EPs® 7630 Stimulates Tissue Repair Mechanisms and Modifies Tight Junction Protein Expression in Human Airway Epithelial Cells.

Airway epithelium repair after infection consists of wound repair, re-synthesis of the extracellular matrix (ECM), and tight junction proteins. In humans, EPs® 7630 obtained from Pelargonium sidoides roots reduces the severity and duration of acute respiratory tract infections. The effect of EPs® 7630 on tissue repair of rhinovirus-16 (RV-16) infected and control human airway epithelial cells was assessed for: (i) epithelial cell proliferation by manual cell counts, (ii) epithelial wound repair by "scratch assay", (iii) ECM composition by Western-blotting and cell-based ELISA, and (iv) epithelial tight junction proteins by Western-blotting. EPs® 7630 stimulated cell proliferation through cAMP, CREB, and p38 MAPK. EPs® 7630 significantly improved wound repair. Pro-inflammatory collagen type-I expression was reduced by EPs® 7630, while fibronectin was increased. Virus-binding tight junction proteins desmoglein2, desmocollin2, ZO-1, claudin1, and claudin4 were downregulated by EPs® 7630. The RV16-induced shift of the ECM towards the pro-inflammatory type was prevented by EPs® 7630. Most of the effects of EPs® 7630 on tissue repair and regeneration were sensitive to inhibition of cAMP-induced signaling. The data suggest that EPs® 7630-dependent modification of epithelial cell metabolism and function might underlie the faster recovery time from viral infections, as reported by others in clinical studies.

Pelargonium sidoides radix extract EPs 7630 reduces rhinovirus infection through modulation of viral binding proteins on human bronchial epithelial cells.

Bronchial epithelial cells are the first target cell for rhinovirus infection. The course of viral infections in patients with acute bronchitis, asthma and COPD can be improved by oral application of Pelargonium sidoides radix extract; however, the mechanism is not well understood. This study investigated the in vitro effect of Pelargonium sidoides radix extract (EPs 7630) on the expression of virus binding cell membrane and host defence supporting proteins on primary human bronchial epithelial cells (hBEC). Cells were isolated from patients with severe asthma (n = 6), moderate COPD (n = 6) and non-diseased controls (n = 6). Protein expression was determined by Western-blot and immunofluorescence. Rhinovirus infection was determined by immunofluorescence as well as by polymerase chain reaction. Cell survival was determined by manual cell count after live/death immunofluorescence staining. All parameters were determined over a period of 3 days. The results show that EPs 7630 concentration-dependently and significantly increased hBEC survival after rhinovirus infection. This effect was paralleled by decreased expression of the inducible co-stimulator (ICOS), its ligand ICOSL and cell surface calreticulin (C1qR). In contrast, EPs 7630 up-regulated the expression of the host defence supporting proteins ß-defensin-1 and SOCS-1, both in rhinovirus infected and un-infected hBEC. The expression of other virus interacting cell membrane proteins such as MyD88, TRL2/4 or ICAM-1 was not altered by EPs 7630. The results indicate that EPs 7630 may reduce rhinovirus infection of human primary BEC by down-regulating cell membrane docking proteins and up-regulating host defence proteins.

Treatment with long acting muscarinic antagonists stimulates serum levels of irisin in patients with COPD.

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin, is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD.

Mesothelioma cells escape heat stress by upregulating Hsp40/Hsp70 expression via mitogen-activated protein kinases.

Therapy with hyperthermal chemotherapy in pleural diffuse malignant mesothelioma had limited benefits for patients. Here we investigated the effect of heat stress on heat shock proteins (HSP), which rescue tumour cells from apoptosis. In human mesothelioma and mesothelial cells heat stress (39-42 degrees C) induced the phosphorylation of two mitogen activated kinases (MAPK) Erk1/2 and p38, and increased Hsp40, and Hsp70 expression. Mesothelioma cells expressed more Hsp40 and were less sensitive to heat stress compared to mesothelial cells. Inhibition of Erk1/2 MAPK by PD98059 or by Erk1 siRNA down-regulated heat stress-induced Hsp40 and Hsp70 expression and reduced mesothelioma cell survival. Inhibition of p38MAPK by SB203580 or siRNA reduced Hsp40, but not Hsp70, expression and also increased mesothelioma cell death. Thus hyperthermia combined with suppression of p38 MAPK or Hsp40 may represent a novel approach to improve mesothelioma therapy.

Detection of hypoventilation during thoracoscopy: combined cutaneous carbon dioxide tension and oximetry monitoring with a new digital sensor.

BACKGROUND: Changes in Paco(2) have not been described during thoracoscopy under sedation-assisted local anesthesia. We hypothesized that hypoventilation might occur secondary to administration of sedatives and decreased ventilation in one lung. AIM: Prospectively measure cutaneous carbon dioxide tension (Pcco(2)) in addition to pulse oximetric saturation (Spo(2)) using a new combined digital sensor to examine the occurrence of hypoventilation during thoracoscopy under sedation-assisted local anesthesia. SETTING: University hospital. METHODS: Following validation studies, Pcco(2) was prospectively measured in 16 consecutive patients undergoing thoracoscopy under sedation-assisted local anesthesia using a combined digital earlobe sensor measuring Spo(2) (percentage) and Pcco(2) (millimeters of mercury). All patients received supplemental oxygen. Routine BP monitoring and Spo(2) was continued. Patients received IV hydrocodone, 5 mg, and intermittent boluses or IV midazolam and pethidine. RESULTS: Mean baseline Pcco(2) measurement was 39.1 +/- 7.2 mm Hg (+/- SD) [range, 27.5 to 50.5 mm Hg], and peak measurement during the procedure was 52.3 +/- 10.3 mm Hg (range, 37.2 to 77 mm Hg) [p < 0.001]. Median and mean changes in Pcco(2) measurement from baseline were 13.0 mm Hg and 13.2 +/- 5.3 mm Hg (range, 5.5 to 27.8 mm Hg), respectively. Mean fall in Spo(2) during the procedure was 4.6 +/- 3.2% (range, 1 to 14%). CONCLUSIONS: Thoracoscopy performed under sedation-assisted local anesthesia is associated with significant hypoventilation. Combined measurement of Spo(2) and Pcco(2) during thoracoscopy is a novel approach in the monitoring of ventilation, enhancing patient safety, and might allow to guide the administration of sedation in a better way.

Radiofrequency heat ablation for lung tumors: potential applications.

Radiofrequency ablation (RFA) is an image guided percutaneous procedure using thermal energy that is used to treat malignant lesions in various organs including liver, breast and lungs. It has also been used bronchoscopically to treat endobronchial tumors. Current passing through tissue from the active electrode leads to ion agitation, which is converted by means of friction into heat leading to irreparable cellular damage and coagulation necrosis. The potential benefits include decreased cost and morbidity, treating patients who are not surgical candidates due to age, co-morbidity or extent of disease and the possibility of performing the procedure on an outpatient basis. The aim is usually to reduce tumor size. Whether it can be used with a curative intent in well localized primary tumors remains to be determined by well designed studies. However, caution should be exercised because selective tumor resection is not the gold standard to treat potentially resectable lung malignancies that are treated with lobectomy. Obviously, lung volume reduction surgery combined with tumor resection has challenged this approach. RFA might be the treatment of choice for multiple lung metastases that are usually approached surgically for long-term remission. A specific indication may also be bilateral pulmonary metastases. Other potential applications might be tumor size reduction by a non-surgical procedure followed by adjuvant chemotherapy. Currently, these thoughts remain only speculations, until proven by clinical trials with medium to long-term follow up. Furthermore, the risk of this procedure for pulmonary application has to be better defined.