Biomedical subjects
Publications and source records attributed to Andrew Churg.
This article represents a commentary on a controversial hyphothesis described by Dr.Milic-Emili in this issue. The authors discuss the hyphothesis and suggest that a re-examination of longitudinal lung function data could prove or deny his suggestion.
We describe 12 patients with a form of interstitial lung disease characterized pathologically by small airway-centered interstitial fibrosis and metaplastic bronchiolar epithelium extending around and often linking fibrotic and sometimes heavily muscularized bronchioles. Clinically, patients presented with chronic cough and progressive dyspnea. One was a current light smoker and two were ex-smokers. In 8 patients, a history of possible inhalational exposures, including wood smoke, birds, cotton, pasture, chalk dust, agrochemical compounds, and cocaine use, was elicited. Pulmonary function tests showed moderate to severe physiologic abnormalities, in most instances indicating a restrictive lung disease with decreased peripheral flow rates. Chest radiographs revealed predominantly diffuse reticulonodular infiltrates in the central lung fields, with thickening of the bronchial walls and decreased lung volumes. Chest computed tomography demonstrated peribronchovascular fibrosis and interstitial thickening. Bronchoalveolar lavage showed a mild increase in lymphocytes in 4 subjects. Patients were treated with corticosteroids and bronchodilators. Follow-up data were available in 10 patients. In 5 patients, the disease progressed and 4 of them died. Two patients remained stable and 3 improved or healed. We propose that these findings represent a distinct airway-centered disease that mostly behaves as an interstitial lung disease and may exhibit a poor outcome.
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.
Humans are commonly exposed to combinations of particles (occupational or environmental) and exogenous agents such as ozone and cigarette smoke that generate reactive oxygen species (ROS). Particles also evoke production of ROS from inflammatory cells and of mediators such as TNF-alpha that operate through ROS-related mechanisms. The interactions of particles and ROS-generating agents have been little explored. Adhesion of particles to the surface of pulmonary epithelial cells is increased by exposure to cigarette smoke, ozone, and TNF-alpha. Cigarette smoke and ozone increase the uptake of particles by epithelial cells, and both adhesion and uptake can be decreased by scavengers of ROS. Increased adhesion and uptake probably lead to increased levels of inflammatory and fibrogenic mediator production, and cigarette smoke definitely increases whole lung particle retention and enhances the fibrogenic effects of asbestos. In experimental models, the combination of particles plus ozone, cigarette smoke, or reagent hydrogen peroxide augments the inflammatory response to particles, increases cell proliferation, and leads to liberation of increased levels of chemoattractant mediators as well as vascular mediators such as endothelin. The small airways appear to be particular targets of coexposure to smoke or ozone and particles, a phenomenon that may produce chronic airflow obstruction.
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.
There is evidence that chronic exposure to high levels of ambient particulate pollutants (PM) is associated with chronic airflow obstruction, but how this occurs is not known. We exposed rat tracheal explants to Ottawa urban air particles (ECH93) or diesel exhaust particles. After 7 d in air organ culture, both types of PM increased explant procollagen and transforming growth factor (TGF)-beta 1 gene expression, and markedly increased tissue hydroxyproline. For both types of particle, nuclear factor-kappa B inhibitor SN50 completely blocked increased gene expression. With EHC93, procollagen expression was inhibited by the oxidant scavenger, tetramethylthiourea, and by the iron chelator, deferoxamine, but TGF-beta1 expression was not inhibited by deferoxamine. Inhibitors of extracellular signal regulated kinase and p38 kinase did not affect EHC93-induced gene expression. With diesel exhaust particles, tetramethylthiourea and deferoxamine had no effect, but extracellular signal regulated kinase and p38 inhibitors completely blocked effects on procollagen and TGF-beta 1. Fetuin, an inhibitor of TGF-beta receptor binding, prevented increases in procollagen gene expression. We conclude that two common types of PM can directly induce expression of genes involved in fibrogenesis and actual airway wall fibrosis through nuclear factor-kappa B- and TGF-beta-mediated mechanisms. PM-induced airway wall remodeling may play an important role in producing airflow obstruction in individuals living in high PM regions.
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.
Varied mesothelial proliferations are found around the testes. Benign reactive mesothelial proliferations in hydrocoeles may be very florid and histologically worrisome, but these can usually be separated from malignant mesotheliomas of the tunica vaginalis because they are confined to a sharply demarcated zone near the luminal surface. In addition, benign inflamed hydrocoeles tend to show a distinct zonation with cellular areas near the luminal surface and more fibrotic areas beneath. The proliferating mesothelial cells in benign reactions often form lines that are parallel to the surface of the hydrocoele. Malignant mesotheliomas of the tunica vaginalis are usually grossly visible as single or multiple nodules. Histologically, they show an epithelial- or mixed epithelial- and sarcomatous-morphologic image, with evidence of stromal invasion. Well-differentiated papillary mesotheliomas are usually solitary exophytic nodules with a distinctive morphologic appearance and benign course, but they must be carefully separated from malignant mesotheliomas with a focally exophytic papillary growth pattern. By definition, well-differentiated papillary mesotheliomas do not exhibit stromal invasion. Peritesticular adenomatoid tumors are also very common; they are benign circumscribed cellular nodules with an appearance comparable to that of adenomatoid tumors in other body locations such as the uterine serosa.
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.
Most cases of malignant mesothelioma present with obvious diffuse tumor, and the presence of grossly visible diffuse tumor is usually cited as an important criterion for making the diagnosis. We report four cases of unsuspected malignant mesothelioma of the peritoneum presenting as localized acute inflammatory lesions. The clinical diagnoses were acute appendicitis in two cases, acute cholecystitis in the third case, and incarcerated umbilical hernia in the fourth case. In all cases tumor was not evident at initial surgical exploration or on gross pathologic examination, and the diagnosis was only made on microscopic examination of the resected specimens. All cases showed a tubulopapillary form of epithelial mesothelioma with obvious tissue invasion, but the foci of tumor were too small to be seen grossly or were present deep in fibrous tissue. On follow-up all patients developed grossly evident tumor, and one of these patients is alive without evidence of disease 5 years after presentation. We conclude that peritoneal mesotheliomas may occasionally present as inflammatory processes without grossly evident tumor and can be diagnosed by microscopic findings alone.
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.
A remaining uncertainty in the U.S. cohort study of man-made vitreous fiber (MMVF) workers is whether asbestos exposure contributed to 10 questionable cases of mesothelioma. We report further details on one case from our previous mesothelioma investigation, including results of a recent lung tissue analysis. Case is a 68 year-old white male employed 1951-54 in a rock/slag wool plant where asbestos-containing products were manufactured. Cause of death was recorded as "mesothelioma, malignant, right pleural cavity" (ICD9: 163.9). Analysis for presence of asbestos bodies identified 18,300 asbestos bodies per gram of wet lung tissue (AB/gm), which greatly exceeds the normal range of 0-20 AB/gm. No MMVFs were identified in this sample. We conclude that this patient's tumor was not a mesothelioma, but a carcinoma possibly arising in the lung or mediastinum, and that this case supports the view that the few suspected mesotheliomas found in the U.S. cohort may have been caused by asbestos exposure.
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.
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.
Exposure to ambient particulate matter (PM) is linked to increases in respiratory morbidity and exacerbation of cardiopulmonary diseases. However, the important components of PM and their mechanisms of action in lung disease are unclear. We demonstrate the development of dose-related proliferation and apoptosis after exposure of an alveolar epithelial cell line (C10) to PM or to ultrafine carbon black (ufCB), a component of PM. Ribonuclease protection assays demonstrated that increases in mRNA levels of the early response protooncogenes c-jun, junB, fra-1, and fra-2 accompanied cell proliferation at low concentrations of PM whereas apoptotic concentrations of PM caused transient increases in expression of fos and jun family members and dose responsive increases in mRNA levels of receptor-interacting protein, Fas-associated death domain, and caspase-8. Significant increases in steady-state mRNA levels of protooncogenes and apoptosis-associated genes, TNFR-associated death domain, and Fas were also observed after exposure of epithelial cells to ufCB, but not fine carbon black or glass beads, respectively, suggesting that the ultrafine particulate component of PM is critical to its biological activity.
BACKGROUND: The behavior of diffuse peritoneal mesotheliomas in women and the possible relation between tumor morphology and outcome are uncertain. Reported survival has ranged from < 1 month to > 14 years, and a previous study found that tumor morphology could not be used reliably for predicting outcome. The authors examined the behavior of diffuse epithelial peritoneal mesotheliomas in women and the possible relation between pathologic features and outcome. METHODS: Twenty-five female patients with diffuse peritoneal epithelial malignant mesotheliomas were divided into two groups: those who survived for < 4 years (60%) and those who survived for > 4 years (40%). Both groups were compared in terms of age, presentation, treatment, survival, tumor architecture, mitotic rate, necrosis, nuclear grade, and immunohistochemical profile. RESULTS: Patients in the two groups were similar in terms of age at diagnosis (median ages, 50.7 years and 49.9 years), presentation, initial tumor burden, and treatment. In both groups, the most common initial clinical presenting features were ascites and abdominal pain. The tumors typically took the form of multiple nodules measuring < 1.5 cm in greatest dimension. Slightly less than 50% of patients in both groups received some form of chemotherapy or radiation therapy after undergoing tumor-reductive surgery or biopsy. Overall survival ranged from 1 month to 15 years. The median survival was 12 months in the group of women who survived for < 4 years and 7 years in the group of women who survived for > 4 years. Overall, 10 of 25 patients survived for > or = 5 years. One patient was alive with disease 15 years after diagnosis. Although there was a suggestion that the tumors in patients with short survival more often had solid architecture and high-grade nuclei, these findings were not significant statistically. The frequency of necrosis and the mitotic activity were the same in both groups. CONCLUSIONS: The spectrum of diffuse epithelial peritoneal mesotheliomas in women includes tumors that are highly aggressive and behave much like pleural mesotheliomas, although a sizeable number of tumors, unlike the pleural tumors, are relatively indolent. However, because there do not appear to be morphologic features that reliably identify favorable tumors versus unfavorable tumors, aggressive therapy for all women with diffuse peritoneal mesotheliomas may be warranted.
The pulmonary vasculitides are a group of rare but serious disorders that require early recognition, accurate diagnosis, and effective therapy. Churg-Strauss syndrome (CSS) is classified as small vessel vasculitis. Four different definitions for the diagnosis of CSS have been developed: (1) the pathologic criteria put forth by Churg and Strauss, (2) the criteria based on clinical grounds from Lanham and colleagues, (3) the criteria based on clinical grounds from the American College of Rheumatology, and (4) the criteria from the Chapel Hill Consensus Conference, which closely concur with the Churg and Strauss definition. It is apparent that cessation, diminution, or even a switch from low-dose systemic to inhaled corticosteroid therapy can precipitate the appearance of CSS. The term forme fruste has been used to indicate that the signs and symptoms of CSS were (inadvertently) suppressed by cortico-steroids. The clinical risk factors for CSS are moderately severe or severe asthma, chronic sinusitis, or reductions in systemic corticosteroid therapy. Differential diagnosis, treatment, and ongoing monitoring of CSS therapeutic responses are reviewed. The introduction of leukotriene modifiers and high-potency inhaled corticosteroids have allowed control of asthma symptoms, which results in avoidance or reduction in oral corticosteroid use. The advent of these agents has been associated with reports of CSS appearing in patients with asthma. The available data regarding the association of CSS and antiasthma agents are most consistent with the unmasking of a previously contained pathologic condition (forme-fruste CSS) or disease that progresses because systemic corticosteroids were avoided. Early recognition and immunosuppressive therapy are the keystones of successful treatment of this rare disorder.
To evaluate the usefulness of determinations of telomerase activity for distinguishing malignant from benign mesothelial lesions, immunohistochemical (using a rabbit polyclonal antibody and the peroxidase method; n = 68) and in situ hybridization (using sense and antisense oligonucleotide probes; n = 46) studies were made on malignant mesotheliomas (epithelioid, 39; sarcomatoid, 18, including 2 of the desmoplastic type; and biphasic, 11) and 19 benign mesothelial lesions (benign mesothelial hyperplasia, 3; and reactive pleuritis, 16). In addition, biochemical studies of telomerase activity were made in 9 of the malignant mesotheliomas. Telomerase activity was detected histochemically in all but one of the malignant mesotheliomas, but only in one (pleuritis) of the benign lesions, in which it was present only in activated lymphocytes. Antisense hybridization signals indicated the presence of telomerase mRNA mainly in the cytoplasm of the malignant cells. Sense probes gave negative results. Biochemical determinations revealed a strong telomerase activity in the 9 malignant mesotheliomas examined. This study demonstrates the usefulness of immunohistochemical staining for the evaluation of mesotheliomas. The required immunostaining can be performed using paraffin sections of formalin-fixed tissues.