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1.  Elastin expression in very severe human COPD 
The European respiratory journal  2009;34(2):324-331.
Alveolar elastic fibres are key targets of proteases during the pathogenesis of chronic obstructive pulmonary disease (COPD). In the current study, we hypothesised that a response to injury leads to enhanced alveolar elastin gene expression in very severe COPD.
Lung samples obtained from 43 patients, including 11 with very severe COPD (stage 4), 10 donors, 10 with moderate/severe COPD (stage 2–3) and 12 non-COPD subjects, were analysed for elastin mRNA expression by real-time RT-PCR and in situ hybridisation. Alveolar elastic fibres were visualised using Hart's staining of sections of frozen inflated lungs obtained from 11 COPD stage 4 patients and three donor lungs.
Compared with donors, non-COPD and stage 2–3 COPD, elastin mRNA expression was significantly increased in very severe COPD lungs (12-fold change), and localised in situ hybridisation induced elastin expression to alveolar walls. Compared with donors, alveolar elastic fibres also comprised a greater volume fraction of total lung tissue in very severe COPD lungs (p<0.01), but elastic fibre content was not increased per lung volume, and desmosine content was not increased.
The present study demonstrates enhanced alveolar elastin expression in very severe COPD. The efficiency of this potential repair mechanism and its regulation remain to be demonstrated.
PMCID: PMC3758126  PMID: 19357152
Chronic obstructive pulmonary disease; elastin; emphysema; gene expression
2.  Prediction of the rate of decline in FEV1 in smokers using quantitative computed tomography 
Thorax  2009;64(11):944-949.
A study was undertaken to determine if quantitative CT estimates of lung parenchymal overinflation and airway dimensions in smokers with a normal forced expiratory volume in 1 s (FEV1) can predict the rapid decline in FEV1 that leads to chronic obstructive pulmonary disease (COPD).
Study participants (n = 143; age 45–72 years; 54% male) were part of a lung cancer screening trial, had a smoking history of >30 pack years and a normal FEV1 and FEV1/forced vital capacity (FVC) at baseline (mean (SD) FEV1 99.4 (12.8)%, range 80.2–140.7%; mean (SD) FEV1/FVC 77.9 (4.4), range 70.0–88.0%). An inspiratory multislice CT scan was acquired for each subject at baseline. Custom software was used to measure airway lumen and wall dimensions; the percentage of the lung inflated beyond a predicted maximal lung inflation, the low attenuation lung area with an x ray attenuation lower than −950 HU and the size distribution of the overinflated lung areas and the low attenuation area were described using a cluster analysis. Multiple regression analysis was used to test the hypothesis that these CT measurements combined with other baseline characteristics might identify those who would develop an excessive annual decline in FEV1.
The mean (SD) annual change in FEV1 was −2.3 (4.7)% predicted (range −23.0% to +8.3%). Multiple regression analysis revealed that the annual change in FEV1%predicted was significantly associated with baseline percentage overinflated lung area measured on quantitative CT, FEV1%predicted, FEV1/FVC and gender.
Quantitative CT scan evidence of overinflation of the lung predicts a rapid annual decline in FEV1 in smokers with normal FEV1.
PMCID: PMC3035577  PMID: 19734130
3.  Why does airway inflammation persist after the smoking stops? 
Thorax  2006;61(2):96-97.
Important new observations on the behaviour of T lymphocytes and plasma cells following prolonged smoking cessation in patients with COPD
PMCID: PMC2104586  PMID: 16443703
plasma cells; T lymphocytes; chronic obstructive pulmonary disease; smoking cessation
4.  Convergence of the epidemiology and pathology of COPD 
Thorax  2006;61(1):86-88.
The epidemiology of chronic obstructive pulmonary disease (COPD) has been dominated by one hypothesis stating that cigarette smoking and chronic bronchitis were the key to pathogenesis and another that asthma, chronic bronchitis, and even emphysema are related to different expressions of a primary airway abnormality. The first hypothesis was rejected in the late 1960s based on a longitudinal study of working men where only a fraction of smokers developed COPD and where development of COPD was independent of the absence or presence of chronic bronchitis. Chronic bronchitis in more advanced COPD was subsequently associated with a more rapid decline in lung function and more frequent exacerbations. The second hypothesis is more difficult to test but longitudinal studies have shown that the presence of bronchial hyperresponsiveness may predict the subjects who go on to develop COPD. This brief review attempts to reconcile these findings with the pathology found in the lung.
PMCID: PMC2080699  PMID: 16227325
chronic obstructive pulmonary disease; pathology; epidemiology; smoking; pathogenesis
5.  Lung structure and function in cigarette smokers. 
Thorax  1994;49(5):473-478.
BACKGROUND--Cigarette smoking produces an inflammatory response in the airways of everyone but only 15-20% of smokers develop airways obstruction. The present study concerns the relative importance of peripheral airways inflammation and the emphysematous destruction of the parenchymal support of the airways in the pathogenesis of this obstruction. METHODS--A total of 407 patients with a diagnosis of lung tumour performed pulmonary function tests a day or two before a lung or lobar resection. The specimens were fixed in inflation and analysed at the gross and microscopic level to determine the extent and severity of the emphysematous process, the number of alveoli supporting the outer walls of the airways, and the average distance between alveolar walls. The severity of the inflammatory process in the respiratory and nonrespiratory bronchioles was also assessed using a previously established grading system. RESULTS--The lung function test showed that a decline in FEV1 was associated with an increase in residual volume and a decrease in the diffusing capacity for carbon monoxide and a reduction in the lung maximum elastic recoil pressure. The prevalence of grossly visible emphysema increased as FEV1 declined, but the extent and severity of these lesions and the number of alveoli supporting the outer walls of the peripheral airways was similar at all levels of FEV1. The system used to grade inflammatory response in the peripheral airways failed to identify a specific defect responsible for the physiological abnormalities. CONCLUSION--The reduction in FEV1 associated with chronic cigarette smoking can be partially explained by loss of lung elastic recoil pressure which reduces the force driving air out of the lung. This loss of elastic recoil pressure is attributed to microscopic enlargement of the air spaces rather than to grossly visible emphysema. The exact nature of the lesions responsible for the peripheral airways obstruction remains to be identified.
PMCID: PMC474869  PMID: 8016769
6.  Transforming growth factor beta 1 gene expression in human airways. 
Thorax  1994;49(3):225-232.
BACKGROUND--Asthmatic airways have a characteristic deposition of connective tissue under the epithelial basement membrane, but the mediators involved in this alteration are unknown. Several authors have postulated that transforming growth factor beta 1 (TGF-beta 1) could be overexpressed in asthmatic airways. METHODS--Lung samples from 16 asthmatic patients, six patients with chronic obstructive pulmonary disease (COPD), and six non-obstructed smokers were analysed. RNA was extracted from these tissues to measure expression of TGF-beta 1 by Northern blot analysis using a cDNA probe for TGF-beta 1. The level of expression was quantitated by densitometry using glyceraldehyde 3-phosphate dehydrogenase mRNA as a control. TGF-beta 1 was localised to specific cell types in these lungs by immunohistochemical analysis using polyclonal antibodies specific for intracellular and extracellular TGF-beta 1. RESULTS--The 2.5 kb TGF-beta 1 mRNA was seen in all 18 samples analysed by Northern blotting and densitometric analysis showed no difference between the asthmatic group (mean (SD) 108% (43%)), the group with COPD (122% (33%)), and the non-obstructed group (100% (49%)). The TGF-beta 1 precursor was immunolocalised throughout the airway wall including the epithelium and in alveolar macrophages. The mature TGF-beta 1 was localised primarily within the connective tissue of the airway wall. These patterns of expression of both forms of TGF-beta 1 were similar in lungs from asthmatic patients, those with COPD, and controls. CONCLUSIONS--While TGF-beta 1 mRNA and protein are abundantly expressed in human lungs, there is no clear difference in expression between the airways of asthmatic subjects and those of smokers with and without COPD.
PMCID: PMC1021150  PMID: 8202878
9.  Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function. 
Thorax  1987;42(11):843-848.
Forty-five patients who underwent thoracotomy and lung resection for tumour were studied to compare the structure of the central airways in current smokers and ex-smokers. The patients were divided into four groups: current smokers with mucus hypersecretion (n = 15), current smokers without mucus hypersecretion (n = 14), ex-smokers with mucus hypersecretion (n = 5), and ex-smokers without mucus hypersecretion (n = 11). Quantitative histological studies of the airway wall showed no difference in gland size, smooth muscle, connective tissue, or Reid index between the groups. The central airways of patients with mucus hypersecretion showed increased mucosal inflammation. The five ex-smokers in whom mucus hypersecretion persisted after they had stopped smoking had both central and peripheral airways affected by the inflammatory response, and these patients also had an abnormal result in the nitrogen washout test.
PMCID: PMC461007  PMID: 3424265
10.  Effects of pulmonary edema on regional blood volume and red blood cell transit time. Comparison of high pressure and oleic acid-induced edema. 
Journal of Clinical Investigation  1986;77(6):1780-1785.
The present study was designed to determine the effects of pulmonary vascular pressure, vascular injury, and pulmonary edema on regional blood volume (Vr) and regional red blood cell (RBC) transit time (Tr) in the lung. The experiments were carried out in 15 dogs. Six served as controls, six had oleic acid-induced pulmonary edema (OAPE), and three had high pressure pulmonary edema (HPPE). Regional blood flow (Qr) was measured with 99mTc macroaggregates, Vr with 51Cr homologous RBC, and regional transit time was calculated (Vr/Qr). The dogs were killed, and the lungs removed and sampled completely. Regional extravascular lung water (EVLW) was measured in grams per gram of dry lung and ranged from 3.7 +/- 1.1 in the control group to 6.0 +/- 1.3 in OAPE and 5.6 +/- 0.6 in HPPE. The data show that in normal lungs, increased Qr was associated with a recruitment of blood volume. In OAPE, data show that regional blood volume was decreased and that vascular injury and edema formation interfered with a further increase in Vr as Qr increased. In HPPE, Vr has already fully distended and it changed little with increased blood flow. We conclude that oleic acid-induced pulmonary injury and edema interfere with vascular recruitment and shorten regional RBC transit times. HPPE, on the other hand, is associated with normal regional RBC transit times because the vessels are fully recruited.
PMCID: PMC370534  PMID: 3711335
11.  Dynamic Changes in Neutrophil Defensins during Endotoxemia 
Infection and Immunity  2001;69(12):7793-7799.
Bacterial endotoxin or lipopolysaccharide (LPS) is an important causative agent of sepsis. This study determines the expression of defensins NP-2 and NP-5 and the function of polymorphonuclear leukocytes (PMN) in rabbits treated with LPS. PMN functional activity was assessed by measuring CD18 expression and H2O2 production and by examining the lungs. NP-2 and, to a minor extent, NP-5 of circulating PMN increase during endotoxemia. This early increase is concomitant with neutrophilia and elevated CD18 expression and H2O2 production, as well as with enhanced NP-2 immunoreactivity in pulmonary microvessels. A decline in defensins, shortly after the last LPS treatment, is associated with a decrease in the circulating activated PMN and enhanced immunoreactivity in the inflammatory cells, as well as with lung tissue damage. This study shows that LPS-induced changes in the defensins of circulating PMN correlate with the number and activated condition of these cells and suggests that PMN-derived products implement the inflammatory reaction that leads to lung injury and sepsis.
PMCID: PMC98875  PMID: 11705961
12.  The pathophysiology of asthma 
Because postmortem studies of humans provide little information on the initial pathophysiologic events in asthma, animal models have been developed. Recently the Ascaris-allergic rhesus monkey has provided an opportunity to examine the onset of pathophysiologic changes following challenge and to correlate them with airway structure. These studies have suggested that the initial interaction between antigen and mast cells may occur in the bronchial lumen or in the epithelium superficial to the tight junctions, where a small but significant percentage of airway mast cells exist. It also appears that this initial antigen-antibody interaction results in the release of mediators that both stimulate the rapidly adapting stretch receptors in the mucosa and alter the mucosal barrier so that proteins of large molecular weight can penetrate. The fact that antigen challenge results in hyperresponsiveness to a subsequent dose of inhaled histamine and increased systemic absorption of histamine suggests that the airway hyperresponsiveness could be related to increased penetration of histamine into the bronchial wall. These observations suggest that the initial event in an acute asthmatic attack is the release of mediators from superficial mast cells, and that this amplifies the allergic response by altering the mucosal permeability so that more antigen reaches the submucosal mast cells. This altered permeability may also help explain the hyperreactivity of the airways to nonspecific airway stimulants in persons with asthma.
PMCID: PMC1704390  PMID: 89006
13.  Expression of bcl-2 and Epstein-Barr virus LMP1 in lymphocytic interstitial pneumonia 
Thorax  1997;52(1):12-16.
BACKGROUND: Epstein-Barr virus (EBV) genome has been demonstrated in lung tissues of patients with lymphocytic interstitial pneumonia (LIP) but its role in the pathogenesis of this condition is unclear. In vitro studies have shown that EBV can immortalise and transform cells by upregulation of the cellular proto-oncogene, B cell leukaemia-2 (bcl- 2), via the viral latent membrane protein, LMP1. The purpose of this study was to determine whether bcl-2 expression is upregulated in the lungs of patients with LIP and whether EBV LMP1 has a role in this bcl- 2 expression. METHODS: Immunohistochemical analysis using alkaline phosphatase anti-alkaline phosphatase (APAAP) was performed on formalin fixed, paraffin embedded lung tissues from 13 patients with LIP using anti-LMP1 and anti-bcl-2 monoclonal antibodies. Lung tissues from nine patients with idiopathic pulmonary fibrosis (IPF) and nine necropsy cases without pulmonary disease served as controls. LMP1 positivity was estimated as the number of LMP1 positive cells per unit area of lung tissue. Immunostaining for bcl-2 expression was assessed by a pictorial- based semiquantitative grading system. RESULTS: Positive immunostaining for LMP1 was localised to airway epithelial cells of lung tissue. Ten out of 13 (77%) patients with LIP were positive for LMP1 compared with three of nine cases (33%) in each control group. LMP1 positivity of LIP cases was significantly greater than that of non-LIP cases: LIP versus IPF (mean difference, 95% confidence interval (CI)) 2.39 (1.54 to 3.24); LIP versus necropsy controls 2.62 (1.77 to 3.47). bcl-2 immunostaining was localised to lymphocytes within the alveolar septa and lymphoid aggregates of patients with LIP. The cumulative score for bcl-2 immunostaining was significantly higher in the lungs of patients with LIP than in those of patients with IPF and necropsy controls: LIP versus IPF and LIP versus necropsy controls (mean difference, 95% CI) 7.55 (7.18 to 7.92). CONCLUSIONS: These immunohistochemical studies have shown the presence of EBV LMP1 protein in airway epithelial cells and overexpression of the cellular bcl-2 protein in lymphoid cells of lung tissue in patients with LIP. These geographically distinct staining patterns of immunostaining suggest that the involvement of EBV LMP1 in the upregulation of cellular bcl-2 is more complex in LIP than was thought from previous in vitro observations. The respective roles of EBV LMP1 and bcl-2 in the pathogenesis of LIP require further studies. 

PMCID: PMC1758406  PMID: 9039233
14.  Identification of Bacterial Species Associated with the Sheep Scab Mite (Psoroptes ovis) by Using Amplified Genes Coding for 16S rRNA 
This was the first molecular study of the bacterial flora of the sheep scab mite (Psoroptes ovis). A sequence analysis of genes coding for 16S rRNA revealed that Serratia marcescens and bacteria closely related to Staphylococcus intermedius or Staphylococcus chromogens and Alloiococcus otitidis were present. These bacteria were associated with skin lesions, dermatitis, and otitis media caused by P. ovis.
PMCID: PMC99765  PMID: 10473440
15.  Epstein-Barr virus and cryptogenic fibrosing alveolitis. 
Thorax  1995;50(12):1232.
PMCID: PMC1021341  PMID: 8553292
16.  Polymorphonuclear leucocyte traffic in lung inflammation. 
Thorax  1995;50(8):819-820.
PMCID: PMC474887  PMID: 7570429
19.  Angeioma of Larynx 
PMCID: PMC2204710  PMID: 19989612
21.  Pulmonary vascular structure and function in chronic obstructive pulmonary disease. 
Thorax  1988;43(3):183-189.
Cardiac catheterization data from eight patients with severe chronic obstructive lung disease and pulmonary hypertension at rest (greater than 25 mm Hg) were compared with those obtained from 14 patients with mild to moderate disease whose pulmonary artery pressure was within the normal range at rest (mean 15 (SEM 1) mm Hg), but increased with exercise (30 (2) mm Hg). We obtained lung sections from necropsy material from the group with severe disease, and from surgical specimens in the group with mild to moderate disease, and compared the structure of the vasculature in these groups with that obtained from surgical specimens in a non-smoking control group of seven patients. Oxygen administration either at rest or during exercise did not greatly affect the pulmonary arterial pressures. When cardiac index was plotted against pulmonary artery pressure at rest and during exercise and extrapolated to the axis there was no evidence for a critical closing pressure in either group. The vessels in the groups with mild to moderate and severe chronic obstructive lung disease showed intimal thickening (each 19% (SD 0.5%)) by comparison with the non-smoking group (16% (0.5%]. The group with severe disease, in addition, had medial hypertrophy (27% (0.5%) versus 24% (SD 1%) in the non-smoking group). These data are consistent with the idea that the diseased vessels are distorted and rigid. The lack of effect of breathing oxygen on the vascular response at rest and during exercise suggests that hypoxic vasoconstriction has a minimal role in the pulmonary hypertension of chronic obstructive lung disease. The data suggest that the intimal changes could narrow the vessel calibre in those patients with mild to moderate disease, and that the thickened media present in the vessels from patients with severe disease may act in concert with the enlarged intima to produce more severe vascular obstruction.
PMCID: PMC461159  PMID: 3406902
22.  Alveolar epithelial damage. A critical difference between high pressure and oleic acid-induced low pressure pulmonary edema. 
Journal of Clinical Investigation  1986;77(6):1786-1796.
The present study was designed to compare high pressure pulmonary edema (HPPE) and oleic acid-induced low pressure pulmonary edema (OAPE) in dogs when similar amounts of extra vascular water were present in the lung. The high pressure edema was produced by intravenous fluid overload and by inflating an aortic balloon catheter (n = 6). The low pressure edema was produced by the injecting 0.08 mg/kg oleic acid suspended in 5 ml saline (n = 6). Comparison of the difference between initial control measurements and final measurements in the edematous states showed that the animals with OAPE had a greater fall in percent oxygen saturation and a greater increase in shunt fractions. The light microscopic studies showed that OAPE was associated with greater amounts of alveolar flooding than HPPE where the edema fluid was located to a greater extent in the peribronchial interstitial space. The electron microscopy studies showed that the alveolar flooding in OAPE was associated with epithelial disruption, and tracer studies carried out in rabbits showed that dextran (150,000 mol wt) could pass from blood to airspace and that dextran (40,000 mol wt) could pass from air-space to blood in OAPE. We conclude that epithelial disruption is responsible for the excessive alveolar flooding in OAPE and that this results in a greater impairment in gas exchange.
PMCID: PMC370535  PMID: 2423558
23.  Editorial: Pathophysiology of asthma. 
PMCID: PMC1947311  PMID: 4812827
24.  Elastic properties of the centrilobular emphysematous space 
Journal of Clinical Investigation  1969;48(7):1306-1312.
Bronchograms were performed using finely particulate lead on emphysematous lungs obtained at necropsy. X-ray films were taken of these lungs at distending pressures of 0, 5, 10, and 20 cm H2O. The volumes of individual centrilobular emphysematous spaces were calculated at each distending pressure from measurements made on these bronchograms and pressure-volume curves were constructed for each space. The pressure-volume characteristics of seven normal lungs and one lung with centrilobular emphysema was also measured. The normal lungs, the lung with centrilobular emphysema, and the centrilobular emphysematous spaces were compared by expressing the volume of air contained in them at each distending pressure as a per cent of the volume contained at 20 cm H2O distending pressure. We conclude that centrilobular emphysematous spaces have a high residual volume, are less compliant than normal lung tissue, and are much less compliant than the emphysematous lungs which contain them. Furthermore, these spaces undergo little volume change in the tidal breathing range and probably add a relatively nondistensible series dead space to the surrounding lung parenchyma.
PMCID: PMC322354  PMID: 5794252
25.  Reassessment of inflammation of airways in chronic bronchitis. 
The term chronic bronchitis has been criticised because it is associated with hypersecretion of mucus rather than bronchial inflammation. This study was designed to establish the presence or absence of clinical chronic bronchitis and measure pulmonary function in 45 patients about to undergo resection of the lung. The condition in the cartilaginous and small airways and the severity of the emphysema were then measured in the resected specimen. The results from 20 patients who had clinical chronic bronchitis were compared with those in 25 patients who did not. The data show that patients with chronic bronchitis had greater inflammation (a) on mucosal surfaces (p less than 0.05) of all bronchi larger than 2 mm luminal diameter and (b) around glands (p less than 0.005) and gland ducts (p less than 0.05) in bronchi larger than 4 mm diameter. A variable degree of inflammation was present in the submucosa of smaller bronchi. The groups had equivalent proportions of mucous glands and Reid's indices in central airways, and no differences were noted in measurements of pulmonary function, condition of small airways, or emphysema. These data show that the term chronic bronchitis is justified by inflammation of cartilaginous airways and suggest that this abnormality may be the cause of the chronic productive cough.
PMCID: PMC1417096  PMID: 3933614

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