Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function. METHODS: Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS(®) trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials. RESULTS: One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ≥ 1 dose reduction to 100 mg bid (27.9% versus 3.8%) or treatment interruption (23.7% versus 9.9%). Adverse events led to permanent treatment discontinuation in 19.3% and 13.0% of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4% of patients in the nintedanib group versus 18.4% in the placebo group; however, only 4.4% of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption. CONCLUSION: Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS(®) trials. TRIAL REGISTRATION: clinicaltrials.gov NCT01335464 and NCT01335477.

Newer modes of treating interstitial lung disease.

PURPOSE OF REVIEW: This review critically discusses recent advances in the treatment of idiopathic pulmonary fibrosis (IPF). Moreover, it also focuses on the practical approach of a patient diagnosed with IPF and uncovers challenges for the future. RECENT FINDINGS: Treatment can be divided into three major parts. Firstly, many new agents have been tested, but only the combination of N-acetylcysteine with corticosteroids, azathioprine and pirfenidone was able to show some significant effects. In the mean time, many second-generation agents are under development. Lung transplantation has made some major progress by introducing an appropriate allocation system. Finally, as part of best supportive care, several studies show that pulmonary rehabilitation might induce some important effects on quality of life. SUMMARY: So, it is clear that major progress has been made in the treatment of IPF, but we are convinced that an orchestrated effort will lead to a better understanding and treatment of this devastating condition.

Clinical use of biomarkers of survival in pulmonary fibrosis.

BACKGROUND: Biologic predictors or biomarkers of survival in pulmonary fibrosis with a worse prognosis, more specifically in idiopathic pulmonary fibrosis would help the clinician in deciding whether or not to treat since treatment carries a potential risk for adverse events. These decisions are made easier if accurate and objective measurements of the patients' clinical status can predict the risk of progression to death. METHOD: A literature review is given on different biomarkers of survival in interstitial lung disease, mainly in IPF, since this disease has the worst prognosis. CONCLUSION: Serum biomarkers, and markers measured by medical imaging as HRCT, pertechnegas, DTPA en FDG-PET are not ready for clinical use to predict mortality in different forms of ILD. A baseline FVC, a change of FVC of more than 10%, and change in 6MWD are clinically helpful predictors of survival.

Lung function in idiopathic pulmonary fibrosis--extended analyses of the IFIGENIA trial.

BACKGROUND: The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set. METHODS: We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients. RESULTS: In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower. CONCLUSION: This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.

Hypogonadism in male outpatients with sarcoidosis.

Hypogonadism is assumed to be present in sarcoidosis. Nevertheless, a comparison of circulating sex hormone concentrations of male sarcoidosis patients with those of healthy men has never been done. Moreover, it remains unknown if hypogonadism may contribute to a reduced muscle function, exercise intolerance, diminished vitality and depressed mood in male sarcoidosis patients. Pulmonary function, muscle function, exercise tolerance, vitality, mood, circulating sex hormone concentrations and C-reactive protein were assessed in 30 male sarcoidosis patients and 26 age-matched men with a normal pulmonary function. On average, patients had a restrictive pulmonary function, worse inspiratory and quadriceps muscle function, functional exercise intolerance, diminished vitality, depressed mood and increased systemic inflammation. Moreover, patients had significantly lower circulating (free) testosterone concentrations, while circulating sex hormone-binding globulin tended to be lower (p=0.0515). Circulating gonadotrophin concentrations were comparable. Non-significant relationships were found between sex hormones, clinical outcomes and C-reactive protein in patients with sarcoidosis. A significant number of male outpatients with sarcoidosis (46.7%) had low circulating testosterone concentrations, which was most probably caused by hypogonadotrophism. The clinical relevance of hypogonadism in male outpatients with sarcoidosis, however, remains currently unknown. Indeed, poor inspiratory and quadriceps muscle function, exercise intolerance, diminished vitality and depressed mood were not related to hypogonadism in these patients.

Endobronchial ultrasonography in bronchoscopic occult pulmonary lesions.

INTRODUCTION: The diagnostic yield of flexible bronchoscopy for peripheral pulmonary lesions is variable and often limited. Endobronchial ultrasonography (EBUS) has been reported to help localize a bronchoscopic occult pulmonary lesion and thereby improve the diagnostic yield of transbronchial biopsy (TBB). METHODS: We evaluated the yield of EBUS-guided TBB in 50 consecutive patients with a bronchoscopic occult pulmonary lesion. RESULTS: The mean diameter of the lesions was 36.6 mm (SD = 19.7 mm). We could visualize 74% of the bronchoscopic occult lesions with EBUS, and in these patients, a histologic diagnosis on TBB was obtained in 84%. However, the diagnostic yield was very poor for lesions <20 mm. CONCLUSION: EBUS-guided TBB is effective for localizing and diagnosing bronchoscopic occult pulmonary masses > or =20 mm, but its yield remains unsatisfactory for lesions <20 mm.

Differentiation between the sensory and affective aspects of histamine-induced bronchoconstriction in asthma.

Respiratory symptom perception research has focused mainly on respiratory sensations. Because dyspnea is multidimensional, affective aspects should be investigated. Patients with asthma (N=25) underwent a histamine provocation until a 20% fall in forced expiratory volume in 1s (FEV(1)). After each dose level, 6 symptoms of dyspnea intensity and 6 symptoms of dyspnea affectivity were rated. Individual perceptual sensitivity was determined by calculating the linear slope between the fall in FEV(1) and the increase in the total symptom score, and for affective and sensory symptoms separately [Bijl-Hofland, Folgering, van den Hoogen, et al. Perception of bronchoconstriction in asthma patients measured during histamine challenge test. Eur Respir J 1999;14:1049-54]. Trait anxiety, baseline state anxiety, daily asthma symptoms and catastrophizing during an asthma exacerbation were also assessed. Sensitivity was unrelated to physiological indices of disease severity (i.e., baseline FEV(1) and histamine dose level at 20% fall in FEV(1)), whereas it was positively related to trait anxiety, state anxiety, daily asthma symptoms and catastrophic thinking during an asthma exacerbation in daily life. These relationships were overall much stronger for affective than for sensory symptom slopes. In stepwise multiple regressions, state anxiety was the best predictor of the affective symptom slopes, whereas catastrophic thinking during an asthma exacerbation was the best predictor for the sensory symptom slopes. The differentiation between sensory and affective components of dyspnea adds to the understanding of respiratory symptom perception in asthma.

Effect of adenovirus-mediated gene transfer of nitric oxide synthase on vascular reactivity of rat isolated pulmonary arteries.

Aerosol gene transfer of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) to rat lungs increased NOS expression and activity, and prevented hypoxic pulmonary vasoconstriction (HPV) in vivo. Hereby, we examined the effect of eNOS and iNOS aerosol gene transfer on the endothelium-dependent relaxation (EDR) and on acute HPV in isolated rat pulmonary arteries. Changes in isometric forces were recorded in organ baths for large conduit arteries (diameter 1.8+/-0.1 mm) and in a wire myograph for small resistance arteries (258+/-35 microm). Male Wistar rats were randomly aerosolized with adenovirus (Ad) encoding beta-galactosidase (control), eNOS, or iNOS. Four days later, exhaled nitric oxide was measured, NOS expression within rat lungs was evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry, vasoconstricting agonist and acetylcholine concentration response curves were generated, and the time course of HPV was recorded. Human eNOS and murine iNOS were expressed within rat lung tissue mostly in parenchyma and endothelial cells. Large arteries isolated from Ad-i, eNOS-aerosolized rats developed lower agonist-induced tension than those of control rats. The first and second contractions of the HPV were smaller in the Ad-i, eNOS-aerosolized rats. Contractions were modestly, but significantly and inversely, related to exhaled NO. Agonist- and hypoxia-induced contractions were even more reduced after eNOS aerosolization. There was no significant effect on EDR and no notable difference between small and large vessels. We conclude that adenovirus (Ad)-mediated NOS gene transfer can counteract both pharmacologically and hypoxia-induced increases in pulmonary vascular tone in isolated rat pulmonary arteries. eNOS seems as efficient as iNOS in regulating pulmonary vascular tone.

High-dose acetylcysteine in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive disorder with a poor prognosis. METHODS: We conducted a double-blind, randomized, placebo-controlled multicenter study that assessed the effectiveness over one year of a high oral dose of acetylcysteine (600 mg three times daily) added to standard therapy with prednisone plus azathioprine. The primary end points were changes between baseline and month 12 in vital capacity and in single-breath carbon monoxide diffusing capacity (DL(CO)). RESULTS: A total of 182 patients were randomly assigned to treatment (92 to acetylcysteine and 90 to placebo). Of these patients, 155 (80 assigned to acetylcysteine and 75 to placebo) had usual interstitial pneumonia, as confirmed by high-resolution computed tomography and histologic findings reviewed by expert committees, and did not withdraw consent before the start of treatment. Fifty-seven of the 80 patients taking acetylcysteine (71 percent) and 51 of the 75 patients taking placebo (68 percent) completed one year of treatment. Acetylcysteine slowed the deterioration of vital capacity and DL(CO): at 12 months, the absolute differences in the change from baseline between patients taking acetylcysteine and those taking placebo were 0.18 liter (95 percent confidence interval, 0.03 to 0.32), or a relative difference of 9 percent, for vital capacity (P=0.02), and 0.75 mmol per minute per kilopascal (95 percent confidence interval, 0.27 to 1.23), or 24 percent, for DL(CO) (P=0.003). Mortality during the study was 9 percent among patients taking acetylcysteine and 11 percent among those taking placebo (P=0.69). There were no significant differences in the type or severity of adverse events between patients taking acetylcysteine and those taking placebo, except for a significantly lower rate of myelotoxic effects in the group taking acetylcysteine (P=0.03). CONCLUSIONS: Therapy with acetylcysteine at a dose of 600 mg three times daily, added to prednisone and azathioprine, preserves vital capacity and DL(CO) in patients with idiopathic pulmonary fibrosis better than does standard therapy alone.

Interleukin-17--induced interleukin-8 release in human airway smooth muscle cells: role for mitogen-activated kinases and nuclear factor-kappaB.

BACKGROUND: It has recently become clear that interleukin (IL)-8 plays a role in chronic neutrophilic inflammatory disorders, such as chronic rejection after lung transplantation. We have shown that IL-17--stimulated human airway smooth muscle cells (HASMC) are able to produce IL-8. The aim of this study was to determine whether p38 mitogen-activated protein kinase (MAPK), c-Jun amino-terminal kinase (JNK), p42/p44 extracellular signal-related kinase (ERK) and nuclear factor-kappaB (NF-kappaB) are involved in IL-17--induced IL-8 production in HASMC in vitro. METHODS: We used human airway smooth muscle cells in culture. Western blotting was done to obtain data regarding activation of MAPK. Furthermore, we used specific inhibitors of MAPK to investigate their involvement in IL-17--induced IL-8 release, which was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Western blotting clearly demonstrated that p38 MAPK, JNK and p42/p44 ERK were activated by IL-17 in HASMC. Using SB203580, a specific inhibitor of p38 MAPK, we detected a concentration-dependent inhibition of IL-17--induced IL-8 production with a maximal decrease of 63 +/- 5% (n=8, p<0.01). Curcumin, a specific inhibitor of JNK, also concentration-dependently reduced IL-17--induced IL-8 production, with a maximal decrease of 82+/-4% (n=8, p<0.01). U0126, a specific inhibitor of p42/p44 ERK, induced a maximal decrease of 84+/-5% (n=8, p<0.001). Pyrrolydine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, caused a 70+/-5% (n=8, p<0.01) decrease in IL-17--induced IL-8 production. CONCLUSIONS: We found that IL-17 induces activation of p38MAPK, JNK and p42/p44ERK in HASMC. We also found that p38MAPK, JNK, p42/p44 ERK and NF-kappaB play an important role in IL-17--induced IL-8 production in HASMC in vitro. This may open up new opportunities for further treatment of this disease.

Can subjective asthma symptoms be learned?

OBJECTIVE: We investigated whether perception of subjective asthma symptoms can be brought under control of biomedically irrelevant cues in the environment, i.e., whether subjective asthma symptoms can be learned in response to harmless stimuli. METHODS: Twenty patients with asthma and 20 healthy participants were presented with two placebo-inhalers presented as new chemicals for diagnosing asthma. One inhaler was coupled three times with rebreathing 5% CO2 in oxygen, the other inhaler was coupled three times with rebreathing oxygen. In the subsequent test phase, both inhalers were coupled once with oxygen. We assessed airway resistance and subjective symptoms throughout the study. RESULTS: Both groups expected and reported more symptoms with the inhaler that was previously associated with the CO2 trials compared with trials with the inhaler that was used on trials without CO2 without concomitant effects on respiratory resistance. The learning effects were most pronounced in a subgroup of patients reporting symptoms of hyperventilation during asthma exacerbations in daily life. CONCLUSIONS: Subjective respiratory symptoms can be learned in response to harmless stimuli and a substantial proportion of patients with asthma might be especially vulnerable to this phenomenon. Because asthma patients rely mainly on perceived symptoms for their medication use, it is likely that they will take reliever medication based on expected symptoms instead of real exacerbations of respiratory dysfunction.

Negative affectivity and the influence of suggestion on asthma symptoms.

OBJECTIVE: To investigate the effect of suggestion on subjective and objective asthma symptoms as a function of negative affectivity of the patients. METHODS: Asthmatics (n=32) took puffs from three separate placebo inhalers, being described as an inert (practice) substance, a bronchoconstrictor, and a bronchodilator. Negative affectivity, social desirability, probability of medication-intake, intensity of asthma symptoms and total respiratory resistance were measured at onset. The latter three measures were repeated after each trial. Heart rate, end tidal PCO(2), and breathing behaviour were measured during each trial. RESULTS: Asthmatics with high negative affectivity had overall more intense asthma symptoms. They also reported more airway obstruction after suggested bronchoconstriction and less after suggested bronchodilation, whereas persons with low negative affectivity did not show such variation. These effects were unrelated to social desirability. Respiratory symptoms correlated with the odds of medication intake. Neither negative affectivity nor suggestion influenced lung function and only breathing parameters under voluntary control changed as a function of suggestion. CONCLUSION: Self-reported symptoms of asthmatics with high negative affectivity are more influenced by suggestion than those of patients with low negative affectivity.

Dyspnea: the role of psychological processes.

Breathlessness or dyspnea-the subjective experience of breathing discomfort-is a symptom in many pulmonary, cardiovascular, and neuromuscular diseases. It occurs in normals as well during intense emotional states and heavy labor or exercise. In clinical cases, it generally causes severe suffering. Dyspnea has multifactorial causes and the explanation for the symptom may differ largely among patients. Explanatory models imply the involvement of mechanisms at several levels of functioning, such as afferent signals from the respiratory muscles or blood gas levels related to hypercapnia and hypoxia. Depending on the relative involvement of specific mechanisms and their interactions, dyspnea may be experienced differently and subtypes can be distinguished. More recently, perceptual-cognitive and emotional processes related to symptom perception and interpretation have been investigated in the context of dyspnea. In this review, we focus on the psychological processes that play part in the perception of dyspnea and formulate some practical guidelines for those who are confronted with dyspnea.

Interstitial lung diseases: characteristics at diagnosis and mortality risk assessment.

As the diagnostic assessment of the different forms of interstitial lung disease (ILD) is similar, this study aims to compare age, sex, the functional and broncho-alveolar lavage fluid (BALF) findings at diagnosis between the different forms of ILDs. In addition we want to determine which of these variables determine survival. We evaluated 315 patients (176 males and 139 females) in whom the diagnosis was made of sarcoidosis (n = 87), ILD due to connective tissue disease (n = 56), hypersensitivity pneumonitis (n = 50), idiopathic pulmonary fibrosis (IPF) (n = 64), other forms of idiopathic interstitial pneumonia (n = 29) or ILD due to an undefined form of fibrosis (n = 29). We analysed the role on outcome of type of disease, gender, age at diagnosis, type of cells in BALF, FVC and DLCO. In a Kaplan-Meier analysis IPF has the worst outcome in comparison with other types of ILDs. A Cox regression analysis showed that type of ILD, FVC, age at diagnosis and % of macrophages in BALF predict outcome of patients affected by ILD.

N-acetylcysteine inhibits interleukin-17-induced interleukin-8 production from human airway smooth muscle cells: a possible role for anti-oxidative treatment in chronic lung rejection?

BACKGROUND: Long-term survival of lung transplantation is threatened by obliterative bronchiolitis, or its clinical equivalent, bronchiolitis obliterans syndrome. With a prevalence of >50% at 5 years after transplantation, it has emerged as the most significant long-term complication. Neutrophilic inflammation and increased interleukin (IL)-8 production seem to be part of the basic pathophysiologic mechanism of chronic rejection. Recently, it has been suggested that reactive oxygen species may also play an important role in the pathogenesis because they are known to induce smooth muscle proliferation. METHODS: Human airway smooth muscle cells in vitro were stimulated with IL-17 (0.1 to 10 ng/ml) or with IL-17 (10 ng/ml) and the anti-oxidative agent N-acetylcysteine (1 micromol/liter to 10 mmol/liter). Production of 8-isoprostane was measured with a commercially available enzyme immunoassay kit and production of IL-8 was measured using a standard enzyme-linked immunoassay technique. RESULTS: IL-17 produced a concentration-dependent increase in 8-isoprostane with a maximum of 136.5 +/- 15.5 pg/ml with IL-17 (10 ng/ml, p < 0.001, n = 12, vs unstimulated cells). N-acetylcysteine (NAC) was able to decrease IL-17-induced 8-isoprostane production, with a maximum decrease of 59.3 +/- 9% (p < 0.001, n = 12) with 10 mmol/liter of N-acetylcysteine, which also decreased IL-17-induced IL-8 production in a concentration-dependent manner (with maximum inhibition of 86.3% when combined with NAC 10 mmol/liter as compared with IL-17 alone). CONCLUSIONS: We demonstrated that human airway smooth muscle cells, when stimulated with IL-17, are able to produce 8-isoprostane, which could be inhibited by adding N-acetylcysteline, and which was also able to decrease IL-17-induced IL-8 production. The clinical significance of these in vitro findings for prevention or treatment of chronic rejection after lung transplantation remains to be investigated.

Clinical-radiological presentation and outcome of surgically treated pulmonary carcinoid tumours: a long-term single institution experience.

PURPOSE: To determine the presenting features and the outcome of surgically treated pulmonary carcinoid tumours. METHODS: Retrospective analysis of all consecutive cases with preoperatively suspected or proven pulmonary carcinoid, treated between 1964 and 1994, in order to have full 5-year survival data. RESULTS: Seventy-three patients were retrieved, six had a postoperative histology other than carcinoid. The mean age of the 67 eligible cases was 44 years (range 17-74). There were 59 typical and eight atypical carcinoids. The most frequent presenting symptom was infection, followed by haemoptysis. Sixteen patients were asymptomatic, 15 of these had an abnormal chest X-ray, showing a solitary nodule in 13. Bronchoscopy was abnormal in almost all symptomatic patients. Bronchial biopsy results suggested a malignancy other than carcinoid in seven of eight patients whose postoperative histology was found to be atypical carcinoid. There were 40 lobectomies, 14 bi-lobectomies, nine pneumonectomies, and four limited resections. Ten patients had lymph node involvement (seven typical and three atypical). There was no correlation between the diameter of the primary tumour and the presence of nodal involvement. In particular, three of eight peripheral lesions <30 mm were found to have metastatic lymph nodes. The 5-year survival was 92% (95% in N0 versus 56% in N1-2; 92% in typical versus 67% in atypical). The 10-year survival was 84%. CONCLUSION: The specific diagnosis of atypical carcinoid cannot be reliably made on bronchial biopsies. No relationship was found between tumour size and the presence of lymph node metastases, suggesting that radical excision with detailed lymph node sampling is as important in carcinoids as in other lung cancers. Long-term survival was excellent, nodal status and pathology (typical/atypical) were independent prognostic factors.

Interleukin-17 stimulates release of interleukin-8 by human airway smooth muscle cells in vitro: a potential role for interleukin-17 and airway smooth muscle cells in bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome is the major constraint on the long-term survival after lung transplantation. Both neutrophils and interleukin (IL)-8, a potent neutrophil attractant, have been shown to play an important role in the pathophysiology of obliterative bronchiolitis. We investigated the potential role of human airway smooth muscle cells in obliterative bronchiolitis by studying their release of IL-8 after stimulation with IL-17, a novel T-cell-derived chemokine capable of attracting and activating neutrophils. We demonstrated a significant increase in IL-8 release, reaching a concentration of 86.6 ng/ml (SEM 1.9 ng/ml) with 100 ng/ml IL-17 (p < 0.01, n = 4), as compared with non-stimulated cells. This IL-17-mediated IL-8 release could not be inhibited by dexamethasone. We conclude that human airway smooth muscle cells may play an important pro-inflammatory role in neutrophilic inflammatory diseases such as chronic rejection after lung transplantation; furthermore, IL-17 may be the link between lymphocytes and neutrophils.

Involvement of p38 MAPK, JNK, p42/p44 ERK and NF-kappaB in IL-1beta-induced chemokine release in human airway smooth muscle cells.

Asthma is an inflammatory disease, in which eotaxin, MCP-1 and MCP-3 play a crucial role. These chemokines have been shown to be expressed and produced by IL-1beta-stimulated human airway smooth muscle cells (HASMC) in culture. In the present study we were interested to unravel the IL-1beta-induced signal transduction leading to chemokine production. Using Western blot, we observed an activation of p38 MAPK, JNK kinase and p42/p44 ERK when HASMC were stimulated with IL-1beta. We also observed a significant decrease in the expression and the release of eotaxin, MCP-1 and MCP-3 in the presence of SB203580, an inhibitor of p38 MAPK (71 +/- 6%, P < 0.05, n = 8 and 39 +/- 10% P < 0.01, n = 10 respectively), curcumin, an inhibitor of JNK kinase (83 +/- 4.9% and 88 +/- 3.4% respectively, P < 0.01, n = 4). U0126, an inhibitor of p42/p44 ERK, also produced a significant decrease in chemokine production (46.3 +/- 9%, P < 0.01 n = 10 and 67.8 +/- 12%, P < 0.01, n = 12). Pyrrolydine dithiocarbamate, an inhibitor of NF-kappaB was also able to reduce the eotaxin, MCP-1 and MCP-3 expression and production (50 +/- 13%, P < 0.05, n = 10 and 23 +/- 7%, P < 0.05, n = 12). We conclude that p38 MAPK, JNK kinase, ERK and NF-kappaB are involved in the IL-1beta-induced eotaxin, MCP-1, and MCP-3 expression and release in HASMC.

The use of ECG and respiratory triggering to improve the sensitivity of oxygen-enhanced proton MRI of lung ventilation.

Changes in lung signal between normal breathing and breathing pure oxygen is the basis for oxygen-enhanced ventilation MRI. An optimal technique guarantees a significant response to pure oxygen in well-ventilated lung tissue. To improve the sensitivity, we investigated the effect of ECG and respiratory triggering. Centric reordered single-shot rapid acquisition relaxation enhancement sequences (TE 4.2 ms, echo spacing 4.2 ms, bandwidth 650 Hz/pixel), with an inversion recovery preparation pulse (TI 700 ms), were used. Series of 20 measurements were performed with and without ECG and respiratory triggering in five young volunteers. Subsequently, series of 100 images were acquired during breathing normal air and pure oxygen (as "stimulus"). Ventilation maps showed by means of the z-score how far the response deviates from the signal intensities during the normal air condition. The standard deviation of the lung signal intensities was lowest for the cardiac-triggered series. In the ventilation maps, on the other hand, signal changes were statistically more significant in the respiratory than in the cardiac-triggered series. The average z-scores in the right (left) cranial part of the lung were 12.4 (13.0) and 9.2 (9.7) for respiratory and ECG-triggered acquisitions. We propose to use respiratory triggering as a means to improve the sensitivity of MR ventilation studies.