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.

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor present in most cell types. Upon ligand binding, the GR is activated and translocates into the nucleus where it transmits the anti-inflammatory actions of glucocorticoids. Here, we describe the ligand-independent activation of GR by the ␤ 2 -adrenergic receptor (␤ 2 -AR) agonists, salbutamol and salmeterol, in primary human lung fibroblasts and vascular smooth muscle cells. Immunohistochemistry demonstrated expression of GR and the ␤ 2 -AR by fibroblasts and vascular smooth muscle cells. Treatment of the cells with the ␤ 2 -AR agonists, salbutamol or salmeterol, resulted in translocation of GR into the nucleus beginning at 30 min, as shown by immunohistochemistry and Western blotting of cytosolic and nuclear cell extracts. In comparison, activation of GR induced by the corticosteroids dexamethasone and fluticasone occurred at the same time after treatment (30 min) but resulted in a more complete depletion of GR from the cytosolic compartment. Electrophoretic mobility shift assays confirmed that nuclear GR, activated by both ␤ 2 -AR agonists and glucocorticoids, actively bound to the GR consensus sequence (GR element). Functional activation of the GR was confirmed by a Luciferase reporter gene assay, using a GR driven promoter fragment from the p21 (WAF1/CIP1) gene. The effects of the ␤ 2 -AR agonists, salbutamol and salmeterol, were dependent upon binding to the ␤ 2 -AR, because blocking of ␤ 2 -AR with propranolol abrogated GR activation. GR activation appeared to involve cAMP. In summary, these data show that ␤ 2 -AR agonists are potent activators of GR. Ligandindependent activation of GR by ␤ 2 -AR agonists may substantially mediate the anti-inflammatory actions of these drugs observed in vitro and in vivo.

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: primary pulmonary hypertension (PPH); vasoactive intestinal peptide (VIP); pulmonary artery smooth muscle cells (PASMCs); mean pulmonary arterial pressure (MPAP).

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: primary pulmonary hypertension (PPH); vasoactive intestinal peptide (VIP); pulmonary artery smooth muscle cells (PASMCs); mean pulmonary arterial pressure (MPAP).

Background: Pulmonary hypertension is a frequent complication of severe chronic obstructive pulmonary disease (COPD) and a major cause of morbidity and mortality in this condition. Based on the improved survival of these patients due to long term oxygen therapy and the potent and selective pulmonary vasodilation by inhaled nitric oxide, the safety and effectiveness of the combined inhalation of these two gases over a 3 month period was assessed. Methods: Forty patients with secondary pulmonary hypertension due to COPD were randomly assigned to receive either oxygen alone or "pulsed" inhalation of nitric oxide with oxygen over a period of 3 months. "Pulsed" inhalation of nitric oxide was used to reduce pulmonary ventilation-perfusion mismatch and formation of toxic reaction products of nitric oxide and oxygen. Results: Compared with oxygen alone, the combined inhalation of nitric oxide and oxygen caused a significant decrease in mean (SE) pulmonary artery pressure (from 27.6 (4.4) mm Hg to 20.6 (4.9) mm Hg, p<0.001) and pulmonary vascular resistance index (from 569.7 (208.1) to 351.3 (159.9) dynezs