Biomedical subjects

G M Verleden

Publications and source records attributed to G M Verleden.

At least 19 recordsLinked to original sources

PubMed2006

Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells.

Lung transplantation is hampered by bronchiolitis obliterans syndrome (BOS), although recently azithromycin treatment has a published response rate of about 42% in patients with established BOS. We linked this improvement to a reduction in airway neutrophilia and IL8. In the present study, we further investigated the intracellular mechanisms of azithromycin, looking at the possible involvement of mitogen-activated-protein kinases (MAPK) and oxidative stress. Simultaneously, currently used immunosuppressive agents were investigated. Human primary airway smooth muscle cells were stimulated with IL17 and incubated with increasing concentrations of steroids, immunosuppressive agents (tacrolimus, cyclosporine and rapamycin) or macrolides (erythromycin and azithromycin). We measured supernatant IL8 protein, 8-isoprostane and cell lysate MAPK. IL17-induced IL8 production was decreased by both erythromycin and azithromycin. In nonstimulated condition, IL8 production only increased at the highest dose of azithromycin. Dexamethasone failed to attenuate IL8 production, whereas immunosuppressive agents significantly increased IL8 production in both IL17-stimulated and nonstimulated conditions. 8-isoprostane production and MAPK activation proved to be decreased by the macrolides. We conclude that macrolides (but not steroids/immunosuppressive agents) inhibit IL17-induced IL8 production in human primary airway smooth muscle cells via a reduction in MAPK activation and 8-isoprostane production. In BOS patients, these phenomena may explain the anti-inflammatory effects of azithromycin.

Azithromycin↗

PubMed2006

Listeria pleuritis 1 week after lung transplantation.

Listeria monocytogenes is an important bacterial pathogen in immunocompromised patients, the elderly, pregnant women and transplant patients, but until now it has not been reported in lung transplants. We report the first case of listeriosis in a lung transplant recipient who presented with a pleural effusion 8 days after transplantation. After the introduction of a thorax drain and the administration of intravenous antibiotics during 3 weeks, the patient recovered completely. This case highlights the increased risk for uncommon respiratory infections in lung transplant patients and examines the specific management of listeria pleuritis.

Ampicillin↗

PubMed2006

The pH of exhaled breath condensate of patients with allograft rejection after lung transplantation.

Endogenous airway acidification, as assessed by the condensate pH, has been implicated in the pathophysiology of inflammatory airway diseases such as cystic fibrosis and asthma. The aim of this study was to investigate the pH of condensate in patients after lung transplantation (LTX). From the cohort of transplanted patients at our center, 83 patients (9 heart-lung transplantation, 48 double-lung transplantation, 26 single-lung transplantation) were recruited and analyzed in a cross-sectional manner: 26 patients were diagnosed with chronic rejection or bronchiolitis obliterans syndrome (BOS), 7 patients were diagnosed with acute rejection (AR) while 50 patients had no evidence of rejection according to the International Society for Heart and Lung Transplantation criteria. The condensate pH was significantly reduced in patients with BOS and AR when compared to patients without rejection and control subjects (5.8 +/- 0.5 and 6.2 +/- 0.4 versus 6.6 +/- 0.4 and 6.5 +/- 0 .4, respectively; p < 0.05). Moreover, there was a significant correlation between condensate pH levels and the BOS grade (r =-0.62; p < 0.01), the FEV(1) (r = 0.39; p < 0.01) and the total cell and neutrophil count in bronchoalveolar lavage fluid (r =-0.39 and r =-0.56, respectively; p < 0.01). Airway acidification occurs in BOS and may directly or indirectly reflect airway inflammation in patients with allograft rejection after LTX. Measuring condensate pH might thus be a new tool for the evaluation of rejection in lung transplant patients.

Adult↗

PubMed2006

The role of interleukin-17 during acute rejection after lung transplantation.

Acute rejection (AR) is an important complication that can occur after lung transplantation and constitutes a risk factor for bronchiolitis obliterans syndrome, which is characterised by a neutrophilic airway inflammation. The specific aim of this study was to investigate the role of interleukin (IL)-17, which promotes chemotaxis of neutrophils by inducing IL-8 production, in AR. Cell differentials, mRNA and protein levels were quantified in bronchoalveolar lavages (BALs) taken from patients at 28 and 90 days after lung transplantation. The patient's rejection status was assessed by transbronchial biopsy. An AR was found in nine out of the 26 patients examined, 28 days after transplantation. The number of BAL neutrophils and lymphocytes were increased in these patients. IL-17 mRNA and protein levels in the BAL were increased in patients with AR. Analysis of BAL obtained at day 90 after transplantation, demonstrated that the increase in IL-17 had disappeared, whereas the increase in neutrophils and lymphocytes persisted. These data showed that interleukin-17 is temporarily upregulated in bronchoalveolar lavage during acute rejection. The number of lymphocytes and neutrophils are increased in bronchoalveolar lavage during acute rejection and may persist up to 2 months after acute rejection. These findings suggest that interleukin-17 is important in the pathophysiology of acute lung rejection.

Acute Disease↗

PubMed2005

[Surgical aspects of (cardio) pulmonary transplantation].

UNLABELLED: INTRODUCTION AND STATE OF THE ART: Both short and long-term outcomes following lung transplantation have improved substantially in recent years as a result of advances in the selection and management of donors, organ preservation, immunosuppressive therapy, and the treatment of infectious and malignant complications. In addition surgical techniques have evolved over time and have contributed to this increase in success rates. PERSPECTIVES AND CONCLUSIONS: This review outlines surgical aspects of lung transplantation including a historical note, techniques of lung harvesting, some anaesthetic considerations, the different transplant types and incisions, as well as anastomotic techniques and their pitfalls.

Anesthesia↗

PubMed2005

Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal?

Chronic rejection (obliterative bronchiolitis) is the single most important cause of chronic allograft dysfunction and late mortality after lung transplantation. As this condition is difficult to prove using biopsy specimens, a clinical term, bronchiolitis obliterans syndrome (BOS) has been in use for >10 yrs to describe the progressive decrease of pulmonary function. However, before diagnosing a patient as having BOS, based on a sustained and progressive decrease in forced expiratory volume in one second and/or forced mid-expiratory flow between 25-75% of forced vital capacity, different confounding factors have to be eliminated. Treatment of BOS mainly consists of an increase or a change in the immunosuppressive drug regimen, which may lead to more pronounced infectious complications. Recently, two new options have become available to treat patients with BOS, treatment of gastro-oesophageal reflux and azithromycin. In the present paper, the authors give an overview of the current data on these two modalities, which may lead to a restoration of the pulmonary function in some of the patients, illustrating once more the fact that bronchitis obliterans syndrome is not always a manifestation of chronic rejection.

Anti-Bacterial Agents↗

PubMed2003

Exhaled nitric oxide after lung transplantation: impact of the native lung.

It has already been demonstrated that exhaled nitric oxide (eNO) is increased in lung transplant patients with chronic rejection, although it is not known whether the diseased native lung after single lung transplantation (SLTx) contributes to the increased eNO values. This study aimed to compare the eNO values in stable lung transplant patients (SLTx versus sequential (S)SLTx and heart (H)LTx) and in patients with established chronic rejection. Altogether, 42 LTx patients (25 females, 13 SLTx, 18 SSLTx, 11 HLTx), with a mean follow-up of 1149 days and a mean age of 44.6 yrs at transplantation, were included. Twenty-six patients had no signs of chronic rejection (five SLTx and 21 SSLTx/HLTx). There was no difference in their eNO values (10.2 in SLTx versus 12.2 (parts per billion) ppb in SSLTx/HLTx). Sixteen patients (eight SLTx and eight SSLTx/HLTx) had a chronic rejection (eight bronchiolitis obliterans syndrome (BOS) potential stage, four BOS stage 1, three BOS stage 2 and one BOS stage 3). Their eNOs were 18.1 (SLTx) and 17.0 (SSLTx/HLTx) ppb, respectively, which were significantly different to the stable LTx patients and showed a trend towards significance for SSLTx/HLTx. There was no significant difference in eNO between the patients with chronic rejection who underwent SLTx and those who underwent SSLTx/HLTx. The diseased native lung after single lung transplantation probably does not contribute much to the exhaled nitric oxide values, either in stable lung transplant patients or in lung transplant patients with chronic rejection.

Adolescent↗

PubMed2003

N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells.

Reactive oxygen species are involved in the activation of several mitogen-activated protein kinases (MAPKs), key-players in the production of several cytokines. Therefore the current study investigated whether N-acetylcysteine (NAC), an antioxidative agent, inhibits the interleukin (IL)-1beta-induced expression and production of eotaxin and monocyte chemotactic protein (MCP)-1 in human airway smooth muscle cells (HASMC). NAC (10 mM) decreased the expression of eotaxin and MCP-1, by 46 +/- 11% (n=7) and 87 +/- 4% (n=6), respectively; the eotaxin release was inhibited by 75 +/- 5% (n=7), whereas the MCP-1 release was decreased by 69 +/- 41% (n=10). NAC (1 mM) also decreased the IL-1beta-induced activation of p38 MAPK. Compared with unstimulated cells, a four-fold increase in 8-isoprostane production in IL-1beta-stimulated HASMC was observed, which could be inhibited by NAC in a concentration-dependent way, with a maximum inhibition of 39 +/- 12%, with 1 mM NAC. The present study demonstrated that N-acetylcysteine inhibits the interleukin-1beta-induced eotaxin and monocyte chemotactic protein 1 expression and production due to a decreased activation of p38 mitogen-activated protein kinase. This study has also shown that N-acetylcysteine decreases the interleukin-1beta-induced production of reactive oxygen species, as suggested by a reduction in the 8-isoprostane production.

Acetylcysteine↗

PubMed2003

Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells.

Inflammatory cells, such as eosinophils, seem to be key players in the inflammatory process of asthma. These cells are attracted by chemokines, for example eotaxin and monocyte chemotactic protein (MCP-1). In this study, the authors investigated whether eotaxin and MCP-1 expression and release in human airway smooth muscle cells could be modulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. The possible involvement of cAMP-dependent protein kinase A (PKA) was also studied. Forskolin, a direct stimulator of adenylyl cyclase, decreased the interleukin (IL)-1beta-induced eotaxin and MCP-1 release by 73+/-8 and 65+/-6%, respectively. 8Bromo-cAMP, a cAMP analogue, similarly decreased the chemokine production by 58+/-9 and 63+/-8% for eotaxin and MCP-1, respectively. Prostaglandin E2, known as an activator of the prostanoid receptors EP2 and EP4, which are positively coupled to adenylyl cyclase, also decreased the IL-1beta-induced eotaxin and MCP-1 production by 57+/-17 and 53+/-4%, respectively. H-89, an inhibitor of PKA, was able to inhibit the decrease in eotaxin and MCP-1 protein release induced by forskolin. Using Western-blot analysis, no effect of cAMP was found on the IL-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. This study shows that an increase in intracellular cyclic adenosine monophosphate concentration may decrease the interleukin-1beta-induced eotaxin and monocyte chemotactic protein-1 expression and production. This can be inhibited by addition of H-89, an inhibitor of cyclic adenosine monophosphate-dependent protein kinase. No decrease was observed in interleukin-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. These findings may be important for the further development of new anti-inflammatory drugs.

Bronchi↗

PubMed2002

Assessment of asthma severity and treatment by GPs in Belgium: an Asthma Drug Utilization Research Study (ADUR).

A prospective study was performed between June 1996 and December 1997, to identify how general practitioners (GPs) in Belgium assess asthma severity and how they treat asthma according to their severity assessment. Three hundred and sixty-five GPs included 1376 already diagnosed and treated asthmatics. The GPs used a questionnaire providing data on patient demographics, aetiology of asthma, symptoms and medication use. The patients provided a complete diary card of day and night symptoms and morning and evening peak expiratory flow rates during a 3-week period. Asthma severity as assessed by GPs was compared with the severity according to the GINA guidelines. Along the same line, asthma treatment was evaluated according to the GPs assessment of severity and according to the GINA guidelines. Confronting the assessment of asthma severity by the GPs with the GINA criteria revealed that about 20% and 2% of the patients' asthma severity respectively were under- and over-estimated, respectively (using a discrepancy between GPs and GINA assessment of severity by 2 or more classes). Using the GINA criteria for treatment, only 37.5% of the patients seemed to be correctly treated. Taking a discrepancy between GINA assessment and treatment of two classes as an error, 2.3% and 23.4% of the asthmatics are over- and under-treated, respectively. In conclusion, this study provides evidence that GINA guidelines seem not to be adequately interpreted and implemented by GPs in Belgium. Improvement of the assessment of asthma severity is definitely needed and may lead to more appropriate use of asthma medication.

Acute Disease↗

PubMed2002

Activity related increase of exhaled nitric oxide in Crohn's disease and ulcerative colitis: a manifestation of systemic involvement?

Nitric oxide (NO) is an important mediator of inflammation in several pathological conditions. Patients with lung diseases, like asthma, have higher levels of exhaled NO (eNO) in active disease in comparison with healthy volunteers. Aspirated colonic gas in patients with ulcerative colitis (UC) showed more than 100 times higher levels of NO in comparison with normal subjects. Crohn's disease (CD) and UC are associated with a variety of systemic manifestations, although lung diseases as an extra-intestinal expression of inflammatory bowel disease (IBD) are not well investigated. In some studies, clinical and subclinical pulmonary abnormalities are described in active IBD as well as in the stable situation. The aim of the present study is to evaluate whether eNO is increased in patients with active IBD and to investigate whether there exists a correlation between (1) the eNO levels and the disease activity, and (2) the spirometry and the disease activity in a subgroup of patients. In 31 patients with CD (mean age 36.8 +/- 12.9 years) and 24 patients with UC (mean age 38.0 +/- 14.7 years) the Crohn's Disease Activity Index (CDAI) and Colitis Activity Index (CAI) were measured, respectively. Exhaled NO was measured with a chemiluminescence analyzer, according to standardized criteria. In a subgroup of CD patients, spirometry was also performed according to standardized criteria. The mean CDAI in CD patients was 192.4 +/- 94.3 and their mean eNO value was 13.5 +/- 4.6 ppb. For UC the mean CAI was 6.2 +/- 4.8 and the mean eNO value was 15.8 +/- 6.2 ppb. In a matched control group of 27 healthy, non-smoking volunteers (mean age of 33.7 +/- 13.2 years) the eNO was 10.2 +/- 2.5 ppb (P < 0.05 compared to CD and P < 0.01 compared to UC). There was a disease-activity-related increase of the eNO level in patients with IBD. For patients with UC the correlation coefficient (r = 0.63, P < 0.001) was more pronounced than for CD (r = 0.39, P < 0.05). In 17 patients with CD, spirometry was available at the time of the eNO measurement. We found a significant negative correlation between the CDAI and the FEV1 and FVC in these patients (r = -0.559, P = 0.02 and r = -0.634, P = 0.006, respectively). We conclude that eNO is increased in active IBD and correlates with the activity of the disease; furthermore, we found a negative correlation between spirometry and disease activity in patients with CD. These observations strengthen the arguments that IBD is a systemic disease. Further research is needed to try to explain the significance of an increased eNO in IBD.

Acute Disease↗

PubMed2001

Chronic allograft rejection (obliterative bronchiolitis).

Lung and heart-lung transplantation are currently recognized as effective treatment for selected patients with end-stage lung or heart-lung disease. Although the survival rates have improved in recent years, long-term survival is still hampered by the development of chronic rejection. Histologically chronic rejection is manifested by obliterative bronchiolitis (OB), a process that leads to airways obstruction, with a gradual decline in pulmonary function tests. Extensive research efforts have attempted to unravel the pathophysiology of OB and identify key cytokines and growth factors involved in the process. Since the histological diagnosis of chronic rejection remains difficult, a clinical grading system has been proposed, determined as bronchiolitis obliterans syndrome (BOS), divided into four and, more recently, five categories, depending on the severity of airflow obstruction. This paper reviews the current knowledge of chronic rejection after heart-lung and lung transplantation.

Journal Article↗

PubMed2001

Mechanisms of interleukin 1beta-induced human airway smooth muscle hyporesponsiveness to histamine. Involvement of p38 MAPK NF-kappaB.

We have investigated the effect of IL-1beta on histamine H(1)-receptor (H(1)R)-mediated inositol phosphate (IP) accumulation in human airway smooth muscle cells (HASMC) and on histamine-induced contraction of human bronchial rings. Stimulation of HASMC for 24 h with IL-1beta resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine- induced contraction of IL-1beta-treated human bronchial rings. An inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1beta-induced H(1)R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1beta. IL-1beta has been demonstrated to induce cox-2 expression and PGE(2) synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1beta on H(1)R, whereas exogenously added PGE(2) was able to desensitize H(1)R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1beta. Here, we have demonstrated that IL-1beta desensitizes H(1)R, which involves the activation of p38 MAPK and NF-kappaB, leading to the expression of cox-2 and the synthesis of PGE(2). PGE(2) increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H(1)R. Our results suggest that IL-1beta protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H(1)R signaling.

Blotting, Western↗

PubMed2001

Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin.

Understanding of the cellular and cytokine interactions associated with inflammation and fibrosis in interstitial lung diseases (ILDs) has increased substantially during the past few years. Presently, many agents are known to have the ability to induce ILDs, although only a small percentage of exposed individuals will develop the disease. In addition, the majority of ILDs are of unknown origin and many are labelled "idiopathic". Therefore, host susceptibility, genetic factors and, possibly, environmental cofactors may be important for the clinical expression of ILDs. The present review reports evidence of the genetic predisposition to develop ILDs of unknown origin, more specifically sarcoidosis, idiopathic pulmonary fibrosis (IPF), lymphangioleio-myomatosis and ILDs, in systemic sclerosis. For instance, for sarcoidosis and IPF several histocompatibility antigens have been associated with the development and/or the clinical presentation of the disease. Furthermore, there are also several types of ILD that are associated with inherited disorders, of which the tuberous sclerosis complex is only one example. This clearly indicates that pulmonary fibrosis can be influenced by genetic factors. Familial occurrence of sarcoidosis and IPF is also well known, although the exact modes of inheritance are debatable. Several studies have shown that extrinsic factors, such as single or multiple fibrosing agents, probably contribute to the development of clinical ILDs of unknown origin. It is probable that some of these studies deal with patients who do not have classical IPF, as recently defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus. Therefore, the true role of these extrinsic factors in the development of IPF, or even sarcoidosis, remains speculative. With the help of animal studies and, more specifically, by using knock-out mice, it may be possible in the near future to unravel at least some of the genes that are responsible for the increased susceptibility of the development of interstitial lung diseases.

Animals↗

PubMed2000

Airbags and asthma.

Explore the source record for details and available documents.

Air Bags↗

PubMed2000

Femoral venoarterial extracorporeal membrane oxygenation for severe reimplantation response after lung transplantation.

Severe pulmonary reimplantation response after lung transplantation is not very common, although the mortality can be high. We present a patient who developed an extremely severe reperfusion injury after bilateral lung transplantation. Because of severe hypoxia and hemodynamic instability, despite aggressive ventilator settings, venoarterial extracorporeal membrane oxygenation (ECMO) was instituted using the femoral approach at the bedside. During ECMO, the patient developed a thoracic wall hematoma that was treated with transfusion alone. After 50 h of ECMO, his chest radiograph had dramatically improved, his oxygen need had been reduced to 50%, and he was successfully weaned from ECMO. Two years later, he is doing extremely well. Therefore, institution of ECMO using the femoral approach can be performed safely at the bedside in the ICU, and can be lifesaving in the context of a very severe reimplantation response after lung transplantation.

Catheters, Indwelling↗

PubMed2000

Bronchiolitis obliterans syndrome after lung transplantation: medical treatment.

Obliterative bronchiolitis (OB) or the clinical correlate bronchiolitis obliterans syndrome (BOS) is the main cause of late morbidity and mortality after heart-lung and lung transplantation. Although several risk factors for the development of OB/BOS have already been identified, very effective preventive therapy remains Utopian, although there has been much improvement in recent years. This paper attempts to summarize current experience in the medical treatment of OB/BOS, either by tackling the known risk factors for the development of OB/BOS or by changing the immunosuppressive drug regimen for treating established OB/BOS. The current treatment options, however, are rather anecdotal and mostly single-centre experiences. Therefore, multicentre studies are definitely needed to try to identify the most appropriate drug regimen either to prevent and to treat obliterative bronchiolitis/bronchiolitis obliterans syndrome.

Bronchiolitis Obliterans↗

PubMed1999

Cyclophosphamide rescue therapy for chronic rejection after lung transplantation.

BACKGROUND: Obliterative bronchiolitis remains the leading cause of late mortality after heart-lung and lung transplantation. Although several treatment options have been advocated, none has proven to be very successful. Cyclophosphamide is effective in the treatment of idiopathic pulmonary fibrosis, and chronic rejection after lung transplantation is also a fibroproliferative process. We therefore conducted an open, uncontrolled study to look at the effect of cyclophosphamide rescue therapy in the treatment of chronic rejection in lung transplant recipients. METHODS: Between October 1996 and March 1998 cyclophosphamide was prescribed to 7 patients with chronic and persistent rejection who failed to respond to conventional therapy (pulse steroids or antilymphocyte products or both). RESULTS: Cyclophosphamide therapy was initiated on postoperative day 478+/-366. At that time 2 patients were in bronchiolitis obliterans syndrome stage 0, 3 patients in stage 1, and 2 patients in stage 2. Their best postoperative forced expiratory volume in one second (FEV1) was 2.19+/-0.75 L. Three months before the start of cyclophosphamide the FEV1 had declined to 1.90+/-0.83 L, with a further decline to 1.63+/-0.64 L at the time of initiating cyclophosphamide. In 6 of the 7 patients the FEV1 stabilized or increased after cyclophosphamide had been started (mean FEV1 3 and 6 months after cyclophosphamide of 1.77+/-0.58 L and 1.79+/-0.48 L, respectively). One patient died 18 months after the introduction of cyclophosphamide due to progressive obliterative bronchiolitis. In one patient cyclophosphamide had to be stopped because of persistent leucopenia. CONCLUSIONS: Cyclophosphamide might be a promising therapeutic alternative for the treatment of chronic persistent rejection after lung transplantation.

Adult↗