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Little is known about the pathogenesis of cough in idiopathic pulmonary fibrosis (IPF). We hypothesized that abnormalities of respiratory tract tachykinin-containing sensory nerves may be implicated. We studied cough response to capsaicin, substance P (SP), and bradykinin in 10 healthy control subjects and 10 patients with IPF. Six patients were tested before and after steroid therapy. Induced sputum cell counts and neurotrophic factor levels were also measured in 13 patients and 13 control subjects. The results show that cough sensitivity to capsaicin was greater in patients (p < 0.01). Neither SP nor bradykinin induced cough in normal subjects. SP and bradykinin induced cough in 7/10 patients (p < 0.002) and 2/10 patients (not significant) with IPF, respectively. Prednisolone caused a reduction in cough sensitivity to capsaicin (p < 0.05) and SP (p < 0.05) in all six patients treated. There were significantly more neutrophils (p = 0.001) and higher levels of nerve growth factor (p < 0.01) and brain-derived neurotrophic factor (p < 0.01) in patient's sputa. These findings suggest functional upregulation of lung sensory neurones in IPF. The cough response to inhaled SP in most patients may reflect disrupted respiratory epithelium. The response to corticosteroids demonstrates that the cough is amenable to therapy. [ABSTRACT FROM AUTHOR]

Background: Little is known about the mechanistic basis for the exercise intolerance characteristic of patients with respiratory disease; a lack of clearly defined, distinct patient groups limits interpretation of many studies. The purpose of this pilot study was to investigate the pulmonary oxygen uptake ([Formula: see text] O 2 ) response, and its potential determinants, in patients with emphysema and idiopathic pulmonary fibrosis (IPF)., Methods: Following a ramp incremental test for the determination of peak [Formula: see text] O 2 and the gas exchange threshold, six emphysema (66 ± 7 years; FEV 1, 36 ± 16%), five IPF (65 ± 12 years; FEV 1 , 82 ± 11%) and ten healthy control participants (63 ± 6 years) completed three repeat, heavy-intensity exercise transitions on a cycle ergometer. Throughout each transition, pulmonary gas exchange, heart rate and muscle deoxygenation ([HHb], patients only) were assessed continuously and subsequently modelled using a mono-exponential with ([Formula: see text] O 2 , [HHb]) or without (HR) a time delay., Results: The [Formula: see text] O 2 phase II time-constant (τ) did not differ between IPF and emphysema, with both groups significantly slower than healthy controls (Emphysema, 65 ± 11; IPF, 69 ± 7; Control, 31 ± 7 s; P < 0.05). The HR τ was slower in emphysema relative to IPF, with both groups significantly slower than controls (Emphysema, 87 ± 19; IPF, 119 ± 20; Control, 58 ± 11 s; P < 0.05). In contrast, neither the [HHb] τ nor [HHb]:O 2 ratio differed between patient groups., Conclusions: The slower [Formula: see text] O 2 kinetics in emphysema and IPF may reflect poorer matching of O 2 delivery-to-utilisation. Our findings extend our understanding of the exercise dysfunction in patients with respiratory disease and may help to inform the development of appropriately targeted rehabilitation strategies.

Introduction: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE) are common complications in patients with cancer, affecting up to 18% of patients. VTE risk is increased by surgery and disease progression, whilst chemotherapy further increases risk up to 7-fold compared to patients without cancer. VTE contributes significantly to morbidity and mortality in patients with cancer, and is the second most common cause of death. Lung cancer is well established to be high risk for VTE, with up to a 22-fold increase in VTE risk associated with this malignancy, and 12% incidence in a recent study of patients with lung cancer undergoing chemotherapy. Furthermore, platinum based chemotherapy agents used in treatment of lung cancer are further associated with increased VTE risk., Aim: Current risk assessment tools have little value in predicting VTE risk, but prophylactic anticoagulation of patients with cancer increases bleeding incidence and no overall survival benefit. There is therefore a need for a pragmatic test with which assesses coagulation in patients with cancer, and potentially predict VTE risk, leading to personalised management and targeted treatment. We have previously demonstrated that fractal dimension (df) is sensitive to changes in clot microstructure in patients with lung cancer, assessing global coagulation in these patients. Furthermore, df is significantly different in patients with extensive disease (stages 3&4), which conventional laboratory markers failed to identify. Given the increased risk of VTE associated with chemotherapy, FATCAT will aim to assess changes in df in a larger cohort of patients with lung cancer undergoing chemotherapy, quantifying changes in df and relating these to clinical outcome., Materials and Methods: This is a prospective observational cohort study investigating changes in df in patients with lung cancer undergoing chemotherapy. Patients will have a new diagnosis of cytologically or histologically confirmed lung cancer planned for chemotherapy and no history of previous cancer treatment, any thromboembolic / haemostatic disorders or be on anticoagulation., Results: Following a power calculation, 300 patients will be recruited and followed up for 1 year. df, Doppler ultrasonography and standard coagulation markers will be performed on recruitment, at the mid point, and on completion of chemotherapy in line with standard diagnostic procedures i.e. CT scanning., Conclusions: The primary endpoint of the study will be VTE diagnosis, whilst secondary outcomes will determine the change in df during and after treatment with chemotherapy., (© 2016 Elsevier Ltd. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic interstitial lung disease of unknown origin. It has a median survival of three years but a wide range in survival rate which is difficult to predict at the time of diagnosis. Specialist guidance promotes a patient centred approach emphasising regular assessment, information giving and supportive care coordinated by a multidisciplinary team (MDT). However understanding of patient and carer experience across the disease trajectory is limited and detailed guidance for MDTs on communication, assessment, and triggers for supportive and palliative interventions is lacking. This study addresses uncertainties relating to care needs of patients and carers at different stages of the IPF disease trajectory., Methods: Following ethical approval a multi-centre mixed-methods study recruited participants with IPF at four stages of the disease trajectory. Qualitative analysis was used to analyse 48 semi-structured interviews with patients (27) and paired carers (21)., Results: Patients and carers outlined key elements of MDT activity capable of having significant impact on the care experience. These were structured around: Focus of clinical encounters. Timely identification of changes in health status and functional activity. Understanding of symptoms and medical interventions. Coping strategies and carer roles., Conclusions: Patients diagnosed with IPF have a clear understanding of their prognosis but little understanding of how their disease will progress and how it will be managed. In depth analysis of the experiences of patients and carers offers guidance for refining IPF clinical pathways. This will support patients and carers at key transition points in line with National Institute for Health and Care Excellence (NICE) guidance.

Venous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot microstructure and greatest VTE risk.

Background: Venous thromboembolism (VTE) is common in patients with cancer, contributing significantly to morbidity and mortality Currently, no test reliably identifies patients at increased risk of developing VTE who would therefore benefit from prophylactic intervention. The aim of the current study was to evaluate rotational thromboelastometry (ROTEM) in identifying VTE risk in patients with lung cancer. We also compared parameters of ROTEM in patients with limited and extensive disease., Methods: Parameters of ROTEM were measured in 67 patients with lung cancer and 72 age-matched healthy controls and compared with conventional markers of haemostasis. Patients were followed up for 12 months and VTE incidence recorded., Results: Lung cancer patients had a reduced clotting time (CT), increased maximum clot firmness (MCF) and increased alpha angle compared with controls. Patients also had significantly higher levels of fibrinogen and PAI-1 than controls and in the former group there was a strong correlation between fibrinogen and both MCF and alpha angle. Six patients developed a VTE during the follow-up period and all had values for MCF at or above the upper limit of normal for EXTEM., Conclusions: This study demonstrates that several ROTEM parameters are significantly different in lung cancer patients compared to healthy age-matched controls, whereas only one of the parameters measured is significantly different between extensive compared to limited disease. No differences were observed between patients who developed a VTE compared to those who did not, highlighting the limitations of ROTEM use in patients with lung cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Chronic cough affects more than 70 percent of patients with Idiopathic Pulmonary Fibrosis and causes significant morbidity. Gastroesophageal reflux is the cause of some cases of chronic cough; and also has a postulated role in the aetiology of Idiopathic Pulmonary Fibrosis. A high prevalence of acid; and more recently non-acid, reflux has been observed in Idiopathic Pulmonary Fibrosis cohorts. Therefore, gastroesophageal reflux may be implicated in the pathogenesis of cough in Idiopathic Pulmonary Fibrosis., Methods: Eighteen subjects with Idiopathic Pulmonary Fibrosis underwent 24-hour oesophageal impedance and cough count monitoring after the careful exclusion of causes of chronic cough other than gastroesophageal reflux. All 18 were then treated with high dose acid suppression therapies. Fourteen subjects underwent repeat 24-hour oesophageal impedance and cough count monitoring after eight weeks., Results: Total reflux and acid reflux frequencies were within the normal range in the majority of this cohort. The frequencies of non-acid and proximal reflux events were above the normal range. Following high dose acid suppression therapy there was a significant decrease in the number of acid reflux events (p = 0.02), but an increase in the number of non-acid reflux events (p = 0.01). There was no change in cough frequency (p = 0.70)., Conclusions: This study confirms that non-acid reflux is prevalent; and that proximal oesophageal reflux occurs in the majority, of subjects with Idiopathic Pulmonary Fibrosis. It is the first study to investigate the effect of acid suppression therapy on gastroesophageal reflux and cough in patients with Idiopathic Pulmonary Fibrosis. The observation that cough frequency does not improve despite verifiable reductions in oesophageal acid exposure challenges the role of acid reflux in Idiopathic Pulmonary Fibrosis associated cough. The finding that non-acid reflux is increased following the use of acid suppression therapies cautions against the widespread use of acid suppression in patients with Idiopathic Pulmonary Fibrosis given the potential role for non-acid reflux in the pathogenesis of cough and Idiopathic Pulmonary Fibrosis itself., Study Registration: The study was registered with the Cardiff and Vale University Local Health Board Research and Development Committee (09/CMC/4619) and the South East Wales Ethics Committee (09/WSE04/57).

Tuberculosis involving the pancreas is rare. We report a patient with pancreatic tuberculosis complicated by haemorrhage from a splenic artery pseudoaneurysm. As far as we are aware, the development of a splenic artery pseudoaneurysm in association with a large caseating mass of tuberculous pancreatic lymph nodes has not been reported previously. We review the literature and discuss the varied presentations of tuberculosis involving the pancreas or the pancreatic bed and its draining lymph nodes.

Cough is a common symptom in people who develop interstitial lung diseases (ILD). The pathological features of the ILDs are many and varied suggesting that the cause of cough may also vary with each disease. This article reviews what is currently known about cough in sarcoidosis and idiopathic pulmonary fibrosis; two of the commonest ILDs. It also outlines some of the theories which have been proposed to explain why cough develops in these conditions and describes what little is known about how to treat it.

Background: Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF., Methods: We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at sequential frequencies (20 Hertz (Hz), 40 Hz and 60 Hz) for up to 60 seconds and repeated twice at two minute intervals. The number of subjects achieving two and five-cough responses, total cough counts and cough latency were recorded. In separate experiments, the effect of mechanical stimulation on the pattern of breathing was determined in eight IPF subjects and five control subjects., Results: In patients with IPF, we demonstrated strong correlations between subjective cough measurements, particularly the cough symptom score and Leicester Cough Questionnaire (r = -0.86; p < 0.001). Mechanical percussion induced a true cough reflex in 23/27 (85%) IPF subjects, but only 5/30 (17%) controls (p < 0.001). More patients with IPF reached the two-cough response at a lower frequency (20 Hz) posteriorly than at other positions. Highest mean cough totals were seen with stimulation at or above 40 Hz. Mechanical stimulation had no effect on respiratory rate but increased tidal volume in four (50%) subjects with IPF, particularly at higher frequencies. It was associated with increased urge to cough followed by a true cough reflex., Conclusions: This study demonstrates that patients with IPF show enhanced cough reflex sensitivity to mechanical stimulation of the chest wall whilst normal individuals show little or no response. The observation that low frequency stimulation over the lung base, where fibrosis is most extensive, induces cough in more patients than at other sites supports the hypothesis that lung distortion contributes to the pathogenesis of cough in IPF.

Non-tuberculous mycobacterias (NTMs) have many clinical manifestations in humans, depending on the underlying immunological status. We present a patient with Mycobacterium avium intracellulare pulmonary infection and co-existing, biopsy proven non-granulomatous organising pneumonia in distinct regions within the lungs. Treatment consisting of anti-mycobacterial therapy and corticosteroids led to clinico-radiological resolution. This case represents a potential broader clinico-pathological manifestation of Mycobacterium avium intracellulare.

The benefits of long-term oxygen therapy (LTOT) on mood in Chronic Obstructive Pulmonary Disease (COPD) are unproven. Longitudinal studies are affected by disease progression, the increased package of care (with LTOT) and may not control for known confounders on mood. We compared the point prevalence and severity of mood disturbance in patients with severe COPD, not on LTOT (the -LTOT group) to those with COPD on LTOT (the +LTOT group). We mailed the Hospital Anxiety and Depression (HAD) Score to 182 consecutive patients with severe COPD, identified from respiratory case notes in three UK Hospitals. We compared 57 patients not prescribed LTOT to 57 patients on LTOT, and used stratified sampling to match the groups as far as possible for age, gender, lung function and other possible confounders on mood. Or these, 25% of patients in both groups scored in the 'definite' case range for anxiety (HAD score >or= 11). 37% of the -LTOT group and 33% of the +LTOT group scored in the 'definite' range for depression (HAD score >or= 11) (p=N.S). In both groups, only 11% of responders were prescribed anxiolytics and/or antidepressants. Further multiregression analysis confirmed that socio-demographic variables (e.g., lives alone, feels isolated or recent life events) were stronger predictors of mood than the prescription of LTOT or other traditionally accepted factors such as co-morbidity or the use of antidepressants or anxiolytics. High levels of anxiety and depression are present in severe COPD and appear under-treated. The +LTOT and -LTOT patients had a similar high prevalence of anxiety and depression.

Little is known about the mechanisms which generate cough in patients with diffuse parenchymal lung disease. This article outlines some of the possible mechanisms which cause cough in patients with idiopathic pulmonary fibrosis (IPF). It goes on to discuss what is currently known about the enhanced cough reflex which afflicts patients with this condition, and describes recent evidence for enhanced expression of neurotrophins in the lungs of these patients. Preliminary data indicating that corticosteroids can reduce the cough reflex response to capsaicin and substance P in IPF offer hope that more specific therapies may be developed in the future.

Little is known about the pathogenesis of cough in idiopathic pulmonary fibrosis (IPF). We hypothesized that abnormalities of respiratory tract tachykinin-containing sensory nerves may be implicated. We studied cough response to capsaicin, substance P (SP), and bradykinin in 10 healthy control subjects and 10 patients with IPF. Six patients were tested before and after steroid therapy. Induced sputum cell counts and neurotrophic factor levels were also measured in 13 patients and 13 control subjects. The results show that cough sensitivity to capsaicin was greater in patients (p < 0.01). Neither SP nor bradykinin induced cough in normal subjects. SP and bradykinin induced cough in 7/10 patients (p < 0.002) and 2/10 patients (not significant) with IPF, respectively. Prednisolone caused a reduction in cough sensitivity to capsaicin (p < 0.05) and SP (p < 0.05) in all six patients treated. There were significantly more neutrophils (p = 0.001) and higher levels of nerve growth factor (p < 0.01) and brain-derived neurotrophic factor (p < 0.01) in patient's sputa. These findings suggest functional upregulation of lung sensory neurones in IPF. The cough response to inhaled SP in most patients may reflect disrupted respiratory epithelium. The response to corticosteroids demonstrates that the cough is amenable to therapy.

A 64-year-old man was referred to chest clinic after presenting initially with painless haematuria. Bladder biopsies showed granulomatous inflammation and subsequent urine cultures grew Mycobacterium bovis. He had been treated empirically for genito-urinary tuberculosis twice previously and on both occasions his haematuria ceased. Although the early hospital notes have been destroyed we believe this represents a very late and recurrent relapse of cystitis due to M. bovis.

Prostaglandin E(2) (PGE(2)) inhibits fibroblast proliferation and collagen production. Its synthesis by fibroblasts is induced by profibrotic mediators including transforming growth factor (TGF)-beta(1). However, in patients with pulmonary fibrosis, PGE(2) levels are decreased. In this study we examined the effect of TGF-beta(1) on PGE(2) synthesis, proliferation, collagen production, and cyclooxygenase (COX) mRNA levels in fibroblasts derived from fibrotic and nonfibrotic human lung. In addition, we examined the effect of bleomycin-induced pulmonary fibrosis in COX-2-deficient mice. We demonstrate that basal and TGF-beta(1)-induced PGE(2) synthesis is limited in fibroblasts from fibrotic lung. Functionally, this correlates with a loss of the anti-proliferative response to TGF-beta(1). This failure to induce PGE(2) synthesis is because of an inability to up-regulate COX-2 mRNA levels in these fibroblasts. Furthermore, mice deficient in COX-2 exhibit an enhanced response to bleomycin. We conclude that a decreased capacity to up-regulate COX-2 expression and COX-2-derived PGE(2) synthesis in the presence of increasing levels of profibrotic mediators such as TGF-beta(1) may lead to unopposed fibroblast proliferation and collagen synthesis and contribute to the pathogenesis of pulmonary fibrosis.

Asbestosis is a fibrotic lung disease resulting from inhalation of asbestos fibres. Its pathogenesis is poorly understood but probably involves stimulation of fibroblast proliferation and collagen production by mediators released from inflammatory and resident lung cells. In vitro studies have implicate PDGF, TNF-alpha, IGF-1, TGF-beta, and IL-1 in asbestosis, but the role of these mediators in vivo is not known. This study aimed to characterize mediators in bronchoalveolar lavage (BAL) fluid from patients exposed to asbestos with (n = 24) or without (n = 34) asbestosis, compared with ten normal subjects. Human lung fibroblasts were exposed to serial dilutions of BAL fluids and the effects on fibroblast proliferation were assessed. The median mitogenic activity of BAL fluid from asbestos-exposed (17 per cent above medium control, range 3-44 per cent) and asbestosis (14 per cent, range 2-60 per cent) groups was higher than that of BAL fluid from controls (10 per cent, range 2-20 per cent; P < 0.01 and P < 0.05, respectively), but there was no significant difference between the patient groups. The mitogenic activity of BAL fluids was not reduced by incubation with neutralizing antibodies to PDGF-AA, PDGF-AB, PDGF-BB, TNF-alpha, IGF-1, and IL-1 beta. We conclude that BAL fluids from patients exposed to asbestos contain mitogens for human lung fibroblasts, but that PDGF, TNF-alpha, IGF-1, or IL-1 beta do not contribute to this activity.

A 29-year-old Caucasian woman presented to hospital with a 2-day history of diarrhoea, anorexia and rigors. Investigations showed abnormal liver function tests, hyponatremia, hypoalbuminaemia and lymphopenia. The initial chest radiograph was normal. A bone marrow trephine biopsy showed non-caseating granulomata and she subsequently developed miliary shadowing on the chest radiograph. A transjugular liver biopsy confirmed the presence of acid-alcohol fast bacilli. Despite starting triple therapy for miliary tuberculosis she remained febrile and developed massive hepatosplenomegaly, jaundice and pancytopenia. Standard triple therapy was substituted with ethambutol, streptomycin and oral prednisolone and the patient made a dramatic recovery. The clinical symptoms of miliary tuberculosis are frequently non-specific and the onset of the illness is often insidious. The liver is involved in almost all patients with miliary tuberculosis, but massive hepatosplenomegaly and jaundice are rare. Standard triple-therapy should be discontinued when there is significant liver dysfunction, and corticosteroids should be considered for patients with miliary tuberculosis who fail to respond to conventional therapy.

1. The ability of airway epithelial cells to produce insulin-like growth factor I may be important in the pathogenesis of subepithelial fibrosis observed in the airways of patients with asthma. We determined whether human airway epithelial cells are capable of producing polypeptide mediators that could induce fibroblast proliferative activity, in particular insulin-like growth factor I. 2. We examined 12 primary cultures of human airway epithelial cells grown to confluence on collagen gel-coated dishes. Using a colorimetric assay based on the uptake and subsequent release of Methylene Blue, increased proliferation of human fetal lung fibroblasts was detected in conditioned media from airway epithelial cells. The median stimulation of fibroblast proliferation was 49.9% (range 25.6-113.3%) above control values (observed at 1:2 dilution of media). 3. A neutralizing antiserum to insulin-like growth factor I partly inhibited fibroblast proliferation induced by epithelial cell conditioned media by 52.2% (49.9-109%; n = 5). 4. Radioimmunoassay for insulin-like growth factor I in conditioned media demonstrated a median concentration of 54.1 ng/ml (32.4-96.8 ng/ml). 5. Insulin-like growth factor I mRNA was detected in epithelial cell monolayers by Northern blot analysis using an insulin-like growth factor I cDNA probe. 6. The insulin-like growth factor I gene is expressed in cultured human airway epithelial cells, which also secrete insulin-like growth factor I protein. Insulin-like growth factor I also accounts for the major mitogenic activity for fibroblasts of cultured human epithelial cell conditioned media. Insulin-like growth factor I may function in a paracrine manner to modulate fibroblast behaviour and may be involved in airway processes, such as those occurring in asthma.

Pulmonary fibrosis commonly develops in systemic sclerosis. We assessed the role of thrombin in promoting fibroblast proliferation in the lungs in this disorder. Bronchoalveolar lavage fluid (BALF) thrombin concentrations were higher in ten patients with systemic sclerosis than in 12 healthy controls (14.6 vs 3.6 nmol/L, p < 0.02), but values in patients with cryptogenic fibrosing alveolitis (n = 10) or sarcoidosis (n = 10) were not increased. BALF from all patients induced fibroblast proliferation. This proliferation was attenuated by thrombin inhibitors for BALF from systemic sclerosis patients only. We suggest thrombin contributes to lung fibroblast proliferation in this disorder.

Antithymocyte globulin (ATG) therapy is an established form of treatment for aplastic anaemia and has also been used as prophylaxis against graft rejection of bone marrow and renal allografts. Administration of ATG preparations has been associated with many mild clinical reactions, as have other forms of immunomodulatory therapy. However, serious adverse effects appear to be rare. We report a case of rapidly progressive fibrosing alveolitis and thyrotoxicosis in relation to ATG therapy, highlighting its potential toxicity and emphasising that its administration should be undertaken by experienced physicians in specialised centres.

Histological examination of a lung removed at transplantation revealed multiple peripheral tumourlets and microcarcinoids in close association with bronchioles causing an obliterative bronchiolitis. This was an unexpected finding but explained the progressive airflow limitation which characterised the patient's clinical course.

An increase in subepithelial mesenchymal cells and associated connective tissue is a feature of bronchial asthma. We determined whether neuropeptides could modulate fibroblast activity, particularly with respect to proliferation and chemotaxis. Human lung fibroblasts were cultured with neurokinin A (NKA), substance P (SP), vasoactive intestinal peptide (VIP), and calcitonin-gene-related peptide (CGRP). After 48 h, fibroblast proliferation was measured by a colorimetric assay based on the uptake and subsequent release of methylene blue. The chemotactic response to neuropeptides was determined with the use of a modified Boyden chamber. Both NKA and SP (10(-7)-10(-4) M) stimulated human lung fibroblast proliferation in HFL1 and IMR-90 fibroblasts. VIP and CGRP had no effect on fibroblast proliferation. NKA alone stimulated fibroblast chemotaxis maximally at 10(-10) M. Neutral endopeptidase (NEP) activity of 0.52 and 5.2 pmol/10(6) cells was assayed in IMR-90 and Hs68 fibroblasts, respectively. Phosphoramidon (5 x 10(-6)-10(-5) M), an NEP inhibitor, enhanced fibroblast proliferation in a dose-dependent manner. Thus neuropeptides have the potential to cause activation of mesenchymal cells, and neuropeptide release may contribute to the structural abnormalities observed in asthmatic airways.

Pulmonary fibrosis is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). The pathogenesis of this condition is poorly understood, but one of the earliest pathologic features is endothelial and epithelial cell injury with subsequent regeneration. Endothelial and epithelial cells can release several mediators, including endothelin-1 (ET-1). In this study, we investigated the levels of ET-1 in bronchoalveolar lavage fluid (BALF) from patients with SSc and assessed the contribution of ET-1 to the fibroblast mitogenic activity induced by these fluids. A total of 26 patients were evaluated and divided into those with evidence of pulmonary fibrosis, assessed by thin-section computed tomography (group I, n = 16), and those with a normal scan (group II, n = 10). BALF from both groups of patients stimulated fibroblast proliferation. Values expressed as median (range) percentage increase above media controls were 25.5% (5.0 to 47.8%) and 27.6% (10.9 to 51.6%) for groups I and II, respectively (P < 0.02 in both cases). Mitogenic activity was inhibited by about 40% in the presence of either a neutralizing antibody to ET-1 or two synthetic ET-1 receptor ligands. Levels of ET-1 in BALF, expressed as medians (range) were 2.90 ng/mg albumin (0.68 to 5.75) in patients with SSc and 1.23 ng/mg albumin (0.84 to 2.0) in control patients (P < 0.02). Furthermore, ET-1 levels in BALF from patients in group II (3.83 ng/mg albumin, range 1.76 to 5.75) were elevated compared with those in group I (2.62 ng/mg albumin, range 0.68 to 3.81; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The case is described of a 36 year old woman who presented with a large left sided haemothorax. A thoracic computed tomographic (CT) scan suggested there was a bony outgrowth arising from the fourth rib. This was resected surgically and found to be an osteochondroma which was surrounded by blood clot. No definite site of bleeding was identified, but it is thought that the tumour may have traumatised the lung, the pericardiacophrenic artery, or the superior pulmonary vein, resulting in life threatening haemorrhage.

1. Interstitial lung disease is a common complication of systemic sclerosis. The mechanism by which excess collagen is deposited in the lung is poorly understood, but is thought to involve release of mediators which activate lung fibroblasts. In this study we investigated and partially characterized the fibroblast proliferative activity of bronchoalveolar lavage fluid from 29 patients with systemic sclerosis, 19 with and 10 without evidence of lung disease assessed by thin-section computed tomography. 2. Bronchoalveolar lavage fluid from both groups of patients stimulated fibroblast proliferation compared with control subjects: systemic sclerosis with normal computed tomography, 27.7 (range 10.5-57.9)% above control; systemic sclerosis with abnormal computed tomography, 26.7 (range 5.0-47.8)% above control, P < 0.02 in both cases. 3. The activity was reduced by about one-third by neutralizing antibodies to insulin-like growth factor-1 but not platelet-derived growth factor. Levels of insulin-like growth factor-1 of bronchoalveolar fluid were increased in patients with systemic sclerosis [2.10 (range 1.10-3.48) ng/ml of bronchoalveolar lavage fluid] compared with controls [1.45 (range 1.10-2.05) ng/ml; P < 0.01]. When patients were subdivided into those with abnormal computed tomography [2.10 (range 1.20-3.48) ng/ml] and those with normal computed tomography [1.85 (range 1.10-2.90) ng/ml] only the values for the group with evidence of lung disease were increased compared with control subjects (P < 0.02). Platelet-derived growth factor could not be detected in bronchoalveolar lavage fluid from any group. Fractionation of bronchoalveolar lavage fluid demonstrated activity in several fractions consistent with the molecular masses of insulin-like growth factor-1 associated with binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

To study the role of transforming growth factor-beta 1 (TGF-beta 1) in the pathogenesis of pulmonary fibrosis we have examined lung biopsies from nine patients with systemic sclerosis and interstitial lung disease, eight with 'lone' cryptogenic fibrosing alveolitis, two with cystic fibrosis, two with extrinsic allergic alveolitis, two with Langerhans' cell histiocytosis, one with lymphangioleiomyomatosis, one with giant cell interstitial pneumonia, and one adenocarcinoma of the lung. In cryptogenic fibrosing alveolitis, both 'lone' and associated with systemic sclerosis alveolar macrophages, bronchial epithelium and hyperplastic type II pneumonocytes expressed intracellular TGF-beta 1. Extracellular TGF-beta 1 was found in the fibrous tissue immediately beneath the bronchial and hyperplastic alveolar epithelium. In normal lung, however, the alveolar epithelium and alveolar interstitium were negative for both forms of TGF-beta 1. There was strong expression of TGF-beta 1 in hyperplastic mesothelium and its underlying connective tissue and in Langerhans' cells in the two cases of histiocytosis. In the organizing pneumonia in cystic fibrosis, the intraalveolar buds of granulation tissue reacted strongly for the extracellular form of TGF-beta 1 and the overlying hyperplastic epithelium expressed the intracellular form. In lymphangioleiomyomatosis, the aberrant smooth muscle cells strongly expressed intracellular TGF-beta 1 and the extracellular form was expressed in the adjacent connective tissue. In giant cell interstitial pneumonia, the numerous alveolar macrophage including the multinucleate forms, expressed intracellular TGF-beta 1, as did the hyperplastic alveolar epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Levels of the N-terminal propeptide of type III collagen (PIIINP) in bronchoalveolar lavage fluid (BALF) are thought to reflect type III collagen production by the lungs, and increased levels have been reported in patients with pulmonary fibrosis. We wanted to know more about the relative proportions of these peptides in normal BALF, whether they altered in pulmonary fibrosis, and whether lymphoid tissue is capable of clearing PIIINPs. In this study, we used a radioimmunoassay which detects the different forms of PIIINP-related antigens with equal specificity, to measure PIIINPs in serum and BALF of patients with cryptogenic fibrosing alveolitis (CFA). To investigate why PIIINP profiles in BALF differed from serum, the absolute concentration and relative proportion of PIIINPs in lymph afferent and efferent to the popliteal lymph node of a sheep were also determined. PIIINP concentrations were significantly greater in serum and BALF of patients with CFA, compared with controls. Gel chromatography indicated that serum antigen distribution, both of patients and controls, contained approximately 20% Col 1-3; the remainder being Col 1. In contrast, BALF contained Col 1-3 and Col 1, together with an antigen of high molecular weight (> 150 kD). The relative proportion of each antigen varied quite widely, but there were no apparent differences between patients and controls. The concentration of PIIINPs in afferent lymph was 295 ng.ml-1 and in efferent lymph was 104 ng.ml-1. Gel chromatography demonstrated that a significant amount of Col 1-3, together with a high molecular weight peptide, had been cleared during passage through the node.(ABSTRACT TRUNCATED AT 250 WORDS)

It is over 25 years since Scadding first defined the term fibrosing alveolitis. It has since been established that complex mechanisms underlie its pathogenesis, including epithelial and endothelial injury, vascular leakage, production of inflammatory cells and their mediators, and fibroblast activation. Only through a detailed knowledge of how these cellular and molecular events are interlinked will we learn how to combat this disease, which is notoriously resistant to present treatments. So far the only therapeutic advances have been refinements in immunosuppression, and even these treatments are frequently disappointing. We believe that future advances in treatment will come from the development of agents that protect endothelial and epithelial cells from further injury and agents that can inhibit release of inflammatory mediators. A better knowledge of the mechanisms of collagen gene activation and the biochemical pathways of collagen production may also allow the identification of vulnerable sites at which new treatments may be directed. A combined approach to modifying appropriate parts of both the inflammatory component and the fibroblast/collagen component should provide a new stimulus to research. Further epidemiological studies are also needed to identify the environmental causes of lung injury that initiate the cascade of events leading to interstitial fibrosis.

Background: The relative proportions of fibrosis and inflammation seen by open lung biopsy examination is a predictor of disease outcome in fibrosing alveolitis. This study was designed to assess the ability of high resolution computed tomography to predict the histological appearance of open lung biopsy specimens from patients with systemic sclerosis., Methods: Twenty abnormal biopsy specimens from 12 patients were assessed; abnormalities were categorised as fibrotic (fibrosis exceeding inflammation) or inflammatory (inflammation equal to or exceeding fibrosis). Computed tomography appearances were scored for the lobe from which the biopsy specimen was taken; scans were graded from parenchymal opacification alone through to a reticular pattern alone., Results: Two lobar appearances were identified on computed tomograms: amorphous parenchymal opacification equal in extent to reticulation (grade 3) and a predominantly reticular pattern (grade 4). There was a significant association between a fibrotic histological appearance and a grade 4 computed tomogram, and between an inflammatory histological appearance and a grade 3 computed tomogram. Computed tomography grade 4 was associated with a fibrotic histological appearance in 12 out of 13 lobes, and grade 3 with an inflammatory histological appearance in four out of seven lobes., Conclusion: Computed tomography discriminated between biopsy specimens that were predominantly fibrotic and a smaller group with a larger amount of inflammation.

Type III procollagen N-peptides (PIIINPs) are believed to be released in stoichiometric amounts as type III collagen molecules are secreted from cells. We hypothesized that if the human lung actively produces type III collagen a detectable transpulmonary gradient in PIIINPs would exist in normal individuals that might be altered following a pulmonary insult. PIIINPs were therefore measured by radioimmunoassay in serum taken simultaneously from the pulmonary artery (PA) and left ventricle/aorta (LV) in 11 patients undergoing routine cardiac catheterisation. Mean PIIINP levels +/- SEM in LV were 66.8 +/- 5.4 micrograms.ml-1 and 59.9 +/- 4.1 micrograms.ml-1 in PA (p less than 0.04). In 6 patients, repeat measurements taken 4 h after cardiopulmonary bypass revealed a significant fall in PA values to 43.8 +/- 2.6 micrograms.ml-1 (p less than 0.001) and abolition of the transpulmonary gradient. These results suggest the adult human lung actively synthesis type III collagen and that, in the short term, cardiopulmonary bypass inhibits this process.

Most studies of lung histology in systemic sclerosis have been based on autopsy specimens and consequently emphasize end-stage fibrotic disease. Although occasional pathologic descriptions of open-lung biopsies have recognized the presence of inflammatory cells, suggesting a similarity to "lone" cryptogenic fibrosing alveolitis, the two conditions have never been formally compared. In this study we describe the morphologic features of 49 open-lung biopsies from 34 systemic sclerosis patients with interstitial lung disease, many of whom had their lung disease diagnosed at an early stage. None had pulmonary hypertension. Examination of lung tissue by light microscopy showed the earliest changes to include patchy lymphocyte and plasma cell infiltration of the alveolar walls, interstitial fibrosis, and increased macrophages but only occasional polymorphonuclear cells and lymphocytes in the alveolar spaces. Alveolitis was not observed without fibrosis. Comparison of 22 biopsies with a similar number from patients with lone cryptogenic fibrosing alveolitis, matched for age and sex, revealed no qualitative or quantitative differences, other than a higher prevalence of focal lymphoid hyperplasia (follicular bronchiolitis) in the systemic sclerosis patients than in the lone cryptogenic fibrosing alveolitis controls (23 and 5%, respectively). There was an inverse correlation between the extent of interstitial inflammation and patients' age (p less than 0.05), disease duration (p less than 0.05), and age at onset of systemic sclerosis (p less than 0.01). There was also an inverse correlation between DLCO and interstitial fibrosis (p less than 0.01) and loss of lung architecture (p less than 0.05). Ultrastructural studies of eight systemic sclerosis biopsies showed evidence of endothelial and epithelial injury together with interstitial edema and excess collagen deposition. Occasional mast cells were observed, often in close contact with interstitial fibroblasts, but there were no tubuloreticular structures or evidence of immune complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar lavage fluid from patients with systemic sclerosis was analysed for evidence of pulmonary vascular leakage, inflammatory cell influx, and enhanced type III collagen synthesis. Eighteen patients with systemic sclerosis and computed tomographic evidence of fibrosing alveolitis were compared with 16 patients with a normal scan. The albumin concentration in lavage fluid was higher in all patients than in normal volunteers. Patients with an abnormal computed tomogram as a group had increased proportions of all inflammatory cell types, whereas those with a normal scan had increased neutrophils only. Increased lavage type III procollagen peptides were found in all patients with an abnormal computed tomogram and eight of those with a normal scan. These results suggest that pulmonary vascular leakage and neutrophil influx may be early pathological features of lung disease in systemic sclerosis and frequently associated with enhanced collagen production. Thus lavage of patients with systemic sclerosis may identify lung inflammation and altered collagen metabolism early in the evolution of fibrosing alveolitis.

Fibroblasts adhere to, and readily grow into, fibrin clots that form as a result of the cleavage of fibrinogen by thrombin. Subsequent fibroblast replication is believed to be stimulated by mitogens released by entrapped platelets, such as platelet-derived growth factor. We suggest that the supernatant remaining after the fibrinogen-thrombin reaction could stimulate fibroblast replication, even in the absence of other blood components. To examine this hypothesis we expressed liquid from a fibrin clot and measured its mitogenic activity on human lung fibroblasts, in serum-free conditions, using a colorimetric assay based on uptake and subsequent release of Methylene Blue. The clot supernatant caused a mitogenic response of 51 +/- 6% above control and was equivalent to about half that elicited by medium containing 10% newborn calf serum. On their own, both thrombin and fibrinopeptides A and B (small molecular weight cleavage products released from fibrinogen) showed some mitogenic activity, but there was also activity in higher molecular weight cleavage products, suggesting the presence of uncharacterized mitogens. It is proposed that these agents may play important roles in wound healing and diseases associated with vascular leakage and fibrosis, by stimulating fibroblast replication.