are really blocking IL-1beta (and IL-18) activation rather than blocking apoptosis.
  American Journal of Respiratory Cell and Molecular Biology 11/2008; 40(4):482-90. · 5.13 Impact Factor
• Article: Expression of profibrotic mediators in small airways versus parenchyma after cigarette smoke exposure.

  Andrew Churg, Steven Zhou, Olena Preobrazhenska, Hsin Tai, Rona Wang, Joanne L Wright
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  ABSTRACT: Cigarette smoke-induced lung disease presents a morphologic contradiction in that the small airways become fibrotic but the parenchyma becomes emphysematous over time. To examine the mechanisms behind these phenomena, we exposed mice to cigarette smoke for up to 6 months and isolated small airways from histologic sections by laser capture microdissection. We then removed residual airway tissue and vessels, and collected the remaining parenchymal tissue. Gene expression of 13 fibrogenic growth/signaling factors (particularly TGF-beta-related genes), matrix proteins, or enzymes involved in matrix production was examined by real-time RT-PCR. Combining present and previously published data from our laboratory, in the airways over the long term there was a sustained and marked increase in expression of almost all of these genes. By contrast, in the parenchyma, expression of most genes was elevated at 2 and 24 hours after initial exposure, and all were elevated at 1 month; but by 6 months, when emphysema was present, most genes (9/13) were either at control values or down-regulated below control. At 3 months, several genes that were considerably elevated at 1 month were back to control levels, suggesting that loss of the parenchymal response precedes the development of emphysema. We conclude that with smoke exposure the airways demonstrate an ongoing profibrotic/proelastogenic response and the parenchyma a generally anti-fibrotic/anti-elastogenic response, but one that develops only with long-term exposure to smoke. These observations support the idea that the parenchyma largely fails to repair smoke-induced matrix damage, but this phenomenon is a relatively late event.
  American Journal of Respiratory Cell and Molecular Biology 09/2008; 40(3):268-76. · 5.13 Impact Factor
• Article: Animal models of chronic obstructive pulmonary disease.

  Joanne L Wright, Manuel Cosio, Andrew Churg
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  ABSTRACT: The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role.
  AJP Lung Cellular and Molecular Physiology 08/2008; 295(1):L1-15. · 3.66 Impact Factor
• Article: Mechanisms of cigarette smoke-induced COPD: insights from animal models.

  Andrew Churg, Manuel Cosio, Joanne L Wright
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  ABSTRACT: Cigarette smoke-induced animal models of chronic obstructive pulmonary disease support the protease-antiprotease hypothesis of emphysema, although which cells and proteases are the crucial actors remains controversial. Inhibition of either serine or metalloproteases produces significant protection against emphysema, but inhibition is invariably accompanied by decreases in the inflammatory response to cigarette smoke, suggesting that these inhibitors do more than just prevent matrix degradation. Direct anti-inflammatory interventions are also effective against the development of emphysema, as are antioxidant strategies; the latter again decrease smoke-induced inflammation. There is increasing evidence for autoimmunity, perhaps directed against matrix components, as a driving force in emphysema. There is intriguing but controversial animal model evidence that failure to repair/failure of lung maintenance also plays a role in the pathogenesis of emphysema. Cigarette smoke produces small airway remodeling in laboratory animals, possibly by direct induction of fibrogenic growth factors in the airway wall, and also produces pulmonary hypertension, at least in part through direct upregulation of vasoactive mediators in the intrapulmonary arteries. Smoke exposure causes goblet cell metaplasia and excess mucus production in the small airways and proximal trachea, but these changes are not good models of either chronic bronchitis or acute exacerbations. Emphysema, small airway remodeling, pulmonary hypertension, and mucus production appear to be at least partially independent processes that may require different therapeutic approaches.
  AJP Lung Cellular and Molecular Physiology 05/2008; 294(4):L612-31. · 3.66 Impact Factor
• Article: Animal models of COPD: Barriers, successes, and challenges.

  Joanne L Wright, Andrew Churg
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  ABSTRACT: Animal models have definite utility in the study of chronic obstructive pulmonary disease. However, choice of model must be determined with the full knowledge of their value, or potential limitations.
  Pulmonary Pharmacology &amp Therapeutics 03/2008; 21(5):696-8. · 2.80 Impact Factor
• Article: Hypersensitivity pneumonitis as a cause of airway-centered interstitial fibrosis.

  Mark E Fenton, Donald W Cockcroft, Joanne L Wright, Andrew Churg
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  ABSTRACT: Airway-centered interstitial fibrosis (ACIF) has been postulated to be related to environmental exposures. To describe a patient with ACIF associated with hypersensitivity pneumonitis. We evaluated a patient with a 2-year history of progressive dyspnea and exercise intolerance. We performed computed tomography, pulmonary function tests, and skin prick tests. The patient's computed tomogram suggested hypersensitivity pneumonitis. Pulmonary function testing demonstrated a restrictive pattern. Results of skin prick tests to chicken, goose, canary, and budgie were negative. However, serum precipitins were positive to serum from pigeon, goose, duck, and chicken feathers. The patient was diagnosed as having ACIF. We believe that ACIF may represent a final common pathway for lung injury due to environmental exposure.
  Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 12/2007; 99(5):465-6. · 2.83 Impact Factor