Lutz-Henning Block

A Preliminary Study of Long-Term Treatment with Interferon Gamma-1b and Low-Dose Prednisolone in Patients with Idiopathic Pulmonary Fibrosis

BACKGROUND AND METHODS Patients with idiopathic pulmonary fibrosis have progressive scarring of the lung and usually die within four to five years after symptoms develop. Treatment with oral glucocorticoids is often ineffective. We conducted an open, randomized trial of treatment with a combination of interferon gamma-1b, which has antifibrotic properties, and an oral glucocorticoid. We studied 18 patients with idiopathic pulmonary fibrosis who had not had responses to glucocorticoids or other immunosuppressive agents. Nine patients were treated for 12 months with oral prednisolone alone (7.5 mg daily, which could be increased to 25 to 50 mg daily), and nine with a combination of 200 microg of interferon gamma-1b (given three times per week subcutaneously) and 7.5 mg of prednisolone (given once a day). RESULTS All the patients completed the study. Lung function deteriorated in all nine patients in the group given prednisolone alone: total lung capacity decreased from a mean (+/-SD) of 66+/-8 percent of the predicted value at base line to 62+/-6 percent at 12 months. In contrast, in the group receiving interferon gamma-1b plus prednisolone, total lung capacity increased (from 70+/-6 percent of the predicted value at base line to 79+/-12 percent at 12 months, P<0.001 for the difference between the groups). In the group that received interferon gamma-1b plus prednisolone, the partial pressure of arterial oxygen at rest increased from 65+/-9 mm Hg at base line to 76+/-8 mm Hg at 12 months, whereas in the group that received prednisolone alone it decreased from 65+/-6 to 62+/-4 mm Hg (P<0.001 for the difference in the change from baseline values between the two groups); on maximal exertion, the value increased from 55+/-6 to 65+/-8 mm Hg in the group that received combined treatment and decreased from 55+/-6 mm Hg to 52+/-5 mm Hg in the group given prednisolone alone (P<0.001). The side effects of interferon gamma-1b, such as fever, chills, and muscle pain, subsided within the first 9 to 12 weeks. CONCLUSIONS In a preliminary study, 12 months of treatment with interferon gamma-1b plus prednisolone was associated with substantial improvements in the condition of patients with idiopathic pulmonary fibrosis who had had no response to glucocorticoids.

Interaction of C/EBPα and the glucocorticoid receptor in vivo and in nontransformed human cells

Belonging to the family of steroid hormones, glucocorticoids are essential for development and survival of vertebrates. The cellular response to glucocorticoids is attributed to the glucocorticoid receptor, which functions as a transcription factor. However, the majority of glucocorticoid‐modulated genes lack a DNA binding site for the glucocorticoid receptor, raising the question of which mechanism mediates the responses to glucocorticoids. It has been suggested that besides direct DNA binding of the glucocorticoid receptor, interaction with members of other transcription factor families modulates the effect of the glucocorti‐coid receptor. However, the significance of such transcription factor interaction is not clear. In cultured human mesenchymal cells and peripheral blood leukocytes of human volunteers treated with glucocorticoids, we detected the formation of a complex between the GR and the CCAAT/enhancer binding protein a.Inin vitro experiments, this interaction turned out to be responsible for the inhibitory action of glucocorticoids on lymphocytic and mesenchymal cell proliferation. Our results suggest that complex formation of the GR with C/EBPα accounts for a novel pathway of glucocorticoid action.—Rüdiger, J. J., Roth, M., Bihl, M. P., Cornelius, B. C., Johnson, M., Ziesche, R., Block, L.‐H. Interaction of C/EBPα and the glucocorticoid receptor in vivo and in nontransformed human cells. FASEB J. 16, 177–184 (2002)

The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of athero¬sclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10−6 to 10−8 M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine‐dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP‐α. The underlying pathway apparently in¬volves the action of mitogen‐activated protein kinase or protein kinase C, but not of extracellular signal‐related kinase or changes of intracellular calcium. Amlodipine‐induced p21(Waf1/Cip1) promoter activity and expres¬sion were abrogated by C/EBP‐α antisense oligonucle¬otide or by the GR antagonist RU486. Amlodipinedependent inhibition of cell proliferation was partially reversed by RU486 at 10−8 M (58% ±29%), antisense oligonucleotides targeting C/EBP‐α (91%±26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%±32%, n=6);scrambled antisense oligonucleotides or those directed against C/EBP‐β were ineffective. The data suggest that the anti‐proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.—Ziesche, R., Petkov, V., Lambers, C., Erne, P., Block, L.‐H. The calcium channel blocker amlodipine exerts its antiproliferative action via p21(Waf1/Cip1) gene activation. FASEBJ. 18, 1516–1523 (2004)

Manidipine affects rPDGF-BB-induced gene transcription of low-density lipoprotein receptors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in human mesangial cells

The effects of manidipine, a newly developed Ca2+ channel blocker, on recombinant platelet-derived growth factor BB (rPDGF-BB)-induced transcription of the low-density lipoprotein receptor and the 3-hydroxy-3-methylglutaryl coenzyme A reductase genes in human mesangial cells are reported. The transcription of the rPDGF-BB-induced gene of the low-density lipoprotein receptor was enhanced and maintained over a longer period, whereas the transcription of the 3-hydroxy-3-methylglutaryl reductase gene was blocked by manidipine at nanomolar concentrations. The results suggest that aside from the ability to block manidipines potential-operated Ca2+ channels, manidipine also affects gene transcription of relevant proteins involved in the regulation of cholesterol metabolism at concentrations close to those efficacious for clinical therapies. This may further explain the antiinflammatory and organ-protective activities of the compound.

Unusual microbes in asthma exacerbation: Alcaligenes xylosoxidans and Leishmania

Asthma is a chronic inflammatory condition characterised by a variable degree of airflow limitation. Exacerbations during the course of asthma often occur due to environmental factors or infectious, mostly viral, aetiology. The present study reports the case of a 61-yr-old male with severe asthma hospitalised due to increasing respiratory distress. Since recovery was delayed despite anti-obstructive/anti-inflammatory and antibiotic therapy, further diagnostic procedures, including bronchoscopy, were performed in order to attempt to identify the cause of the worsening respiratory condition. The surprising finding consisted of a rare coincidence of concomitant infection with the bacterial pathogen Alcaligenes xylosoxidans, grown from bronchoalveolar lavage fluid, and the protozoan parasite Leishmania spp., revealed by histopathological examination of bronchial mucosal biopsy specimens. This is the first report of an isolated bronchial mucosal involvement of Leishmania in an HIV-negative asthma patient following brief exposure in Leishmania-endemic regions. Further, to the best of the present authors’ knowledge, this represents the first description of A. xylosoxidans in asthma, although it is questionable whether it was an infection or colonisation. The present observation identifies previously unreported microbial pathogens associated with asthma exacerbation. Further, the report highlights the importance of obtaining a thorough travel history and applying invasive diagnostic procedures in circumstances of treatment failure, even under unfavourable conditions.