Biomedical subjects
A G Nicholson
Publications and source records attributed to A G Nicholson.
Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages.
BACKGROUND AND PURPOSE: Macrophages release cytokines that may contribute to pulmonary inflammation in conditions such as chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have therapeutic benefit. p38 MAPK may regulate cytokine production, therefore, the effect of two p38 MAPK inhibitors, SB239063 and SD-282, on the release of TNF-alpha, GM-CSF and IL-8 from human macrophages was investigated. EXPERIMENTAL APPROACH: Cytokine release was measured by ELISA. Immunoblots and mRNA expression studies were performed to confirm p38 MAPK isoform expression and activity. Macrophages were isolated from lung tissue of current smokers, ex-smokers and emphysema patients and exposed to lipopolysaccharide. These cells then released cytokines in a concentration-dependent manner. KEY RESULTS: SB239063 only inhibited TNF-alpha release (EC50 0.3 +/- 0.1 microM). Disease status had no effect on the efficacy of SB239063. SD-282 inhibited both TNF-alpha and GM-CSF release from macrophages (EC50 6.1 +/- 1.4 nM and 1.8 +/- 0.6 microM respectively) but had no effect on IL-8 release. In contrast, both inhibitors suppressed cytokine production in monocytes. CONCLUSIONS AND IMPLICATIONS: The differential effects of p38 MAPK inhibitors between macrophages and monocytes could not be explained by differences in p38 MAPK isoform expression or activity. However, the stability of TNF-alpha mRNA was significantly increased in macrophages compared to monocytes. These data suggest a differential involvement for p38 MAPK in macrophage cytokine production compared with monocytes. These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA.
Long-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a deadly disease with no effective treatment. The purpose of this randomised prospective multicentric study was to characterise the clinical effects of interferon gamma (IFN-gamma) 1b administered subcutaneously thrice weekly versus colchicine for 2 yrs. This study had no pre-specified end-points. Fifty consecutive IPF patients were randomised. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria. In the intent-to-treat population, five out of 32 (15.6%) IFN-gamma-1b patients and seven out of 18 (38.8%) colchicine patients died after a median follow-up period of 25 months Patients treated with IFN-gamma 1b showed a better outcome after 2 yrs of therapy, and fewer symptoms, as assessed using the St George's Respiratory Questionnaire, after 12 months of therapy. Also, the IFN-gamma-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the two treatment groups. These data suggest that long-term treatment with interferon gamma 1b may improve survival and outcome in patients with mild-to-moderate idiopathic pulmonary fibrosis. Further studies are needed to verify these results.
Extracellular thioredoxin levels are increased in patients with acute lung injury.
BACKGROUND: Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult. METHODS: Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n=30) and healthy controls (n=18, plasma; n=14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n=10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)-8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores. RESULTS: BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9-132.9) v 16.0 ng/ml (IQR 8.9-25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL-8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL-8, and neutrophils were significantly greater in patients with ALI of pulmonary origin. CONCLUSIONS: Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL-8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.
Metastases from bronchioloalveolar carcinomas associated with long-standing type 1 congenital cystic adenomatoid malformations. A report of two cases.
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Pulmonary involvement by Niemann-Pick disease. A report of six cases.
AIMS: Although pulmonary involvement is a known cause of morbidity in Niemann-Pick disease, histological features in the lung are not well characterized. The purpose of this study is to document the histological features seen in pulmonary involvement by types B and C Niemann-Pick disease and to correlate them with clinical and imaging data. METHODS AND RESULTS: Surgical lung biopsies from six patients (four with type B and two with type C disease) were reviewed and all showed diffuse endogenous lipid pneumonia, with lesser involvement of the interstitium by fibrosis and foamy macrophage accumulation. In type B disease only, there was also fine cytoplasmic vacuolation within the cytoplasm of ciliated epithelial cells. Neither disease showed foamy changes within pneumocytes. One patient had a bronchial cast removed on whole lung lavage. Electron microscopy showed abnormal lamellar inclusions within lysosomes of affected cells in type B disease. In patients with type C disease, biopsies were undertaken as part of investigations into acute respiratory failure in the context of multiorgan systemic presentation. Three patients with type B disease had clinical disease limited to the lung, all adults (mean age of 40 years) with unexplained diffuse parenchymal lung disease and mainly ground-glass shadowing on high-resolution computed tomography. CONCLUSIONS: Niemann-Pick disease should be considered for any patient with unexplained diffuse endogenous lipid pneumonia, even when disease is limited to the lungs and presentation is during adulthood.
Interstitial lung disease--the new synergy between radiology and pathology.
In the last 30 years, high-resolution computed tomography (HRCT) has been the major advance in diagnosis of diffuse parenchymal lung disease (DPLD). We review the diagnostic accuracy of HRCT and discuss how the gold standard in diagnosis of DPLD has shifted from histopathological diagnosis in isolation to a multidisciplinary approach. This latter process is now accepted as providing the highest levels of diagnostic accuracy in patients with DPLD and lung biopsy is primarily reserved for cases with atypical clinical or radiological presentations.
Investigation of young children with severe recurrent wheeze: any clinical benefit?
The management of young children with severe recurrent wheeze is difficult because symptoms are often refractory to conventional asthma therapy and other diagnoses must be excluded. The present authors aimed to evaluate the outcome of detailed, invasive investigations in such patients. Children aged between 3 months and 5 yrs with severe recurrent wheezing, who had been referred to a tertiary centre, underwent a protocol of investigations including a chest computed tomography scan, blood tests, nasal ciliary brushings, fibreoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial biopsy and passage of an oesophageal pH probe. A total of 47 children (25 males) with a median age of 26 (range 5-58) months underwent investigation. Of these, 39% were atopic, two-thirds had evidence of gastro-oesophageal reflux and 37 out of 47 had an abnormal bronchoscopy. Findings included structural abnormalities (13 out of 37), excessive mucus (20 out of 37) and macroscopic inflammation (10 out of 37). BAL revealed bacterial growth in 12 out of 44 (27%) patients. Good quality endobronchial biopsies were obtained from 36 out of 46 (78%) patients; of these, 44% had tissue eosinophilia and 28% had a thickened reticular basement membrane. Additional investigations (including bronchoscopy) in young children with severe wheeze may help to identify positive diagnoses and provide information to support a clinical diagnosis of asthma. This hypothesis-generating work should form the basis of future interventional studies.
Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features.
Although acute exacerbations of idiopathic pulmonary fibrosis are well recognised, there are no studies documenting their prevalence or identifying pre-existing risk factors. This study analysed the clinical, radiological and pathological data of 11 patients who satisfied the criteria for acute exacerbation among 147 patients with biopsy-proven idiopathic pulmonary fibrosis. There were five additional patients who had similar demographics, radiology and surgical lung biopsy pathology, but had clinically less severe disease, and so were not included. The 2-yr frequency of acute exacerbation was 9.6% after the diagnosis. Most exacerbations were idiopathic, although two cases presented after surgical lung biopsy and one after bronchoalveolar lavage. No significant risk factor was found by univariate proportional hazard analysis. Imaging revealed diffuse bilateral ground-glass opacification superimposed on subpleural reticular and honeycombing densities. The biopsies of four patients taken during acute exacerbation exhibited diffuse alveolar damage superimposed upon usual interstitial pneumonia. The findings of this study demonstrate that acute exacerbation of idiopathic pulmonary fibrosis is rather common and this exacerbation is likely to have a spectrum of severity.
CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact.
BACKGROUND/AIMS: The diagnosis of small cell lung carcinoma (SCLC) on bronchial biopsy is often problematical as a result of intense crush artefact. Several antibodies are now available to help in the diagnosis of SCLC and their value was assessed in this clinical situation. METHODS/RESULTS: Twenty cases of SCLC and 10 control cases (one non-Hodgkin lymphoma, three non-small cell carcinomas, one follicular reactive hyperplasia, and five chronic non-specific inflammations) with extensive crush artefact were stained using antibodies to CD56, MNF116, thyroid transcription factor 1 (TTF-1), and CD45. All SCLCs showed strong positive staining for CD56 in 75-100% of recognisable tumour cells, even in areas where there was extensive crush artefact. Eighteen of 20 cases were positive for TTF-1 and 16 of 20 were positive for MNF116 in the tumour cells, but both of these antibodies showed little or no staining in areas of crush artefact. Control cases comprising lymphoid cells were positive for CD45 in areas of crush artefact, but all cases of SCLC were negative. CONCLUSION: CD56, along with markers for cytokeratins-TTF-1, and CD45-are useful in the diagnosis of SCLC in biopsies with extensive crush artefact and can help confirm the diagnosis in cases where features are equivocal.
L1CAM, INP10, P-cadherin, tPA and ITGB4 over-expression in malignant pleural mesotheliomas revealed by combined use of cDNA and tissue microarray.
Malignant pleural mesothelioma (MM) is a rare tumour with high mortality, which can exhibit various morphologies classified as epithelioid, biphasic and sarcomatoid subtypes. To investigate the molecular changes in these tumours, we studied gene expression patterns by combined use of cDNA arrays and tumour tissue microarrays (TMA). Deregulation of the expression of 588 cancer-related genes was screened in 16 MM comprising all three subtypes and compared with references, i.e. normal mesothelial cell lines and pleural mesothelium. Array data were analysed using three statistical methods; principal component analysis (PCA), permutation test and receiver operating characteristic (ROC) curves. Eleven genes were verified by real-time RT-PCR. Genes encoding two adhesion molecules [COL1A2 and integrin beta4 (ITGB4)] and a chemokine (INP10) were up-regulated in MM compared with both the cell lines and pleural mesothelium. There was a type-specific up-regulation of semaphorin E, ITGB4 and P-cadherin in epithelioid MM, matrix metalloproteinase 9 (MMP9) and tissue-type plasminogen activator (tPA) in sarcomatoid MM and neural cell adhesion molecule L1 (L1CAM) and INP10 in biphasic MM. Immunohistochemistry on TMA containing 47 MM (26 epithelioid, 15 sarcomatoid and six biphasic) was performed for five proteins, ITGB4, P-cadherin, tPA, INP10 and L1CAM. INP10 expression was increased in MM in general compared with normal mesothelium, while increased expression of P-cadherin, L1CAM and ITGB4 was more specific in MMs exhibiting an epithelioid growth pattern. The over-expression of tPA was more frequent in epithelioid MM despite higher mRNA levels in sarcomatoid and biphasic MM. We conclude that several proteins, associated with cell adhesion either directly (ITGB4, L1CAM, P-cadherin) or as a regulatory factor (INP10), are differentially expressed in MM. In particular, INP10, ITGB4 and COL1A2 were up-regulated in MM compared with both reference sample types, suggesting a relationship with development of these tumours.
Inhibition of adherence of Mycobacterium avium complex and Mycobacterium tuberculosis to fibronectin on the respiratory mucosa.
Mycobacterium species adhere to the respiratory mucosa via mucus and fibronectin of extracellular matrix exposed by damaged epithelium. We have investigated whether inhibiting adherence to fibronectin influences subsequent infection of human respiratory tissue by Mycobacterium avium complex and Mycobacterium tuberculosis. Human respiratory tissue was pretreated with mycobacterial fibronectin attachment proteins prior to infection with M. avium complex and M. tuberculosis and the number of recoverable bacteria over time was compared to untreated controls. Inhibition significantly reduced recovery of M. avium complex at 15min (P= 0.02), 7days (P = 0.04), and 14 days (P= 0.03); whereas recovery of M. tuberculosis was only reduced at 15 min (P = 0.01) and not at later timepoints. We conclude that M. avium complex and M. tuberculosis infection of the mucosa proceeds by different mechanisms, since M. tuberculosis infection is independent of fibronectin adherence.
Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis.
AIMS AND METHODS: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non-specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjögren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. RESULTS AND CONCLUSIONS: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjögren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.
Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking.
AIMS: Respiratory bronchiolitis (RB) and desquamative interstitial pneumonia (DIP) are closely associated histological patterns of interstitial pneumonia, although there are no studies on the extent of individual histological parameters. Furthermore, the term smoking related-interstitial lung disease (SR-ILD) has been proposed as a term to encompass patients with both these histological patterns who give a history of smoking, though it is not well defined how this term relates to historical cases of DIP. The aim of this study was to compare histological parameters in cases of DIP and RB and then to review in detail clinical, imaging and histological data for DIP in relation to a history of smoking. METHODS AND RESULTS: Forty-nine cases were reviewed, 24 with RB and 25 with DIP; five cases of DIP were re-classified as RB on review due to bronchocentricity of the infiltrate. There was a significantly greater extent of interstitial fibrosis (P = 0.02), lymphoid follicles (P < 0.001) and eosinophilic infiltration (P < 0.0001) in patients with DIP compared with RB. In addition, the extents of these three parameters were significantly interrelated. Patients with DIP had a lower incidence of smoking (60%) when compared with patients with RB-ILD (93%) (P < 0.005). Further analysis of smokers versus never-smokers with DIP showed no difference in histological parameters, extent of haemosiderin deposition or the number of CD1a+ macrophages between the two groups, nor were there any differences in clinical data to suggest other aetiologies. Follow-up high-resolution computed tomography data from patients with DIP suggested that a pattern of fibrotic non-specific interstitial pneumonia (NSIP) may develop in the long term in both smokers and never-smokers. CONCLUSION: There are significant differences in the extent of interstitial fibrosis, lymphoid follicles and eosinophilic infiltration between DIP and RB, as well as a much lower incidence of smoking in patients with DIP. Whether the lower reported incidence of smoking in DIP reflects referral bias or conservatism in giving a history of smoking remains uncertain, as neither histological parameters nor clinical data indicate a difference between smokers and never-smokers with DIP. Nevertheless, some cases of DIP are likely to remain idiopathic and unrelated to RB, though still have a good prognosis. Furthermore, they may evolve into a pattern resembling fibrotic NSIP. Therefore, whilst SR-ILD is appropriate in the correct clinical setting, the distinction between the histological patterns of RB and DIP remains appropriate.
A fatal case of disseminated aspergillosis caused by a non-sporulating strain of Aspergillus fumigatus.
This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1-D2 region of the large ribosomal subunit revealed 100% homology with Aspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.
Inter-observer variation between pathologists in diffuse parenchymal lung disease.
BACKGROUND: There have been few inter-observer studies of diffuse parenchymal lung disease (DPLD), but the recent ATS/ERS consensus classification provides a basis for such a study. METHODS: A method for categorising numerically the percentage likelihood of these differential diagnoses was developed, and the diagnostic confidence of pathologists using this classification and the reproducibility of their diagnoses were assessed. RESULTS: The overall kappa coefficient of agreement for the first choice diagnosis was 0.38 (n = 133 biopsies), increasing to 0.43 for patients (n = 83) with multiple biopsies. Weighted kappa coefficients of agreement, quantifying the level of probability of individual diagnoses, were moderate to good (mean 0.58, range 0.40-0.75). However, in 18% of biopsy specimens the diagnosis was given with low confidence. Over 50% of inter-observer variation related to the diagnosis of non-specific interstitial pneumonia and, in particular, its distinction from usual interstitial pneumonia. CONCLUSION: These results show that the ATS/ERS classification can be applied reproducibly by pathologists who evaluate DPLD routinely, and support the practice of taking multiple biopsy specimens.
HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation.
BACKGROUND: This study was designed to measure inter-observer variation between thoracic radiologists in the diagnosis of diffuse parenchymal lung disease (DPLD) using high resolution computed tomography (HRCT) and to identify areas of difficulty where expertise, in the form of national panels, would be of particular value. METHODS: HRCT images of 131 patients with DPLD (from a tertiary referral hospital (n = 66) and regional teaching centres (n = 65)) were reviewed by 11 thoracic radiologists. Inter-observer variation for the first choice diagnosis was quantified using the unadjusted kappa coefficient of agreement. Observers stated differential diagnoses and assigned a percentage likelihood to each. A weighted kappa was calculated for the likelihood of each of the six most frequently diagnosed disease entities. RESULTS: Observer agreement on the first choice diagnosis was moderate for the entire cohort (kappa = 0.48) and was higher for cases from regional centres (kappa = 0.60) than for cases from the tertiary referral centre (kappa = 0.34). 62% of cases from regional teaching centres were diagnosed with high confidence and good observer agreement (kappa = 0.77). Non-specific interstitial pneumonia (NSIP) was in the differential diagnosis in most disagreements (55%). Weighted kappa values quantifying the likelihood of specific diseases were moderate to good (mean 0.57, range 0.49-0.70). CONCLUSION: There is good agreement between thoracic radiologists for the HRCT diagnosis of DPLD encountered in regional teaching centres. However, cases diagnosed with low confidence, particularly where NSIP is considered as a differential diagnosis, may benefit from the expertise of a reference panel.
Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection.
OBJECTIVE: Pulmonary fibrosis is associated with an increased risk of lung cancer and outcome of surgical resection in this setting is unknown. METHODS: We studied 22 patients (24 operations) with pulmonary fibrosis and non-small cell lung cancer treated between 1991 and 2000 (study group) and compared outcome with 951 other patients (964 operations) treated for non-small cell lung cancer over the same period (control patients). RESULTS: The two groups did not differ significantly in age (68 vs 65 years), smoking history (86% vs 95% smokers), forced expiratory volume in 1 second (2.5 L/min vs 2.3 L/min) or forced vital capacity (3.2 L vs 3.7 L), but patients with pulmonary fibrosis were more likely to be male (72% vs 58%, P <.05). The operative mortality was higher in patients with pulmonary fibrosis than in control patients (17% vs 3.1%, P <.01) and there was a higher procedure-specific mortality in pulmonary fibrosis for pneumonectomy (33% vs 5.1%, P <.01) and lobectomy (12% vs 2.6%, P <.01). Patients with pulmonary fibrosis had a higher incidence of postoperative lung injury, (21% vs 3.7%, P <.01) and a longer mean hospital stay (17 vs 9 days, P <.05). In patients with pulmonary fibrosis, the actuarial 3-year survival was 54%. There were 11 deaths in the study group, 4 postoperatively (all acute respiratory distress syndrome) and 7 late deaths (metastatic disease, n = 2; progressive pulmonary fibrosis, n = 5). Median follow-up (to death or last review) was 13 months (range, 0-120 months). Five patients developed postoperative acute respiratory distress syndrome and in 4 of these patients this proved to be fatal. Postoperative acute respiratory distress syndrome was associated with lower preoperative total lung carbon monoxide diffusion capacity (median, 58% vs 70%, P =.03) and lower preoperative carbon monoxide diffusion capacity corrected for alveolar volume (median, 48% vs 58%, P =.05) and a higher preoperative composite physiological index (median, 44 vs 33, P =.008). None of the preoperative lung function parameters or operative finding were predictors of late death. CONCLUSION: Patients with pulmonary fibrosis undergoing pulmonary resection for non-small cell lung cancer have increased postoperative morbidity and mortality, but an important subgroup has a good long-term outcome. Postoperative acute respiratory distress syndrome is associated with low preoperative gas transfer and a high composite physiological index. Resection of non-small cell lung cancer is appropriate in pulmonary fibrosis, provided that the level of functional impairment is carefully factored into patient selection.