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.

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.

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.

Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma.

STUDY OBJECTIVE: Exhaled nitric oxide (NO) levels are significantly elevated in patients with inflammatory airways disorders such as asthma, and the measurement of exhaled NO has been proposed as a noninvasive marker of airways inflammation. The aim of this study was to assess the accuracy of exhaled NO levels for the diagnosis of asthma. METHODS: Two hundred forty consecutive, nonsmoking, steroid-naive patients, who were referred to our outpatient clinic with symptoms suggestive of obstructive airways disease, were investigated. Asthma was diagnosed in 160 patients on the basis of the presence of significant airways reversibility (DeltaFEV(1) > 12% predicted) and/or airways hyperresponsiveness (provocative concentration of histamine causing a 20% fall in FEV(1) < or = 8 mg/mL). Prior to lung function measurements, exhaled NO was measured during a single-breath exhalation, according to European Respiratory Society and American Thoracic Society guidelines. RESULTS: The measurement of exhaled NO in our study population showed, at a cutoff level of 16 parts per billion, a specificity for the diagnosis of asthma of 90% and a positive predictive value of > 90%. CONCLUSIONS: These findings suggest that the simple and absolutely noninvasive measurement of exhaled NO can be used as an additional diagnostic tool for the screening of patients with a suspected diagnosis of asthma.

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.

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.

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.

Activation of the hexose monophosphate shunt in rat type II pneumocytes as an early marker of oxidative stress caused by cobalt particles.

Cobalt metal (mCo) and hard metal, a mixture of cobalt and tungsten carbide (CoWC), are cytotoxic for alveolar macrophages and alveolar type II cells (AT-II). Although the exact mechanisms of toxicity are not entirely elucidated, evidence exists for an oxidant-mediated toxicity. In this study, we exposed primary cultures of rat AT-II, in vitro, to different forms of cobalt (mCo particles, CoWC particles, CoCl(2)) and assessed changes in the activity of the hexose monophosphate shunt (HMS). Activation of the HMS occurs as an early response to (per)oxidative stress. Cobalt metal-containing particles (mCo and CoWC) when freshly immersed in medium, lead to an early concentration-dependent stimulation of the HMS in rat AT-II. The maximum stimulations of HMS (reached after 90 min) were 2.0 +/-1.2, 2.9+/-0.4, 3.3 +/-1.6 and 4.0+/-0.4 fold-increases for 15, 75, 300 and 1200 microg mCo/well, respectively. The observed time course of the activation by mCo particles clearly differed from that caused by paraquat (10(-5 )M), which is known to produce activated oxygen species after cyclic oxidation-reduction reactions. The comparable effect of peroxides (H2O2 and t-butyl hydroperoxide) on HMS and the inhibitory effects of catalase on the mCo-induced stimulation of the HMS strongly suggest the production of peroxides by freshly immersed mCo particles. However, we were not able to show a simple relationship between the stimulation of the HMS and the subsequent cell damage.